Diabetes Treatments

For example, for type 1 diabetes, there is a schema of natural history, Type 1 Diabetes Genetics Consortium (T1D GC), an international consortium to …

FDA/NIH Joint Symposium on Diabetes

Targeting Safe and Effective Prevention and Treatment

May 13-14, 2004

National Institutes of Health
Natcher Conference Center
Main Auditorium
NIH Campus
Bethesda, Maryland

Day 1: Major Challenges to Development of New Therapeutics and Diagnostics

Welcome

Dr David G Orloff, Director, Division of Metabolic and Endocrine Drug
Products, Center for Drug Evaluation and Research CDER, Food and Drug
Administration FDA, US Department of Health and Human Services DHHS,
opened the symposium by noting that this meeting was bringing together
world leaders in the study of diabetes, from basic scientists to clinical
researchers, to epidemiologists, to those directly involved in commercial
therapeutics, devices, and diagnostic tools Dr Orloff thanked those
present for their willingness to assist the FDA and the National Institutes
of Health NIH in identifying therapeutic gaps and challenges for the safe
and effective prevention and management of diabetes, both type 1 and
type
2 Dr Orloff was hopeful that together they could find the most
appropriate and expeditious paths to improve public health in this area

This symposium was sponsored by the FDAs Center for Biologics Evaluation
and Research, the Center for Devices and Radiological Health, CDER, and the
Office of the Commissioner and by NIHs National Institute of Diabetes and
Digestive and Kidney Diseases NIDDK Dr Orloff announced speaker and
panel member changes in the agenda and called the participants attention
to items in their meeting packets and program booklets, including speaker
biographies; copies of previously submitted PowerPoint presentations;
speaker, panel member, and participant lists; and a handout from the
Juvenile Diabetes Research Foundation International JDRF Dr Orloff then
introduced Dr Allen M Spiegel, Director of NIDDK

Dr Spiegel welcomed the attendees and thanked Dr Orloff and Dr Robert
Meyer, Director, Division of Metabolic and Endocrine Drugs, of the FDA and
Dr Judith Fradkin, Director, Division of Diabetes, Endocrinology, and
Metabolic Diseases DDEM , NIDDK, and Dr Sanford Garfield, Senior Advisor
for Biometry and Behavioral Research Program, DDEM, NIDDK, and
other
members of FDA and NIDDK for their efforts in organizing the meeting Dr
Spiegel stated that a number of NIH institutes and offices are working
together to foster research in type 1 and type 2 diabetes They have
created consortia and clinical trial networks to further progress in
prevention and intervention in diabetes For example, for type 1 diabetes,
there is a schema of natural history, partially developed by one of the
days speakers, Dr George S Eisenbarth, that clearly shows that type 1
diabetes is a slowly progressive, autoimmune illness beginning with a
genetic susceptibility and followed by environmental triggers or other
inciting events and a period of silent ?-cell loss, largely because we do
not yet know how to functionally monitor ?-cell mass in a non-invasive way
Dr Spiegel stressed that being able to do so is an important goal of NIH-
supported research through the Beta Cell Biology Consortium, as this would
provide an enormously important biomarker Following this silent ?-cell
loss, the overt onset of diabetes occurs and, in some instances, what is
termed brittle diabetes, as a function of complete loss of ?-cell
reserve

Dr Spiegel highlighted several current
trans-NIH initiatives in type 1
diabetes including the following:

Type 1 Diabetes Genetics Consortium T1D GC, an international consortium
to identify the additional genes that are known to underlie
susceptibility
Environmental Determinants of Diabetes in the Young TEDDY, a consortium
that will follow the prenatal and postnatal development of children to
try to determine the environmental triggers that remain unknown
TrialNet, a network of regional cooperative clinical groups for
prevention and reversal of recent onset type 1 diabetes in partnership
with the Immune Tolerance Network ITN, which looks at the mechanistic
aspects of monitoring T-cell function
A new islet transplant consortium that will be launched in the fall of
2004
DirecNet Diabetes Research in Children Network, a pediatric network to
look at non-invasive glucose monitoring

In presenting a slide depicting the natural history of type 2 diabetes, Dr
Spiegel showed that the disease follows a similar course to that of type 1
There is a genetic susceptibility, along with an environmental trigger,
which, for type 2, is well known This slide was developed by another
speaker, Dr David
Nathan, and his colleagues, and was also based on years
of study of the Pima Indians in Phoenix, Arizona, by NIDDKs intramural
branch Although Dr Francis Collins of the National Human Genome Project
has explained that everyone has some misspellings in their genome, the
natural history of type 2 diabetes follows a spectrum from what is termed
normal to a state now identified as pre-diabetes, due to the stress of
obesity and factors that impinge on ? cells

Dr Spiegel stated that based on new American Diabetes Association
criteria, there may be as many as 40 million individuals in the United
States with pre-diabetes, twice the amount previously estimated Their
overt ?-cell failure can lead to overt type 2 diabetes Many of these
individuals are undiagnosed because, unlike type 1, type 2 diabetes is an
insidious disease He added that the landmark Diabetes Control and
Complications Trial DCCT demonstrated that macrovascular complications
such as cardiovascular disease ensue as a function of poor glycemic
control and ultimately lead to disability and death

Dr Spiegel listed the following major NIH type 2 diabetes studies:

BARI2D Bypass Angioplasty Revascularization Investigation 2
Diabetes
study, which is primarily supported by the National Heart, Lung and Blood
Institute NHLBI, but NIDDK is involved
ACCORD Action to Control Cardiovascular Disease Risk in Diabetes and
LookAHEAD Action for Health in Diabetes studies, which are examining
various measures of glycemic, weight, blood pressure, and lipid control,
as a way of converting cardiovascular complications in established type 2
diabetes
Diabetes Prevention Program DPP and the observational cohort follow-on
DPPOS Diabetes Prevention Program Outcome Study; DPP showed that an
intensive lifestyle intervention or metformin could reduce the incidence
of development of overt type 2 diabetes in those with so-called pre-
diabetes
STOPP-T2D Studies to Treat or Prevent Pediatric Type 2 Diabetes, a
pediatric effort in children and adolescents for treatment of type 2
diabetes in those in whom it is established and an interventional study
to prevent the markers of pre-diabetes in middle-school children

In summary, Dr Spiegel stated that NIH is making major investments and
taking a proactive role at every stage of the spectrum, focusing on primary
prevention wherever
possible, because that is cost-effective, but also
working to ensure that its research investment is fully translated He
emphasized that basic science studies have to be translated for the
development of new therapeutics and new devices and efficacy trials have to
be translated to show effectiveness in the community To accomplish this
requires partnerships with other agencies and organizations, as
demonstrated by this FDA/NIH meeting Dr Spiegel then introduced Dr Janet
Woodcock, FDAs Acting Deputy Commissioner

Dr Woodcock welcomed the group and reminded them that the impending burden
of diabetes is not just a national public health problem but also a
personal one since nearly everyone has a relative or friend affected by
this disorder She explained that the focus of this conference is on state-
of-the-art prevention and treatment interventions for diabetes Dr
Woodcock agreed with Dr Spiegel that there is a growing recognition that
biomedical research needs an increased focus on translating new scientific
knowledge into new therapies, as reflected in NIHs Roadmap Initiative that
was launched 6 months ago In recognition of this need, FDA is partnering
more directly with NIH and is
sponsoring several new initiatives to
facilitate the movement of innovative science into the clinic The
Innovations in Medicine Initiative, launched about a year ago, has as a
goal to write new guidance on diabetes trials and development of new anti-
diabetes products Dr Woodcock expected this symposium to assist the FDA
with that activity

Recently, FDA produced a report called, Innovation or Stagnation:
Challenges on the Critical Path to New Medical Technologies The central
thesis of this report reflected FDAs belief that, in addition to the basic
sciences, more emphasis is needed on product development science and on new
evaluative tools that will move new therapies more quickly into the clinic
Dr Woodcock noted that this thesis is very relevant to the current
meeting, since new tools are needed for drug, biologic, and device
development and evaluation For example, the meeting program calls for
discussion of cellular therapies, such as use of islet cells and so forth,
topics that have been a dream for a long time in this field FDA has
identified a broad series of challenges about the use of cell therapies,
not strictly related to islet cells, but any type of cellular therapy
Dr
Woodcock listed a few of these For example, what tools exist to
characterize these cells? When interventions are studied in the laboratory,
there is a controlled environment However, a very different set of
challenges present themselves when trying to control the cells and keep
them stable in a mass production environment New genomics and proteomics
tools must be developed to evaluate characterization of cells in a
production environment and help developers produce stable products with
predictable characteristics Dr Woodcock said that FDA is working to
develop and introduce genomics and proteomics, now prominent in the basic
science realm, as new fields in industrial production

Dr Woodcock stated that medical devices are going to play an increasingly
important role in the therapy of diabetes as drug delivery systems, as well
as probably in the treatment of complications FDAs Center for Devices and
Radiological Health CDRH has identified a need for new computer tools to
accomplish this The medical device industry is continuously pursuing
engineering type activities to alter devices and improve their performance
Computer models are needed to evaluate the impact of incremental
changes on
a devices performance, rather than the present method of evaluating these
changes through costly and time-consuming clinical trials Otherwise,
clinical use of these improvements falls several cycles behind the
engineers developments This delay also creates a barrier to innovation in
this area

According to Dr Woodcock a range of issues need to be addressed in the
area of drug therapies For example, hepatotoxicity is a major barrier to
drug development Better predictive tools to identify hepatotoxicity and
remove drugs earlier from the production pipeline or to predict who would
be at risk if exposed to the drug would greatly enhance drug development by
saving the billions of dollars of investment in drugs that, either late in
clinical evaluation or once out in the market, are found to have serious
hepatotoxicity Another opportunity for improving drug development would be
to decrease the cost of clinical trials, another large barrier, by
developing improved clinical trial designs

As part of FDAs Critical Path initiative, Dr Woodcock said the agency is
meeting with many people during the spring and summer of 2004 to identify
opportunities for improving development
processes, such as learning what
new scientific tools are needed to assist the development pathways for
various medical products In the fall of 2004, FDA will publish a list of
the outstanding opportunities and enlist support in putting scientific
effort behind solving these challenges Given the challenges the Nations
healthcare system faces, Dr Woodcock emphasized that meetings like this
symposium were essential to help generate ideas and identify the kinds of
problems that have to be addressed to accelerate the pace of innovation in
diabetes, as well as in other serious diseases

The agenda for the 1-1/2 day symposium addressed major challenges to
development of new therapeutics and diagnostics for diabetes and
perspectives on the future of prevention and therapy Presentations covered
the following topics:

Overview of diabetes mellitus and vascular disease outcomes
New molecular targets in type 2 diabetes and immunomodulation in type 1
diabetes
Beta cell preservation in type 1 and type 2 diabetes
Islet transplantation
Glucose monitoring devices and insulin pumps
Prevention of type 2 diabetes including new perspectives on the metabolic
syndrome and findings of
the Diabetes Prevention Program
Industry and advocacy perspectives

Speakers and symposium attendees participated in discussion periods
throughout the meeting, concluding with a panel and participant discussion
on targeting safe and effective prevention and treatment steps as FDA and
NIH move forward in bringing research findings to the primary
practitioners office Copies of Dr Spiegels slides and the speakers
slides used in the following presentations are available at
http://wwwniddknihgov/fund/other/conferences-archhtm The conference
program book containing the agenda, speaker abstracts, and speaker and
participant contact lists is also available at that URL

Session I: Overview/Setting the Stage
Moderator: David Orloff, MD, Director, Division of Metabolic and Endocrine
Drug Products, Center for Drug Evaluation, FDA

Diabetes Mellitus 2004: Biomarkers and the Development of New Therapeutics
and Diagnostics
David M Nathan, MD, Director, General Clinical Research Center, Diabetes
Center, Massachusetts General Hospital; Professor of Medicine, Harvard
Medical School, Boston

Dr Nathan presented information predominantly from clinical trials about
the role of biomarkers or
surrogates in understanding the clinical course
of diabetes mellitus and in the development of new therapeutics

Dr Nathan defined diabetes mellitus as a chronic disease characterized by
abnormal metabolism of glucose, as well as other nutrients such as protein
and fat, and accompanied by the risk of long-term complications specific to
diabetes that affect the eye, kidney, and nervous system Both type 1 and
type 2 diabetes begin with a pre-diabetic phase Diabetes is usually
clinically diagnosed on the basis of hyperglycemia Glycemia is a recurring
theme in discussing diabetes and is, in a sense, a biomarker There is a
latent period, during which the disease or the condition is present but
before the patient develops either early or late complications that
ultimately lead to morbidity and mortality Dr Nathan discussed some of
the surrogates or biomarkers for different stages of the disease

A surrogate is a predictor, or early warning sign, or marker of a
phenomenon present before the disease occurs Dr Nathan explained that one
of the inevitable questions during the development of clinical trials is
always, We want to measure heart disease, but could we reliably measure
something
that is not quite a heart attack? Something that precedes or
predicts a heart attack? Wouldnt that be more efficient and potentially
increase the power of a study? This question leads to What would be an
acceptable substitute for a specific outcome? In such discussions, the
term biomarker has come into common use and been used instead of
surrogate as an indicator of the outcome

Dr Nathan presented the interesting fact that dictionaries did not list
biomarker as a word until very recently, yet there are more than a
quarter of a million citations in PubMed more than 3,000 since the
beginning of 2004 Dr Nathan searched Medline for biomarker and
diabetes in 2004 and found 10 citations, including coronary
calcification, CVD cardiovascular disease, inflammatory markers,
oxidative stress, proteomics, periodontal disease and CVD risk, and urinary
isoprostanes For the purposes of the meeting, Dr Nathan defined a
biomarker as a biological process or biochemical indicator that precedes
the development of disease and is usually indicative of the future
development or progression of the disease, and as such can be used to
measure the effects of treatment

Primary Prevention-Type 1 Diabetes
Using Dr Eisenbarths concept of the
natural history of type 1 diabetes, Dr Nathan listed specific analytes
that accompany the different stages: first, genotyping looking at cytotoxic
T-cells and autoimmune T-cell profiles; antibody generation during the
developmental stages; then, later on, abnormal insulin secretion that can
eventually be measured with a stress test such as an intravenous glucose
tolerance test; and finally, relatively late, abnormal glycemia For
primary prevention, an important question is whether any of these would
substitute as an indicator for the actual development of hyperglycemia,
which is a rather late phenomenon As an example, since the generation of
antibodies, and especially multiple antibodies, is quite a good indicator
of who is going to develop type 1 diabetes, would preventing antibody
generation be an acceptable biomarker for prevention of type 1 diabetes?

In the Diabetes Prevention Trial-1 DPT-1, the outcome was hyperglycemia
detected by oral glucose tolerance testing The study demonstrated a high
level of accuracy in predicting the development of diabetes Dr Nathan
asked if some of the analytes from that trial could be used as biomarkers
for new
prevention studies Dr Nathan noted that several studies have used
biomarkers, such as C-peptide secretion, but most investigators have
considered these not reliable enough; however, as stated in the DPT-1
report, increased understanding of development of diabetes may refine
predictive markers and result in alternative outcomes for future
intervention studies

Primary Prevention-Type 2 Diabetes Dr Nathan presented the
pathophysiology of type 2 diabetes as beginning with insulin resistance,
mediated by obesity, genetics, and other endocrine disorders, which leads
to progressive postprandial hyperglycemia, then to impaired glucose
tolerance and to fasting hyperglycemia, and finally to type 2 diabetes He
said there may actually be two different subpopulations of type 2-those who
get fasting hyperglycemia may actually be different than those who progress
through the postprandial route Downstream of all of these stages are the
duration-dependent complications

Dr Nathan referred to the wounded ?-cell and resultant cyclic decrease
in insulin secretion as the important players in the progression of this
disorder that finally leads to glucose toxicity The various measurements
used to chart
the course of the disease process-from clamp, HOMA, and
minimod to the oral glucose tolerance test OGTT and finally fasting
glucose and hemoglobin A1c HbA1c-could be used as biomarkers in
prevention studies if investigators were convinced that changes in the
results of these measurements at the various stages in disease progression
would equate to a decrease in the risk of developing type 2 diabetes

Dr Nathan pointed out that all of the studies for prevention of type 2
diabetes-DPP, the Finnish Diabetes Study, the Da Qing Study, and the STOPP-
T2D-have used development of diabetes based on fasting or glucose tolerance
testing, indicating general acceptance of diabetes as a disorder of
hyperglycemia Dr Nathan suggested that other potential biomarkers could
include lesser degrees of glucose intolerance Changes in insulin
resistance and other metabolic changes such as changes in free fatty acids
might also be used as markers He added that the importance of looking at
different levels of hyperglycemia or insulin resistance goes beyond the
issue of diabetes Affecting sub-diabetic levels of hyperglycemia may have
a benefit in and of itself For instance, glucose intolerance and
insulin
resistance are components of the metabolic syndrome, which is a risk
indicator for cardiovascular disease CVD as well as diabetes

To illustrate the relationship of glycemia to the metabolic syndrome and
CVD risk, Dr Nathan presented data from the Framingham Offspring Study, a
population-based study of the children and spouses of the children of the
original Framingham cohort During the fourth 4-year cycle of the offspring
study, the participants were given glucose tolerance tests and then divided
into normal, impaired glucose tolerance IGT, and diabetic groups The
normal glucose tolerance group was divided into quintiles The curves
showing the level of glucose tolerance in these groups relative to elements
of the metabolic syndrome, such as hypertension and hyperlipidemia, and the
presence of the metabolic syndrome itself which requires a grouping of
factors, showed levels increasing along with glycemia Dr Nathan stressed
the continuous risk function based on glycemia in the sub-diabetic range
for both men and women for all of the elements of the metabolic syndrome
Every one of the elements of cardiovascular disease risk goes up
continuously in the sub-diabetic, and even
in the sub-pre-diabetic range,
which indicates that rising glucose levels, perhaps mediated by increasing
insulin resistance and by other factors, play a role here Thus, examining
glycemia as a biomarker of cardiovascular disease risk may be of benefit
Other biomarkers, such as inflammatory and hemorheologic abnormalities,
followed the same trend across all quintiles

Dr Nathan noted that the Diabetes Prevention Program also had the goal of
determining whether the interventions would decrease cardiovascular
disease, cardiovascular disease risk factors, or biomarkers for
cardiovascular disease He offered data currently in press that was
presented at the American Diabetes Association meetings in 2003 Year one
mean change in t-PA, a biochemical risk factor or a biomarker for CVD,
was reduced in the intensive lifestyle group and in the metformin group,
compared with the placebo group Similarly, CRP C-reactive protein was
significantly lower in the female population in both the intensive
lifestyle and the metformin groups

Secondary Intervention Dr Nathan presented possible surrogates or
biomarkers used in the Diabetes Control and Complications Trial DCCT and
the United Kingdom
Prospective Diabetes Study UKPDS In DCCT and most
studies of diabetes, HbA1c is used as an index of chronic glycemia and as
the usual surrogate for chronic glycemia Dr Nathan presented data showing
that it has been known for some time that there is an association between
glycemia and complications, such as retinopathy and kidney disease For
example in DCCT, a 10-percent reduction in HbA1c through intensive glycemic
control resulted in a 43-percent reduction in risk for retinopathy
Retinopathy was tested using fundus photography that assessed changes in
the vasculature of the eye Since the tight relationship of HbA1c and the
biomarker for pre-retinopathy changes in the eye associated with
development of vision loss, not actual vision loss was demonstrated
strongly in DCCT and in a 4-year follow-up, Dr Nathan suggested that pre-
disease levels of retinopathy or HbA1c could be used as biomarkers in
primary and secondary intervention trials for type 1 diabetes DCCT also
showed decreases in kidney disease predominantly microalbuminuria, another
biomarker associated with decreased HbA1c; thus decreases in HbA1c could
be used as a biomarker in clinical trials of therapies and
interventions to
prevent nephropathy

Since the incidence of CVD events in the DCCT was too low to determine if
intensive therapy reduced cardiovascular disease, Dr Nathan said that it
was decided in the Epidemiology of Diabetes Interventions and Complications
EDIC study, the follow-up to the DCCT, to look at biomarkers of CVD such
as atherosclerosis measured by carotid ultrasonography EDIC showed that in
the DCCT cohort, intensive therapy, compared with conventional therapy,
significantly decreased the rate of progression of thickening in the common
carotid and in the internal carotid arteries Other studies have
demonstrated that IMT intimal medial thickness of the carotid artery may
be a good biomarker for cardiovascular disease Thus, biomarkers of CVD,
such as measures of atherosclerosis as IMT and coronary calcification, have
been shown to be sensitive to glycemic intervention Further follow-up may
demonstrate a benefit of intensive therapy on the CVD events If further
follow-up shows a correlation between the measures of atherosclerosis and
CVD events, then Dr Nathan would urge the use of these measurements in
secondary prevention trials as substitutes for actual hard clinical
events

Tertiary Intervention Until the past 10 years or so, this is the area
decrease in mortality or severe morbidity that received the most
attention Dr Nathan stated that there are a lot of interventional data
available By this late stage of disease progression, lipids and blood
pressure, rather than glycemia, are probably the important targets for
cardiovascular events Dr Nathan noted that the next speaker, Dr Peter
Wilson, would be discussing the possible biomarkers for this stage

Dr Nathan concluded by stressing that diabetes represents a chronic, long-
term, degenerative disease for which there are numerous potential targets
with regard to the biology of disease Use of these targets can certainly
increase the efficiency of future interventional trials

Diabetes Mellitus and Vascular Disease Outcomes
Peter Wilson, MD, Professor of Medicine, Section on Endocrinology,
Diabetes, and Medical Genetics, and Program Director, General Clinical
Research Center; Medical University of South Carolina, Charleston

Dr Wilson began his presentation by stressing that the United States has
an epidemic in diabetes, with obesity contributing to the increasing
numbers of adults with type 2
diabetes, of whom two-thirds will have a
cardiovascular outcome as cause of death Virtually every obese diabetic
will have CVD before they die Dr Wilson also offered data showing that
diabetes, along with hypertension, are the two primary causes of end-stage
renal disease ESRD, another major reason to be concerned about the
diabetes and obesity epidemics Type 1 diabetes also leads to kidney
failure, coronary artery disease, and other complications of diabetes such
as infections; approximately a third of type 1 diabetics eventually die
from CVD The DCCT showed that with tight glycemic control, microvascular
events could be reduced but, as Dr Nathan had said, the number of
macrovascular events was too small for tight glycemic control to be
predictive of these

From NHANES III data M Harris, Diabetes Care, 23:754, 2000, Dr Wilson
showed that of persons with type 2 diabetes in 1994, 45 percent had a body
mass index BMI greater than 30 ie, obese, 63 percent had
hypertension, and 58 percent had HbAlc greater than 7 percent, all risk
factors for complications Dr Wilsons data from the Framingham cohort
indicated that for younger persons ages 35-64, diabetes doubles their
risk for CVD and
stroke for men and triples it for women In the older age
group 65-94, diabetes doubles the risk for men and women, except for
heart failure and stroke, where the risk is higher Dr Wilson stressed
that older persons with diabetes and hypertension tend to slip into heart
failure post-heart attack

Dr Wilson presented data from Dr Steve Haffner and the Finnish East-West
study that indicated a non-diabetic was at lowest risk for a second heart
attack Those at the highest risk were diabetics who had had a prior
myocardial infarction MI At equal risk were non-diabetics with a prior
MI and diabetics with no prior MI, which shows that having diabetes puts a
person at equal risk of a heart attack with a person who has already had a
heart attack Dr Wilson said this is why NHLBI and other groups recommend
treating diabetics as aggressively as one treats people with known coronary
events The Nurses Health Study demonstrated that, like microvascular
disease in type 1 diabetes, the longer the duration of type 2 diabetes, the
greater the risk for macrovascular disease

Glycemia and Vascular Risk Observational data on hyperglycemia in middle-
age adults and risk for vascular complications in type
2 diabetes from the
Wisconsin Epidemiology Study of Diabetic Retinopathy WESDR showed a
higher risk for retinopathy than for cardiovascular disease As with the
lower hyperglycemia in middle age adults with type 2 diabetes in WESDR,
DCCT showed that tight glucose control affected progression of small vessel
disease in the eye in type 1 diabetes and also decreased microalbuminuria
and macroalbuminuria

Dr Wilson noted that the UKPDS was largely about glucose control but also
had a hypertension arm This 10-year study included nearly 4,000 newly
diagnosed non-obese type 2 diabetics whose median age was 54 at onset of
the trial, of whom approximately one-third were treated with a conventional
therapy and diet, receiving drugs if needed, and two-thirds received
intensive treatment with oral agents or insulin Dr Wilson stressed that
10-year studies are no longer an option in this field because answers are
needed sooner and therapies are changing very fast For instance, today
blood pressure treatment is two generations beyond what was used in the
UKPDS hypertension arm Intensive glucose control in NKPDS showed a strong
decrease in microvascular endpoints For coronary artery disease
CAD,
decreases in HbA1c and systolic blood pressure and increases in HDL
cholesterol decreased risk by 11 to 15 percent A 39 mg/dl decrease in LDL
cholesterol decreased risk by 57 percent Dr Wilson pointed out that the
focus on multiple interventions probably produced better results than
focusing on just one intervention does He added that until recently,
diabetics were often excluded from blood pressure trials

Blood Pressure and Vascular Risk Dr Wilson summarized the results of the
following studies that have included blood pressure and vascular risk in
diabetes:

WESDR: Some relationship of systolic pressure, but not diastolic, to
progression of retinopathy in younger diabetics, but in older patients,
the relationship to systolic and diastolic was about equal

SHEP Systolic Hypertension in the Elderly Program: Diabetics benefited
nearly twice as much as non-diabetics from blood pressure treatment with
chlorthialidone

SYSEUR Systolic Hypertension in Europe: Use of a calcium channel
blocker was effective for stroke in both diabetics and non-diabetics, but
less so for cardiac events

HOT Hypertension Optimal Treatment: This Scandinavian-led study

produced lower levels of diastolic pressure in diabetics through
aggressive treatment and led to new guidelines from the American Diabetes
Association ADA a diastolic of 80 for diabetics and 75 for diabetics
with kidney disease and the National Cholesterol Education Program
NCEP

HOPE Heart Outcome Prevention Evaluation: A powerful angiotensin
converting enzyme ACE inhibitor trial using ramipril showed that CVD
risk could be reduced in high-risk patients, including those with
diabetes

UKPDS: Use of beta blockers for tight control of blood pressure indicated
positive endpoint results in heart failure, stroke, diabetes death, and
microvascular disease

RENAAL Reduction of Endpoints in NIDDM with Angio II Antag Losartan:
Using an ARB angiotensin receptor blocker versus placebo, Dr Barry
Brenner and colleagues had positive results for diabetics in endpoint
incidence of chronic kidney disease, ESRD, and death

Dr Wilson stated that the number of positive results from trials of ACEs
and ARBs is producing a strong message for guidelines to include the use of
these sooner rather than later in treating type 2 diabetes

Dyslipidemia and Vascular
Risk Dr Wilson explained that abnormal LDLs are
similar in diabetics and non-diabetics; however, in diabetics, it is common
for HDLs to be low and triglycerides to be high, particularly in women, as
shown by data from the Framingham Offspring Study In four secondary
prevention trials to reduce CVD risk Scandinavian Simvastatin Survival
Study 4S and simvastatin, CARE and pravostatin, LIPID and pravostatin,
and the Veterans Affairs HDL Cholesterol Intervention Trial VA-HIT and
gemfibrozil, regardless of the agent, except for simvastatin, or whether
patients were diabetic or non-diabetic, the results were similar in
reducing relative risk in high-risk patients Dr Wilsons main point was
that these lipid interventions work as well in diabetics as they do in non-
diabetics In the ASCOT study, a joint Scandinavian and Great Britain trial
using atorvastatin, there were not enough diabetics in the group to get a
strong result versus non-diabetics

Multifactorial Issues Dr Wilson presented data Stamler, J Diabetes
Care, 1993, 16:434-44 showing that having multiple risk factors for
coronary artery disease gradually increases risk of death in non-diabetics,
but doubles or triples the risk in
diabetics The Steno-2 study of 160
persons with type 2 diabetes, a mean age of 55, a conventional diabetes
treatment and intensive treatment group 80 in each, with an 8-year follow-
up, was a multifactorial intervention trial that had as outcomes composite
CVD death, nonfatal MI, nonfatal stroke, revascularization, and amputation
The intensive treatment group included total dietary fat and saturated fat
restrictions of less than 30 percent and less than 10 percent,
respectively; 30 minutes of exercise 3 to 5 times each week; smoking
cessation for those who smoked; and treatments to reduce HbA1c, and lower
blood pressure, elevated cholesterol, and elevated triglycerides With the
exception of HbA1c, the intensive group was very successful in reaching
their goals After 8 years, the outcome to prevent CVD was, in Dr Wilsons
words, a real win, with only about 20 percent of the intensive treatment
group developing CVD while nearly 60 percent of the conventional therapy
group had CVD Dr Wilson strongly recommended that the next generation of
aggressive trials build on the Steno-2 model by using multiple
interventions

In summary, Dr Wilson said that for microvascular disease such
as
retinopathy and nephropathy, glycemic control is very important, blood
pressure control is a little less so, and lipids are the least important in
diabetes Macrovascular disease in diabetes is more complicated Abnormal
lipids double the risk in men and triple it in women, especially for women
in middle age Unfortunately, after a cardiovascular event, diabetics have
a higher risk and a very poor prognosis for outcomes He highly recommended
multifactorial interventions to prevent macrovascular disease in diabetics,
including blood pressure therapy, treatment for abnormal lipids, diet and
exercise, and glycemic control for its mild effects on macrovascular
disease

Discussion

Dr Orloff led off the discussion by saying that in adding details to our
understanding of the step-wise progression to overt type 1 and type 2
diabetes, we have arbitrarily defined and redefined diabetes He added that
we have increasingly accepted as valid certain biomarkers of the pathogenic
course of the disease that relate to chronic exposure to glucose and
metabolic abnormalities and the risks that accrue from these, which have
provided us with targets for prevention at a
much earlier stage of the
disease He asked if it should be conceded that our definitions of diabetes
have always been somewhat arbitrary, and, more specifically, should FDA and
NIH be thinking about standards of evidence for safety of new interventions
as we start to intervene earlier and earlier in the course of the disease

Dr Nathan responded that since diabetes is a continuum of pathophysiologic
processes, we must be aware of the clinical trial participants or
patients stage in the continuum when testing or recommending
interventions For example, more risk is taken in doing stenting or
angioplasty on a patient who has had or is close to having an MI in order
to prevent a heart attack than the risk in prescribing a drug or lifestyle
change for someone with high blood pressure One is usually willing to take
a greater risk when the downstream outcome is very near, whereas with a
chronic, degenerative disorder, there is less willingness to risk An
example would be questioning the use of cyclosporin to prevent type 1
diabetes in pre-diabetic children It is a case-by-case decision on how
close the patient is to a life-affecting disease process as opposed to how
early in the disease
process the patient is Another example Dr Nathan
gave was the decision in DPP to stop using troglitazone as the study group
accumulated evidence that it might be dangerous and DPP was working with
high-risk, possibly pre-diabetes, but non-diabetic patients Later the drug
was removed from the market The challenge with cardiovascular disease and
atherosclerosis is that this is a process that takes place over decades and
so one must decide when in the process it is most effective clinically and
economically to intervene and with which drugs With todays statins and
blood pressure medicines, this is mostly a cost-effectiveness issue Still
the questions are Do we start treating young men in their 20s to prevent
an MI at age 50 or 60? And which young men should be treated then? This is
more a health economics issue than a safety issue Dr Nathan said that as
we identify effective, reliable preventive measures to apply early in the
continuum, there will have to be case-by-case decisions made

Dr Orloff remarked that the speakers talks clearly showed that there is a
large amount of basic science data and clinical trial data available and
that thus we need to be careful in moving forward to
not address questions
to which we already have the answers On the issue of treating asymptomatic
disease or pre-clinical disease, this raises the issue of whether we ought
to, in some instances, be thinking not about ultimate proof of
effectiveness trials, but about safety trials He asked Drs Nathan and
Wilson what they saw as the highest priority questions for clinical trials
in prevention and management of type 1 and type 2 diabetes to prevent
sequelae

Dr Wilson recommended trials similar to that of Steno-2, which, since it
was a European trial, has not received much attention from the average
physician in North America It was published in the New England Journal of
Medicine Gaede NEJM 348:383-393, 2003, so scientists in diabetes and
heart disease probably know about it, but again the problem is translation
to the average physician A second issue is that it takes a lot of time to
care for someone with type 2 diabetes and for them to get their protocols
right Most diabetics are on four to eight medicines Hypertension also is
not a one-medication problem British literature has been discussing a
polypill approach for prevention of CVD in type 2 diabetes A trial for
this would not
be simple because the answer is not simple Dr Wilson
therefore suggested trying to design larger trials based on something
simpler with still important outcomes

Dr Nathan felt that trials are large enough now and are designed with
safety considerations For example, for the Diabetes Prevention Trial-Type
1 DPT-1, it was carefully considered whether giving insulin parenterally
would be dangerous; it turned out not to be and a much larger study is not
needed to pick up the half-a-percent or so who had very low level
complications Dr Nathan agreed with Dr Orloff that we have an enormous
reservoir of information as to what we could be doing in prevention but not
enough studies like Steno-2 that show what might happen with CVD if we
applied what we know, even using old-fashioned medications or diuretics He
suggested that what we need is translational research on how to apply what
we know, how to make the therapies more accessible in order to stem the
diabetes epidemic

Dr Simeon Taylor, Bristol-Myers Squibb Company, commented that just as
HbA1c was identified and accepted through epidemiological studies as a
valid biomarker for first one mechanism and then a number of mechanisms,
there
are other biomarkers such as HDL that have been identified through
epidemiology He asked how the scientific community and the regulatory
agencies go from a hypothesis or even validation for a single mechanism to
the next step where it is assumed that this represents a universal truth
for all mechanisms Does the biomarker have to be validated for each novel
mechanism?

Dr Nathan replied that although HbA1c was demonstrated in numerous studies
to be a concrete marker for glycemia and also a surrogate for the glycemia
component of microvascular and neurological complications, the DCCT/EDIC
also did a sub-study that showed that glycated dermal collagen was even
more directly related to a complication Dr Nathans point was that
although a biomarker may be an excellent surrogate across many mechanisms,
there probably exist more direct measures downstream in the pathogenesis of
complications He suggested the most direct way of proving this is to
ensure that there is enough stored tissue specimens in the NIH repository
so as new suggestions come up, associations can be looked for to identify
potential new biomarkers He noted that there is still a great deal to be
explained in the
pathogenesis of complications

Dr Wilson stated that most of the really good markers are now
standardized, such as cholesterol and blood pressure C-reactive protein is
not yet standardized Advanced glycosylated endproducts had great promise
but there were problems with measurement and standardization This is also
true for some of the lipoproteins compared to standard lipids
Standardization of new markers is therefore a key issue and tends to be a
tremendous problem with surrogate markers For example, carotid analysis is
a highly advanced skill unlike testing for glucose

Dr Judith Fradkin, NIDDK, raised the issue of when a clinical trial
finding can be pronounced ready for translation to the community For
example, NIH and the Centers for Disease Control and Prevention CDC have
developed the Small Steps initiative in the National Diabetes Education
Program NDEP to translate the DPP findings about early intervention to
protect loss of ?-cell function before the ?-cells are severely wounded in
those at risk for pre-diabetes The DHHS Agency for Healthcare Research and
Quality, however, feels it has not been clearly demonstrated to their
satisfaction that we should be identifying people
with pre-diabetes or that
it is cost-effective to intervene in that situation FDA will clearly be
faced with this issue as other trials are underway, looking at additional
agents that might prevent progression Dr Fradkin asked what should be the
public health message from such trials

Dr Nathan answered that in the past those who did clinical trials that
ultimately have public health implications have shied away from the issue
of the public health messages The attitude has been We did the science
The message is up to someone else This is changing Dr David Marrero,
who was a member of DPP, is very involved with NDEP and has been very
active in developing the Small Steps program Dr Nathan added that every
clinical trial today needs to be judged as to whether it is translatable
There are very few large clinical trials these days that do not have a
health economics group working side-by-side with the investigators CDC has
been partnering with DCCT/EDIC and with DPP for more than a decade Studies
that use a lot of resources need to keep in mind that ultimately there is
going to be a translation message

Dr Nathan continued that it is not surprising that there are concerns
expressed by
different agencies Further follow-up may be needed to
convince agencies and other groups of the wisdom of the DPP message For
example, the findings from DCCT that were accepted almost universally in
1993 have now been reinforced 10 years later by EDIC and shown to be a very
inexpensive intervention to prevent complications The DPP follow-up will
hopefully do the same

Dr Wilson pointed out that about half of type 2 diabetes occurs after age
65, at a time when persons are beginning to lose muscle mass and brain mass
and developing more adiposity and losing ?-cell function, and this will
continue through the ensuing aging years From Dr Wilsons perspective,
the time to head off the diabetes problem is therefore earlier, between 35
and 65

Dr Nathan agreed by emphasizing that it was critical to shift the focus
from treating disease to preventing disease if we are to stem the epidemic
If not, there will be so much disease around that the entire healthcare
budget and all the limited resources that exist will have to be spent on
late-stage, tertiary prevention of complications in a growing population of
800,000 to 12 million new diabetic patients per year There will not be
enough
resources to take care of the kidney disease, the heart disease, and
everything else that will occur

In response to a question from Dr Richard Pratley, University of Vermont,
regarding the validity of HbA1c as a marker for microvascular disease in
type 2 diabetes and cardiovascular disease, Dr Nathan said that the UKPDS
tends to substantiate this but it was not a Government-supported study and
did not have the tight controls that DCCT had; therefore, some of the
evidence is not firmly established It would be a public policy issue as to
how high a level of resources should be invested in such an effort He
recommended again that trials be designed so that samples exist in
repositories and data is stored in a databank in order to examine new
biomarkers without the large investment of a DCCT With regard to CVD, Dr
Nathan said that clearly blood pressure and lipids have a demonstrably
greater effect than HbA1c does and there is not convincing data to show
that glycemic intervention itself lowers the risk of CVD The ACCORD study
is examining that

An issue of discussion was that given that a primary care physician has
approximately 7 minutes per patient to treat the illness or condition
with
which the patient is presenting at this appointment, there is little
opportunity to diagnose type 2 diabetes or hypertension in the early stages
nor are there protocols for treating the possibly pre-diabetic patient
Although glucose and the components of metabolic syndrome should not be
ignored over time, there are no obvious short-term benefits for the doctor
or the patient in dealing with them immediately since the patient is then
asymptomatic Dr Wilson noted that there are important issues, pro and
con, in performing early intervention with drugs Dr Nathan added that
currently we are initially dealing with sub-clinical events as we face
chronic disease management for the next millennia In terms of immediate,
short-term benefit, he agreed one may have to balance the possible benefit
against the side effects of the medication This is the difference between
trying to prevent and initial MI, rather than treating an already existing
condition Whereas, with regard to the silent epidemic of all the
cardiovascular disease risk factors and diabetes, there is no penalty,
there is no motivation, necessarily, to address these factors right then,
and unfortunately, they tend to float on
Dr Nathans preference would
be to aggressively treat all risk factors

Dr Harold Lebovitz, State University of New York, stated that he felt
early diagnosis and intervention for hyperglycemia was important since
hyperglycemia causes structural damage and most people, by the time they
are diagnosed with diabetes, already have complications or sub-clinical
complications, not just risk factors Dr Lebovitz asked about the issue of
obesity in diabetics Dr Wilson stated obesity is the determinant for type
2 diabetes Diabetologists recognize the need for the patient to lose
weight; now they are concerned with the metabolic syndrome as a risk
factor

Dr Jorge Plutzky, Harvard Medical School, emphasized that there needs to
be outreach to the internist and the family practitioner to identify early
on those 15 million Americans who die from their first cardiac event, of
whom a large percentage are pre-diabetic or have the metabolic syndrome and
could have had a different outcome if there had been an intervention In
patients with late-stage disease, there has to be a lot of catch-up for
disease that is too advanced, so that even if trials show relative risk is
low, persons with pre-diabetes or
the metabolic syndrome would benefit from
earlier treatment

Dr Plutzky asked what happens when an unexpected outcome from a seeming
surrogate occurs, as when an ACE inhibitor decreases convergence to
diabetes He also asked what is necessary to indicate use of a drug to
prevent or delay convergence to diabetes

Dr Nathan responded that several studies, one of which is HOPE, have
suggested that ACE inhibition or a statin may play a role in diabetes
prevention Most of these studies were not designed primarily to study
diabetes prevention, and bias of ascertainment may play a role in some of
them However, the HOPE study has performed detailed secondary analyses
that suggest a beneficial effect of ACE-inhibition Several ongoing
clinical trials are examining whether ACE-inhibition is effective in
diabetes prevention Dr Nathan said he doubted that the currently
available data would affect labeling of ACE inhibitors, which he feels are
not being used enough Without adding diabetes to the list of indications,
ACE-inhibitors are already indicated for the treatment of hypertension, and
are beneficial for cardio-protection and renal protection He thought it
was important to use ACE-inhibition
more frequently for its current, well-
established indications If future studies show that ACE-inhibition or
receptor blockade helps prevent diabetes, it would be an important
development However, no convincing data currently demonstrate this

Dr Plutzky summarized that an internist, recognizing the importance of ACE
inhibitors and seeing a metabolic syndrome patient would then say to
him/herself Blood pressure is 135 and the patient is thick around the
waist so, based on the choices available to me, I am going to take
advantage of an approved indication for an ACE inhibitor, not only to
improve this persons blood pressure, but possibly also to influence
convergence to diabetes or to delay it Dr Plutzky said that those
looking for insulin sensitizers might ask themselves When can I do the
same thing with metformin? based on DPP data

Dr Nathan applauded the emphasis on prevention issues and reminded the
group that even people with recognized cardiovascular disease and its risk
factors in diabetes are currently undertreated, a barrier that needs to be
overcome

Session II: New Targets of Intervention
Moderator: Judith Fradkin, MD, Director, Division of Diabetes,
Endocrinology, and
Metabolic Diseases, NIDDK

New Molecular Targets in Type 2 Diabetes Mellitus
Nancy A Thornberry, Senior Director, Department of Metabolic Disorders,
Merck Research Laboratories, Merck and Company, Inc, Rahway, New Jersey

To set the stage for her review of the molecular targets that have the most
potential within the next 10 years, Dr Thornberry briefly reviewed the
pathogenic defects that result in hyperglycemia-hepatic glucose
overproduction, insulin resistance, and insulin secretory dysfunction She
stated these defects are thus the primary targets for current and future
therapies to treat elevated blood glucose There are three major classes of
oral antihyperglycemic agents AHAs:

Sulfonylureas that stimulate insulin secretion in the pancreas, but may
increase risk of hypoglycemia, cause drug interactions, exhaust ? cells,
or cause weight gain
Metformin and PPARs that lower glucose overproduction in the liver;
metformin may have gastrointestinal side effects and cause lactic
acidosis; PPARs also may have drug interactions, increase weight gain, or
cause edema
PPARs that improve insulin resistance in muscle, but have the possible
side effects listed
above

Dr Thornberry stated that future potential therapeutic classes will
include these three major classes of insulin sensitizers, insulin
secretagogues, and mediators of hepatic glucose output She presented the
rationales and key issues for various therapeutic agents in each of these
classes

Insulin Sensitizers: PPAR? and PPAR? Agonists PPARs are ligand-modulated
transcription factors Dr Thornberry explained that the PPAR is a nuclear
hormone receptor involved in differentiation and function of fat cells;
ligands bind to the nuclear receptor but the downstream mechanism is not
fully understood PPAR? agonists target dyslipidemia and atherosclerosis by
correcting lipid abnormalities PPAR? agonists are a target for type 2
diabetes to correct insulin resistance The rationale for using these as
dual activators is to improve and simplify treatment of diabetes patients
while decreasing cardiovascular risk There is preclinical proof in animal
studies of the efficacy of using them as dual agonists Key issues are
their combined adverse effects For PPAR?, this includes myopathy and a
potential for hepatotoxicity Adverse effects for PPAR? are weight gain,
edema, mild anemia, mild
leucopenia, and the potential for increased risk
of heart failure

Insulin Sensitizers: SPPAR?Ms Dr Thornberry said that safety concerns are
a key barrier in widespread use of PPAR? full agonists such as
thiazolidinediones TZDs, which has led to the selective PPAR? modulator
SPPAR?M hypothesis SPPAR?Ms are potent ligands but only partial
agonists Unlike full agonists, their alternative binding motifs produce
differential coactivator associations and the restricted gene expression
changes profiles, so they may retain efficacy but have reduced toxicity, as
was demonstrated in the db/db mouse study that compared rosiglitazone, a
full agonist, and a partial relative of rosiglitazone that still retained
full efficacy Rodent studies also showed that the partial agonist caused
only modest cardiac effects compared to the rosiglitazone Key issues
include whether or not the SPPAR?Ms will equal the efficacy of current TZD
full agonists while avoiding the safety concerns and adverse effects of
TZDs If they are safer, then there would be an option to test higher
doses

Summarizing, Dr Thornberry said the dual PPAR?/? agents have the potential
to act on co-morbidities but may have the same
safety and tolerability
liabilities as individual PPARs The SPPAR?Ms have a safer profile and may
ultimately allow for treatment at earlier stages of diseases She told the
audience that there is a lot of effort going on in developing the next-
generation insulin sensitizers with a focus on a non-PPAR mechanism,
enhanced efficacy, and improved safety and tolerability

Insulin Secretagogues: Glucagon-like Peptide 1 GLP-1 Analogs The analogs
are one of two GLP-1 based therapies being studied The other is dipeptidyl
peptidase IV DP-IV inhibitors Dr Thornberry described GLP-1 as a
peptide secreted from the stomach in response to food intake that has been
shown in humans to have a number of beneficial effects, including
stimulation of glucose-dependent insulin biosynthesis and secretion,
inhibition of glucagon secretion, and slowing of gastric emptying resulting
in a feeling of satiety and thus reducing appetite In fact, modest body
weight loss has been observed with GLP-1 analogs She added that there is
very intriguing data in rodents to indicate that GLP-1 may have a potential
for regulating islet growth and survival

Dr Thornberry cited a study by Dr Holst and colleagues Holst et
al
Lancet 359, 2002 in Copenhagen that demonstrated that as soon as 1 week
after continuous infusion of GLP-1 in humans there were excellent effects
on both postprandial and fasting glucose compared to saline infusion and
these effects were maintained over a 6-week period Dr Alain Baron has
reported the results of a 5-month open-label study with Exenatide exendin-
4 in 155 patients failing metformin and sulfonylureas in which the interim
analysis showed reductions in HbA1c and positive effects on body weight
There were some safety and tolerability issues such as antibody titers and
nausea and vomiting that is observed with all GLP-1 analogs; however, there
was decreased incidence of the stomach upset with repeated dosing, the
antibody titers apparently did not impact efficacy, and there were no
safety liabilities

According to Dr Thornberry, the vision for GLP-1 analogs is sustained
efficacy, good durability, and the potential to stabilize ?-cell function
GLP-1 analogs do not have any of the adverse effects associated with
current agents-there is no or a low risk of hypoglycemia, no weight gain or
even body weight loss, and no edema They offer an excellent potential for
use in
combination with other agents for the pathology such as insulin
sensitizers and mediators of hepatic glucose output Dr Thornberry cited
rodent data showing a potential for ?-cell regeneration, an attribute that,
if it extends to humans, Dr Thornberry compared to finding a holy grail
that could lead to improvement over time in glycemic control and even
reverse ?-cell loss

Key issues for GLP-1 analogs are that injections are required with the
current agents in development; patients experience nausea due to delayed
gastric emptying, although this may not be a issue in the long run; and the
?-cell effects have not been demonstrated in humans

Insulin Secretagogues: DP-IV inhibitors Dr Thornberry explained that DP-
IV inhibitors are essentially an oral approach to GLP-1 therapy DP-IV is
the key enzyme involved in the regulation of GLP-1, which, like other
peptides, is very rapidly degraded in vivo, with a half-life of less than 1
minute, so that inhibition of DP-IV results in raising the endogenous level
of GLP-1 Proof-of-concept was provided by Dr Holst and his colleagues in
1998 Several compounds are in clinical development A study with a
Novartis compound Arhen et al, 2002, Diabetes
Care 35 in which 93
patients were treated for 4 weeks demonstrated the compound was well
tolerated and had statistically significant effects on fasting,
postprandial, and 24-hour glucose

Dr Thornberry described the vision for DP-IV inhibitors also sustained
efficacy and good durability in stabilizing ?-cell function; tolerance and
a good safety profile; oral therapy versus the GLP-1 injections and the
potential for once-daily dosing; excellent potential for use in combination
with other therapeutic agents; and the potential for ?-cell regeneration

The key issues are the unknown extent of the efficacy with 24-hour, chronic
DP-IV inhibition; the potential that the therapy would have to be limited
to mild diabetes with intact ?-cell function; ability to be used in
combination likely synergistic with PPAR and metformin but may be
difficult to predict efficacy with sulfonylureas and insulin; whether it
will have the potential ?-cell preservation and/or regeneration benefit in
humans; and determination of safety and tolerability Dr Thornberry said
that the enzyme, in addition to its role in GLP-1, has been implicated in a
number of different functions, including T-cell activation and
immune
function, and there are a variety of substrates other than GLP-1 that are
cleaved in vitro by this enzyme, which is true of subsurface peptidases in
general Their in vivo significance and whether or not they are regulated
in vivo is very difficult to establish, which means data is needed on its
long-term safety and tolerability In addition to establishing safety and
tolerability, Dr Thornberrry said the focus for future agents should be
glucose-stimulated insulin secretion, as this is the mechanism by which DP-
IV inhibitors work; greater efficacy; and trying to understand what is
indeed responsible for ?-cell degradation so that can be targeted in a more
rational way Overall, these agents are expected to present many benefits

Mediators of Hepatic Glucose Output Dr Thornberry highlighted these
because there is some human validation for both glucokinase activators and
glucagons receptor antagonists Glucokinase GK is a key enzyme involved
in the metabolism of glucose, catalyzing the phosphorylation to glucose-6
phosphate in both the liver and in the pancreas, where it is predominantly
expressed It is a member of the hexokinase family and a rate-limiting step
of glucose
metabolism Dr Thornberry remarked that the rationale for this
target is clearly the anticipation that dietary glucose would be absorbed
and converted to glucose-6 phosphate, resulting in enhanced hepatic glucose
uptake and decreased glucose production Glucokinase plays a key role in
the glucose sensing in the pancreas that results in insulin secretion;
therefore, GK activation should result in production of insulin In
summary, the combined hepatic and pancreatic effects may translate into
improved efficacy over current agents

Dr Thornberry stated that human validation has been provided in the way of
genetic validation Approximately 150 mutations have been identified in GK
Fifty percent of GK function has been observed in MODY maturity onset
diabetes of the young and gestational diabetes One hundred percent loss
of GK results in neonatal diabetes, and activating mutants have been
identified by Dr Franz Matschinsky Matschinsky, FM Diabetes 51:S394-404,
2002 and a number of other investigators showing increases in fasting and
2-hour glucose in subjects with GK mutations as opposed to their unaffected
relatives Dr Thornberry said that it has been demonstrated that only
modest
activation of GK is required to produce beneficial effects in
rodents A two-fold increase in messenger RNA in the liver of rodents
lowered glucose and improved glucose tolerance Roche published data in
2003 that demonstrated pharmacological proof-of-concept for GK activators
Grimsby et al 2003, Science 301, 370

Potential attributes and advantages listed by Dr Thornberry included
considering GK activators as a single-agent combination therapy affecting
both the ?-cell and the liver, so it could potentially be applied to a
broad range of type 2 diabetic patients with both insulin resistance and
impaired insulin secretion It is also predicted to have a good safety and
tolerability profile and the potential to be used in combination with
insulin sensitizers, DP IV inhibitors, and metformin

Key issues for this target are hypoglycemia and the potential for lipid
accumulation in the liver, as with all gluconeogenesis targets

Dr Thornberry said those present were well familiar with the following
rationale for glucagon receptor antagonists: glucagons have a very
important role in maintaining glucose homeostasis Being secreted by the ?-
cells in response to falling glucose, glucagons
activate the hepatic
glucagon receptor, which in turn results in glycogen breakdown and
gluconeogenesis, which elevates blood glucose Some limited proof-of-
concept in humans has been provided in a study done by Bayer with a
glucagon antagonist that demonstrated it blocked exogenous glucagon effect
in dogs and rhesus, and in man Dr Thornberry gave as potential attributes
and advantages that the glucagons receptor antagonist is predicted to
decrease both fasting and postprandial hyperglycemia; is anticipated to
have a relatively clean safety profile; is an oral agent; and has good
potential for use in combination The key issue is its potential for
hypoglycemia

In summary, Dr Thornberry said the agents furthest along in development
are the dual PPAR?/? agonists, the GLP-1 analogs, and the DP-IV inhibitors
There are a variety of other mechanisms that either are or may be in early
development, including SPPAR?Ms, GK activators, glycogen phosphorylase
inhibitors, SGLT sodium-glucose cotransporter inhibitors, glucagon
antagonists, fructose 1,6 bis-phosphatase inhibitors The insulin receptor
phosphatase looks like an attractive target, the issue being whether or not
one can truly make a
phosphatase inhibitor that has suitable properties for
use in vivo Dr Thornberry stated that chemical tractability is a big
issue here, so there are companies that instead are pursuing an antisense
approach to PTPIB protein-tyrosine phosphatase 1B She concluded by
noting that she may have missed some others in development, but in any
event, there are a number of promising therapies emerging

Immunomodulation in Type 1 Diabetes
George Eisenbarth, MD, PhD, Executive Director, Barbara Davis Center for
Childhood Diabetes; Professor of Pediatrics, Medicine, and Immunology,
University of Colorado, Denver

Dr Eisenbarth noted that we are at a somewhat unusual era in type 1
diabetes: We can predict the disease, we can prevent it in animal models,
but we do not know how to intervene yet in the disease in man The next
decade will focus on taking therapies studied in the animal models and
applying them to humans-a major undertaking

Dr Eisenbarth stated that immunomodulation of type 1 diabetes is a broad
topic and referred the audience to the Barbara Davis Centers website
wwwbarbaradaviscenterorg where a book on the immunology of diabetes
with teaching slides provides more detail than he
would cover in his
presentation He stressed the importance of weighing the benefits of
prevention and treatment of a disease against potential side effects of the
therapies being considered, especially some of the immunologic therapies
for diseases like rheumatoid arthritis or multiple sclerosis This
perspective is also critical in type 1 diabetes

Data from the British Diabetes Association Cohort Study 1972-93, cited by
Dr Eisenbarth, indicated almost a 3 percent excess mortality in these
young individuals ages 1 through 29, compared with the general population
Primarily these are metabolic deaths, not renal or cardiovascular disease
Dr Eisenbarths point was that the immunologic therapies thus need to be
weighed against current problems with therapy, but hopefully, other
therapies such as continuous glucose monitoring, will make inroads into
these metabolic problems

Dr Eisenbarth stated that it is crucial in developing therapies to
understand that type 1 diabetes pathogenesis is basically a balance between
pathogenic T-cells and regulatory T-cells as illustrated by Dr Aldo
Rossinis teeter-totter schema Regulatory T-cells used to be called
suppressor T-cells; but now it is clear
that there are regulatory T-cells
that are essential for immunoregulation in humans Dr Eisenbarth gave as
an example a mutation of the FOXP-3 gene that removes a major subset of
regulatory T-cells Infants with this rare syndrome die, often in the first
months of life, with overwhelming autoimmunity and can develop diabetes at
age 2 to 3 days Introduction of that FOXP-3 gene into a regular T-cell
turns it into a regulatory T-cell

Dr Eisenbarth presented a more complex slide from Dr Len Chess that
depicted many of the players in the development of ?-cell destruction, in
particular, the antigen-presenting cells, with their HLA molecule that
present peptides to CD4 regulatory T-cells Cytotoxic T-cells can directly
destroy ?-cells or influence other portions of the innate immune system
that can produce cytokines that destroy ?-cells Dr Eisenbarth pointed out
there are many therapeutic opportunities in the immunopathophysiology of
diabetes, and drugs are being developed for many of the specific molecules
of this immune regulatory system

In summarizing the general paradigm for prevention and treatment of type 1
diabetes, Dr Eisenbarth listed the major steps as:

Identify genetic
susceptibility
Detect initial presence of autoantibodies
Monitor metabolic decompensation
Treat overt disease prior to morbidity and mortality
Pursue basic and clinical research to develop prevention interventions

Genetic Susceptibility At the first stage of genetic susceptibility, the
major determinant currently known is genes within the major
histocompatibility MHC complex Alleles of these genes make up about 50
percent of the familial risk of type 1 diabetes Explaining the
nomenclature, used in describing the complex, Dr Eisenbarth said each
different polymorphic HLA molecule is given a number that represents the
amino acid sequence of that molecule Risk can be ascribed to a given
allele, like DR4, but on that same chromosome, right next to DR4, there is
DQ8; these molecules present peptide antigens and one forms a high-risk
haplotype What really determines risk of type 1 diabetes in this region is
a persons genotype, the chromosomes inherited, one from each parent The
highest risk genotype for type 1 diabetes in the United States is a DR3/4
heterozygous individual with DQ8/2 With a different DR4 subtype, for
instance, DRB10403, Dr Eisenbarth explained that about three
or four
amino acids would be changed, thus greatly reducing risk

Studies based on this genetic susceptibility information include the
Diabetes Autoimmunity Study in the Young DAISY in Denver, BabyDiab in
Germany, Diabetes Prediction and Prevention DIPP in Finland, and now
NIDDK/CDCs The Environmental Determinants of Diabetes in the Young
TEDDY From DAISY, Dr Eisenbarth spoke of identifying at-risk children
at birth by determining HLA genotypes from umbilical cord blood The
highest risk genotype DR3/4 is present in about 24 percent of children,
of whom 1 of 15 will develop type 1 diabetes, approximately half of all
children in Denver developing type 1 before the age of 5 The genotype also
decreases the age at which the disorder manifests In DAISY, first-degree
relatives of a sibling or offspring of a parent with type 1 diabetes are
also followed from birth

Autoantibodies A series of semi-automated assays for anti-autoantibodies
are now available Some are in a modified ELISA format, but most are high-
sensitivity and high- specificity assays Dr Eisenbarth listed the three
autoantibodies that are primarily measured as insulin, glutamic acid
decarboxylase, and ICA512 IA-2
autoantibodies

Development of autobodies can be followed in the at-risk children
identified at birth Dr Eisenbarth said insulin autoantibodies can be
present at 9 months of age-or first develop at 40 years of age He added
that the practical utilization of this information is limited, because we
do not have the ability currently to prevent type 1 diabetes However, at-
risk children in a close follow-up study as in DAISY do not present with
classical ketoacidosis For the children in the DAISY study versus a
control population, 1 out of 30 children needed to be hospitalized at the
onset of diabetes because of ketoacidosis or some other major metabolic
problem versus about 40 percent of the general population

The DPT-1, in which close to 100,000 relatives were screened and
autoantibodies measured, clearly illustrated that progression to diabetes
can be predicted based on the number of autoantibodies expressed Dr
Eisenbarth emphasized that the DPT-1 data show that risk can be identified
and thus we can do trials for prevention in such a cohort He added that
DPT-1 also revealed that, even given the presence of autoantibodies, there
are also HLA alleles that prevent the development of
diabetes For example,
DQB10602, DR2, even when its combined with the highest risk alleles, like
DR4, has a very low progression to diabetes amongst antibody-positive
individuals

Dr Eisenbarth next referred to the best studied animal model in type 1
diabetes, the NOD non-obese diabetic mouse NOD mice, just like young
children, make insulin autoantibodies, beginning somewhere between 4 and 8
weeks of age The insulin autoantibodies actually peak and go down, and
then the blood glucose rises; thus the autoantibodies are a predictor and a
surrogate, although obviously not perfect as shown by an NOD mouse that
never expressed insulin autoantibodies but did progress to diabetes

Target antigens have been identified in humans and in animal models,
especially at the T-cell level Dr Eisenbarth stated that it is reasonably
clear that autoantibodies per se are not the direct cause of type 1
diabetes, since T-cells and T-cell clones can transfer the disease Among
the autoantigens in the NOD mouse, insulin is prominent Dr Eisenbarth
gave the example of a peptide of the insulin molecule recognized by pre-
diabetic, diabetogenic T-cells in the NOD, the B:9 through 23 sequence,
that can be used to
prevent diabetes or to induce diabetes He added that a
difficulty with the NOD mouse is that it is perhaps too easy to prevent
diabetes given more than 100 reported preventive therapies, For instance
a single injection of the B:9-23 insulin peptide at 4 weeks of age
prevents diabetes in 90 percent of the mice Dr Eisenbarth recommended
that more robust models be developed such as an insulin-2 knockout, in
which the insulin gene expression within the thymus is removed creating a
more robust, more diabetogenic NOD mouse In contrast to prevention of
diabetes, Dr Eisenbarth said that giving the same B:9-23 peptide to a
normal BALB/c mouse induced insulin autoantibodies within weeks The
antibodies reacted with insulin and not with the inducing peptide,
suggesting that, given the genetics of a normal BALB/c mouse, the mouse is
ready to begin part of the process that leads to type 1 diabetes, and with
genetic tricks, a mouse is produced that responds to the peptide by
developing diabetes Dr Eisenbarth cautioned that in the area of
immunologic vaccination there is much to be learned

What Is Missing? Dr Eisenbarth repeated his earlier statement that we can
now predict type 1 diabetes, but
we do not have therapies to prevent the
disorder as illustrated by the parenteral study of DPT-1, where the
prediction was accurate, but there was no effect on delaying the disease

Dr Eisenbarth stated the main thing missing today is an assay for
pathogenic T-cells There are several assays being developed-tetramer,
ELISPOT He cited a study from Drs Trudeau, Tan, and Santamaria JCI,
111:217-223 2003 indicating a T-cell assay that would help in predicting
diabetes Basically, a tetramer takes the MHC molecule, places a peptide in
it, and then it binds to the T-cell receptor, so T-cells can be quantitated
and the specific autoantigenic peptide can be seen In this study, the NOD
mice that went on to diabetes had T-cells reacting with the peptide of an
islet-specific molecule called IGRP islet glucose-related phosphatase,
whereas the NOD mice that did not progress to diabetes did not have those
circulating cells Dr Eisenbarth thought that, eventually, the same
peptide cellular reactivity needs to be defined in the human, which is a
very difficult area of research He suggested that the T-cells will have to
be found in the pancreas because it is too hard to find them in the
peripheral
blood due to their extremely small numbers One possible source
of these disease-causing T-cells might be from programs that screen
cadaveric donors for autoantibodies to obtain a pancreas Then the peptides
the T-cells recognize must be defined and assays developed for those T-
cells

Dr Eisenbarth presented guidelines from the Immunology of Diabetes Society
for designing trials for each stage of the development of type 1 diabetes
and suggested it would be helpful if trials were designed based on specific
guidelines, even though arbitrary, in order to better compare data across
trials and have more confidence in the results of the trials Dr
Eisenbarth said a key factor would be the use of C-peptide as a marker of
loss of ?-cells, since loss of ?-cells is primary in this immune-mediated
disorder

Noting that there are many in process trials of non-antigen-specific
immunotherapies, Dr Eisenbarth said the furthest advanced probably is the
anti-CD3 trials of Dr K Herold and Dr L Chatenoud The anti-CD3
antibodies are, at this point, thought to work not simply by depleting T-
cells, which has the effect of clearing the insulitis, but of stimulating
regulatory T-cells, in particular
T-cells that are making a cytokine TGF-?
There are also trials in newborns, with dietary interventions, that are
underway or about to occur Results of these non-antigen-specific therapies
are still forthcoming

Listing some of the trials for antigen-specific therapies, Dr Eisenbarth
mentioned the parenteral insulin trial that had no effect and the DPT-1
oral insulin trial, which overall had no effect, although a subgroup
analysis of those individuals with the highest levels of insulin
autoantibodies suggested the possibility of an effect that the TrialNet
group will follow up There is a trial at the Joslin Diabetes Center of the
insulin B chain; also altered peptide ligands in the B9 through 23 peptide;
trials of hGAD from Diamyd;, and trials of heat shock protein peptides
There are a lot of potential agents to be evaluated Dr Eisenbarth
particularly noted that to have an immunologic vaccination that prevents or
delays diabetes would be a remarkable accomplishment Multiple sclerosis is
the only disease having an FDA-approved therapy in this realm with an
unusual peptide

In summary, Dr Eisenbarth stressed that prevention of diabetes and
prevention of ?-cell loss after the onset of
type 1 diabetes is very
important Predicting high risk is, in quotes, easy Although it can be
debated that not everyone who has a single autoantibody progresses to
diabetes and probably not everyone with multiple autoantibodies will
develop diabetes, the probability is over 90 percent There are multiple
therapies in animal models There is an explosion of immunotherapies in
man Dr Eisenbarth pointed out the tremendous change in comparing the PDR
Physicians Desk Reference listing for therapies for immunologic disorders
from 20 years ago to what is in the PDR now and what will be in the PDR
within the next 10 years He believes it is only a matter of time before
there is an immunotherapy for chronic active insulitis, just as there is
now a therapy for chronic active hepatitis People with chronic active
hepatitis do not have overt disease, but they are likely to develop overt
disease As outcomes, Dr Eisenbarth listed overt diabetes and C-peptide
and suggested that a short-term outcome of prevention of hypo- and severe
hyperglycemia will be available within a 2-year trial because of
improvement in continuous glucose monitoring He commended the
international collaboration represented by
the ITN and TrialNet and the
public support provided by NIH

Discussion

Dr Fradkin, NIDDK, asked Dr Thornberry and Dr Eisenbarth to suggest how
NIH could best foster bench-to-bedside translation of basic discoveries of
NIH-supported scientists into development of therapeutics Dr Thornberry
replied that continuing support for basic research in ?-cell dysfunction
and support of academic endeavors to identify next generation targets would
be extremely helpful Most pharmaceutical companies increasingly have
collaborations with external academic investigators in order to exploit the
genomic revolution and proteomics and better understand new targets for
insulin sensitization and preservation of ?-cell function

Dr Eisenbarth responded that he understood that NIH, and particularly
NIDDK and the National Cancer Institute NCI, had developed a mechanism to
further pharmaceutical drug development, including animal toxicity testing,
which is not easily done in an academic laboratory He added that
partnering with the pharmaceutical industry is helpful but sometimes their
priorities differ with those of the academic researcher The availability
of a parallel
system to facilitate development of a drug without
pharmaceutical support is, therefore, very useful

Dr Fradkin explained that Dr Eisenbarth was referring to a newly
developed program T1D-RAID in which NIDDK is partnering with NCI to use a
mechanism the institute had developed for cancer-rapid access to
intervention development-and to make those resources available for type 1
diabetes, particularly because type 1 is a smaller market than type 2 and
thus commands less industry interest and resources in developing
therapeutic agents

In response to a request from Dr Laura Shawver, Phenomix Corporation,
about other DP-IV family members, Dr Thornberry said DP-IV, a member of an
emerging protease family, is the only enzyme for which function is well
understood There is no clear evidence that any of the other enzymes play a
role in glucose control The issue of selectivity is an open one right now,
and one that Merck and others are working very hard to resolve

Dr Nathan asked Dr Eisenbarth to answer an either-or situation Given
that type 1 diabetes evolves over time, screening is difficult, and only a
small percent of those at risk develop the disease, but the major burden
for those who
do lasts over a lifetime, would Dr Eisenbarth choose to
address the disease during its early development, pre-clinical stage or
reverse it at a later stage?

Dr Eisenbarth said he preferred to do both because there are therapies
that work only in the pre-diabetic phase and therapies that work in the new-
onset phase, which is a tremendous spectrum Although called new-onset
diabetes, studies like DAISY suggest that people have had their diabetes
for 6 months to 1 year before identified People vary greatly in the amount
of C-peptide that remains There are times to intervene even in the
genetically susceptible by simply changing the diet He agreed that
screening solely for type 1 diabetes on a population level would be
expensive; however, in the future it will probably fall into a category of
many other immune-mediated diseases that would be screened for at the same
time For example, as a public health measure, Colorado screens newborns
for more than 20 different disorders As this public health policy and
practice develops, the screening cost per disease will come down, because
of the package approach

Dr Amy Rosenberg, FDA, asked Dr Thornberry if the to GLP-1 analogs
were
neutralizing and also what the normal circulating levels of GLP-1 are and
do they fluctuate Dr Thornberry answered that she understood they had no
effect on efficacy and there were no safety concerns thus far Secreted in
response to food intake, GLP-1 circulates at very low levels Total GLP-1
postprandially is about 20 to 25 picomolar, and a large amount is degraded
peptide, so at any given time, perhaps only 20 percent is actually active
Fasting levels are closer to 5 picomolar or less Dr Rosenberg commented
that this probably would explain the low level of immunologic tolerance

In reply to Dr Rosenbergs request to comment on the finding that T-
regulatory cells are CD25 positive, and antibody to CD25 is actually
salutary for transplant rejection, Dr Eisenbarth said there are many
different subsets of T-regulatory cells and we do not have great markers
for them nor understand what some of our therapies are doing, particularly
antibodies to CD25 cells There are CD4 and a CD25 regulatory cell that
is extremely important, but T-cells, as they become activated, also express
the CD25 marker Since there is efficacy of those markers, Dr Eisenbarth
suggested they are probably not
doing anything near like what a FOXP-3 gene
knockout does

Dr Thornberry responded to a question from Dr David Karph, Metabolex,
Inc and Stanford University, that she had no specific data suggesting a
differential role for partial PPAR? agonists in the efficacy side on lipid
parameters or on inflammatory markers of cardiovascular disease Based on
pre-clinical data, she thought that, at least in rodents, one could
anticipate achieving efficacy comparable to that of full agonists with
respect to glucose for partial ? agonists, but she could not comment on the
lipid effects

Dr Simeon Taylor, Bristol-Myers Squibb, commented that currently there are
at least five approved mechanisms for treatment of type 2 diabetes in many
compounds and from Dr Thornberrys presentation, there could be 10 or 15
more approved over the next few years He wondered how physicians were
going to decide on the best way of treating patients He asked if Dr
Thornberry envisioned a time when there would be either pharmacogenomics or
biomarkers or some other scientific evidence-based way to select who was
more or less likely to benefit or to have toxicity from a particular
mechanism She said that was one of the
promises of microarrays, for
example Scientists are trying to use microarrays to categorize various
subsets of diabetics and pre-clinically to look at whether or not there are
markers to anticipate potential toxicities It remains to be seen if
ultimately we can predict responders and non-responders

Dr Fradkin offered the idea that, potentially, some of the samples being
sent to repositories from clinical trials can subsequently be used to
examine those kinds of questions after the potential predictors are
identified She noted this concept has been very exciting in the cancer
field recently

Dr Louis Herlands, Chief Operating Officer, DARA Biosciences, Inc, asked
Dr Eisenbarth what the potential therapeutic implications were of a
prevalent population of CD8 T-cells in the NOD mouse-possibly amounting to
as much as 40 percent of the CD8 T-cells in the islets, possibly more-
recognizing IGRP Dr Eisenbarth answered that this is crucial to the
antigens to which the dominant immune response is directed and raises
several questions For instance, if you knock out the IGRP gene, which is
doable, and a number of groups are in the process of doing it, will that
completely prevent the
development of diabetes? Knocking out the insulin-1
gene reduces the development of diabetes by almost 90 percent A major
question is, Is it multiple different antigens that are all crucial, or is
it just one antigen whose recognition is crucial to the disease, whereas
other reactivities mirror the disease as it is occurring? Obviously, IGRP
is a very important target to look at in the human Thus far, there are no
autoantibodies to IGRP, and T-cells are just being studied in relationship
to the IGRP molecule Dr Eisenbarth asked, Will we be able to develop a
predictive assay with IGRP? Will creating tolerance to the IGRP molecule
prevent the disease?

Dr Jerry Palmer, University of Washington, commented that we normally
divide studies into classic type 1 and type 2 diabetes trials He asked how
often does the type 1 autoimmune attack on the ?-cell participate in
diabetes in general, both type 1 and type 2 This could potentially be very
important therapeutically Dr Eisenbarth noted that actually there are
good studies for latent autoimmune diabetes in adults LADA Between 5 and
15 percent of individuals who are called type 2 diabetics really have anti-
islet autoantibodies, lose
C-peptide faster, and, in his opinion, their
genetics reflect this and he would call them a type 1 diabetic On the
other side, insulin resistance is likely a key determinant when someone
presents with diabetes and is losing ? cells In the DPT-1 study, some
children who were becoming diabetic had fasting insulins of 50 or 60;
therefore, it might be possible to treat those children with an oral agent
for several years, even without affecting their autoimmunity, which would
be an advantage for those children He added that as Dr Palmer had
mentioned, we have classic diseases, but there is no reason that they do
not overlap

Dr Fred Murray, Aventis Pharmaceuticals, followed up Dr Palmers remarks
by saying if one takes the BB rat, which is an animal model with type 1
diabetes, and breed it with the Zucker rat, which is an obese animal model,
the result is the BBZ rat that in the male has type 2 diabetes and in the
female has impaired glucose tolerance Dr Murray also presented the
question: Since it is known or believed that type 2 diabetes and
cardiovascular disease are both inflammatory diseases, and some agents,
like the PPARs, have anti-inflammatory effects as well as
insulin-
sensitizing effects, are there inflammatory markers we can use to identify
a pre-diabetes condition that occurs before impaired glucose tolerance? For
instance, there are several ongoing trials to prevent diabetes in those
with impaired glucose tolerance Some of the problems there have to do with
the hypoglycemia seen in type 1 diabetes If there were better biomarkers,
perhaps cytokines, to identify early diabetes, then trials and agents would
be safer

Dr Eisenbarth replied that we have the techniques now to look across a
broad spectrum of cytokines for inflammatory changes in both type 1 and
type 2 diabetes and in the pre-diabetic group Dr Thornberry agreed that
there is a great deal going on in the inflammation arena about which we
need to be aware

Dr Alex Szidon, DARA Biosciences, commented that one of the issues with
type 2 diabetes is the number of target tissues for interventions to
regulate metabolism as a whole For example, recently, there have been
findings regarding interventions at the hypothalamus actually affecting
both gluconeogenesis in the liver and food intake He asked Dr Thornberry
where she looked to affect metabolic change and what her general sense
was
of intervening at targets in the hypothalamus to treat multiple facets of
the disease Dr Thornberry agreed that this was an emerging area of
interest and there is accumulating evidence that lipogenic targets may
indeed control effects such as feeding and glucose metabolism via effects
in the brain AMPK, is a recent example that has been implicated in
controlling metabolism via its effects in the brain Dr Thornberry felt
that it is too early to know if there are going to be good targets there
and whether or not it will be consistent to target them both in the
periphery and in the brain

Dr Christopher Saudek, The Johns Hopkins University School of Medicine,
asked what the current thought was on the so-called 1B or non-autoimmune
type 1 diabetes Dr Eisenbarth said that, for the most part, if there is
not an identified genetic mutation, then the disorder is classified either
type 1A or type 1B The trouble is, according to Dr Eisenbarth, that he is
not sure just what he would classify as a type 1B diabetic Reports from
Japan, where they have a low percentage overall of type 1 diabetes, report
a significant percentage of patients with what they call fulminant
diabetes These are
patients, some of them adults, who present with a
normal HbA1c and an extremely elevated blood glucose, which is rarely found
in the United States Originally, it was proposed that they were an initial
example of type 1B, but it turns out their HLA reflects the HLA of high
risk for type 1A diabetes in Japan and they have infiltration, especially
of the acinar pancreatic tissue by lymphocytes Dr Eisenbarth said the
question is whether these individuals are a form of type 1A that is
extremely fulminant and without time to make the auto-antibodies On the
other hand, there are other surprising results that have not been factored
in yet, such as the detection or evidence of chronic enteral viral
infection within ?-cells

In response to the question of whether there is a role for antibodies and
their ability to cause epitope spreading and enhanced antigen presentation
in T cells and whether there might be a ping-ponging effect, Dr Eisenbarth
said he thought both B-lymphocytes and antibodies might well participate in
the disease There is good evidence in the NOD mouse that antibodies are
important to development of the disease If there are no transplacental
antibodies, the incidence of
diabetes goes down by about 90 percent Also,
B-lymphocytes are potentially very important for antigen presentation

Dr Jose Caro, Aventis Pharmaceuticals, asked about the relative importance
of different antibodies as predictors of type 1 diabetes ie, is anti-GAD
glutamic acid decarboxylase more important than anti-islet The response
was that there are fine distinctions and specific antibodies do make a
difference At first cut, probably the number of auto-antibodies is very
important The IA2 auto-antibodies are the most predictive They are
usually associated with the presence of the other auto-antibodies and, in
some ways, they are the easiest to measure This might depend on assay
ability The insulin auto-antibodies are highest in the youngest children
developing type 1 diabetes There is a very peculiar log inverse linear
relationship GAD, if anything, is fairly flat and just the opposite and IA-
2 is shallow So the specific antibodies make a difference

Dr Caro asked Dr Eisenbarth if in the DAISY cohort, did they look at the
number of children who were antibody-negative initially and then developed
positive antibodies over time and ultimately developed diabetes Dr
Eisenbarth
answered that, if you measure early enough, say at 3 months,
most are antibody-negative and then develop the antibody later As best as
they could tell, children are not born with the antibodies, although there
is transplacental passage for a group that is probably not pathogenic He
said that if the fundamental question was what is the best timing for
measuring antibodies, at what ages, this had not absolutely been defined
Dr Eisenbarths guess was antibodies can be picked up in the first 9
months of life, and in very young children, an annual testing might be
necessary

In response to a question about investigation of altered antigen
presentation mechanisms in high-risk genotypes, Dr Eisenbarth said there
is a debate in the field about whether or not there is less stability in
the highest risk genotypes, but he felt the bulk of the data is that these
HLA molecules are normal, even though they are creating diabetes
susceptibility For instance, the haplotype that prevents 98 percent of
type 1 diabetes is the high risk haplotype for multiple sclerosis It
appears that these HLA molecules are determining which target antigen and
thus which tissue, rather than being abnormal in overall
function

Dr Alain Baron, Amylin Pharmaceuticals, referred to the seriousness of
type 1 diabetes as evidenced by Dr Eisenbarths data on the high mortality
rate in patients between the ages of 20 and 30 This brings up the risk
benefit issue regarding novel therapies, when the only current agent is
insulin He asked where Dr Eisenbarth would rank type 1 diabetes on a
scale of 1 to 10 with cancer ranking as a 7 or 8 Dr Eisenbarth said
therapies needed to be weighed against problems with diabetes from age 0 to
30, even before the chronic complications occur Type 1 diabetes is a
difficult disease to treat It completely changes family members lives
The risk of hypoglycemia is a major limitation as efforts are made to lower
blood sugar The Barbara Davis Center cares for about 3,000 children and
2,000 young adults Over the past decade, there have been at least 20
deaths in that cohort, so this is a very serious disease for anyone Dr
Eisenbarth stressed that if there was no hypoglycemia and there was good
metabolic control, the mortality rate would change dramatically

Session III: Beta Cell Preservation
Moderator: Ilan Irony, MD, Medical Officer, Division of Therapeutic
Biological Internal
Medicine Products, Center for Drug Evaluation and
Research, FDA

Assessment of Beta Cell Preservation in Type 1 Diabetes
Jerry P Palmer, MD, Professor of Medicine and Director of the Diabetes
Endocrinology Research Center, University of Washington, Seattle; Director
of Endocrinology, Metabolism, and Nutrition, Veterans Affairs Puget Sound
Health Care System, Seattle

Dr Palmer began by stressing that the target of the type 1 auto-immune
disease process is the pancreatic ?-cell, so it makes excellent sense to
try to preserve the function of that target cell Studies of the
preservation of ?-cell function fall into two categories: intervention
studies with persons who already have type 1 diabetes and prevention
studies for those at risk

Dr Palmer noted that intervention studies have, with varying degrees of
success, tested azathioprine and steroids; cyclosporin; anti-CD3, an
antibody to T-cells; and DiaPep 277, a fragment of heat shock protein A
trial of MMF mycophenolate mofetil and DZB has begun in TrialNet, and a
future trial of anti-CD20, a monoclonal antibody directed at ? -cells, is
under consideration

Of the many studies of cyclosporin, Dr Palmer considers the
Canadian-
Diabetes-France Plus Study to be the most important because patients were
randomized, received intensive therapy, and if patients went into
remission, rather than stop the cyclosporin, it was continued until they
again went out of remission The results showed that immunomodulatory
therapy in type 1 diabetes can work Almost 50 percent of patients who
received cyclosporin versus placebo went into remission, defined as being
insulin-free Remissions also were longer in the patients treated with
cyclosporin versus placebo Although these results are remarkable, Dr
Palmer explained that the medical community has essentially decided that
cyclosporin therapy is too toxic a way to try to alter the type 1 disease
process

As Dr Nathan had said earlier, the DPT-1 prevention study showed that
parenteral insulin was not effective, nor was the overall trial for oral
insulin, although in a subset of persons with high auto-antibodies, there
may have been a treatment effect and that is being followed up A large-
scale European trial of nicotinamide also was unsuccessful in preventing
type 1 diabetes The large international Trial to Reduce the Incidence of
type 1 Diabetes in the Genetically
at Risk TRIGR, led by the National
Institute of Child Health and Human Development NICHD, is asking whether
the first formula that an infant uses, whether cow-milk-based or not, has
an effect The primary endpoint of TRIGR is the development of antibodies
and then over 10 years the development of type 1 diabetes

TrialNet, an NIDDK-led international network of 18 regional cooperative
clinical centers in the United States, Canada, Europe, and Australia, has
as its goal to alter the type 1 disease process in those who already have
disease, in relatives at risk of disease, and in those who have a high
genetic risk It also will further define the epidemiology, natural
history, and risk factors of this disease The network has a coordinating
center and core laboratories in genetics, immunology, metabolism,
biochemistry, and viral infections Dr Palmer heads up the ?-cell function
core laboratory

TrialNet selected measurement of C-peptide as the endpoint for its
intervention strategies Dr Palmer listed several of the advantages of C-
peptide as an endpoint In the structure of the proinsulin molecule, C-
peptide connects the ?- and the ?- chains of insulin There is a one-to-one
molar ratio
of insulin to C-peptide in terms of secretion Insulin
undergoes a variable and substantial first-pass extraction in the liver of
up to 50 percent but C-peptide does not For a number of years, there have
been excellent assays that accurately measure the very low levels of C-
peptide in persons with type 1 diabetes These assays are effective even
when treating the patient with insulin, and also the insulin auto-
antibodies that patients develop do not interfere with the assays TrialNet
also is also planning to test omega-3 fatty acids, GLP-1, and oral insulin

Dr Palmer explained that the literature can be confusing because there are
two major ways c-peptide is reported, either as ng/ml or nmol/l; therefore,
it is important to pay attention to which of the units the reader is
seeing The detection limits of the standard assays is 01 ng or 003
nmol/l Dr Palmer stressed that a very important point is that the half-
life for insulin and C-peptide are dramatically different, which is
important in interpreting C-peptide values For insulin, it is about 3
minutes; for C-peptide it is closer to 35 minutes

Factors that affect residual ?-cell function include age at diagnosis,
duration of
diabetes, metabolic control, and marked inter-individual
variation Dr Palmer cited data from TrialNet showing that, in terms of
age at diagnosis, C-peptide is lower in those who are in the 12- to 17-year-
old age group than in those over 18, and it is much lower in those who were
diagnosed prior to age 12

C-peptide was an entry criteria for the DCCT with the cut-point for entry
being stimulated C-peptide of 05 nmol/l Mixed meal tolerance tests
MMTTs were performed on 3,736 type 1 diabetic patients to identify the
1,441 patients who ultimately participated in that study Dr Palmer showed
two slides that plotted the C-peptide levels in those screened, one for
those diagnosed over the age of 18 and one for those diagnosed under the
age of 18 He noted that a remarkably large proportion of people 48
percent who had type 1 diabetes for up to 5 years according to their
physicians diagnoses after the age of 18, still had meaningful and
biologically important C-peptide For those diagnosed under the age of 18,
the values tended to be lower, although again there were a lot of
individuals with C-peptide above 02 nmol/l, a level that has been shown in
a number of studies to be associated with
better diabetes control and less
complications

In the DCCT, those individuals who had diabetes from 1 to 5 years and C-
peptides between 02 and 0 5 nmol/l were brought back each year for a
follow-up mixed meal stimulation test Dr Palmer said the control in the
DCCT had a dramatic effect on C-peptide levels For the 303 individuals
meeting the criteria stated above and randomized to intensive therapy
versus conventional therapy, the intensive group had a 57 percent reduction
in risk of C-peptide falling below 02 Dr Palmer emphasized that DCCT is
the largest and best study showing that intensive glycemic control is a
powerful means to protect underlying ?-cell function

In the feasibility stage of the DCCT, Dr Palmer said one of the things
asked was, How much C-peptide does it take to be important in terms of
metabolism? At the time of screening, patients were divided into those
with very low C-peptides, those between 005 and 01, 01 to 02, and
above 02 Patients above 02 had substantially lower fasting glucose and
HbA1c levels There was evidence for a dose-response curve, because even
though glycemic control becomes significantly better at 02 versus 01
nmol/l c-peptide,, it took
less insulin to achieve the same degree of
control with stimulated c-peptide of 01 nmol/l Similar data were observed
in a later stage of the DCCT In intensively treated patients who were
defined as non-responders ie, with C-peptide less than 02 or
responders, the responders had lower HbA1c Dr Palmer described what he
called a virtuous cycle as opposed to a vicious cycle: Better diabetes
control leads to less ?-cell damage, less ?-cell damage preserves ?-cell
function, which leads to better diabetes control

Dr Palmer presented DCCT data regarding the 3 step change in retinopathy
progression that showed that the intensely treated responders, who achieved
?-cell preservation as measured by C-peptide levels, had a dramatically
greater risk reduction than the non-responders In another analysis of DCCT
data, Dr Palmer showed that those who sustained their C-peptide levels
from entry to 1 year at 021 to 05 had a 46 times difference in
retinopathy and a 44 times difference in albuminuria as a measure of
nephropathy Another observation from the DCCT is that not only is there
better HbA1c and less complications when C-peptide is preserved and thus ?-
cell function, but the Achilles heel of
intensive therapy, namely
hypoglycemia, is also helped In the responders in the intensive treatment
group those with C-peptide above 02, there was a 62-percent risk
reduction in hypoglycemia with coma and seizures

Dr Palmer said there is additional data some of the best from Dr
Christian Binder that demonstrates that stimulated C-peptide around 02 is
the level at which differences in ease of metabolic control and improvement
in complications are clearly seen To show the relationship between C-
peptide and hypoglycemia, Dr Palmer presented data from a Japanese study
Diabetes 37:81-88, 1988 that used what the researchers called a
supersensitive assay, but was really an extraction method The study
recruited patients who were C-peptide negative in a standard assay and
divided them into those who were responders and non-responders to C-peptide
with their supersensitive assay and induced hypoglycemia in these
individuals They then measured glucose, glucagon, epinephrine, nor-
epinephrine, and cortisol The responders had less severe hypoglycemia but
they also had better measurements for the counter-regulatory hormones

Dr Palmer mentioned literature covering a variety of animal and
human
studies with either acute or chronic administration of C-peptide showing
that the possible direct effects of C-peptide include lowering of diabetes-
induced increased blood flow; decreased microalbuminuria, improvement in
nerve conduction velocity and autonomic function, and augmented glucose
utilization Thus, in addition to being a biomarker

Dr Palmers take home home messages about C-peptide were the following:

Excellent assays are available
C-peptide levels are higher than commonly assumed many years after
diagnosis of type 1 diabetes, contrary to the textbooks that say C-
peptide is undetectable 5 years after onset of type 1 diabetes
Glycemic control preserves C-peptide
Preserved C-peptide results in improved glycemic control
Higher C-peptide results in less retinopathy and nephropathy
Higher C-peptide results in less hypoglycemia
C-peptide may have direct beneficial effects beyond being a biomarker for
?-cell function

In conclusion, Dr Palmer listed several ongoing activities on C-peptide as
the primary outcome measure for type 1 diabetes clinical trials to preserve
?-cell function The Immunology of Diabetes Society published
recommendations
Diabetes 52:1059-65, 2003 The report of an American
Diabetes Association-sponsored workshop on markers that could be used for
type 1 intervention studies was recently published Diabetes 53:250-264,
2004 Currently there is a Wet Workshop coordinated by the University of
Missouri on the optimal assay for C-peptide and asking how it can be
standardized so that results are comparable from one lab to another There
is an international program comparing the MMTT, the test usually done on
this side of the Atlantic versus the glucagon-stimulated test GST, the
test done in Europe, to determine how comparable they are and whether one
test is preferable to the other

The Case for ?-Cell Preservation in Type 2 Diabetes Mellitus
Steven Kahn, MB, ChB, Professor of Medicine, Division of Metabolism,
Endocrinology, and Nutrition and Associate Director, Diabetes Endocrinology
Research Center, University of Washington, Seattle; Director of Research
and Development, Veterans Affairs Puget Sound Health Care System, Seattle

Dr Kahn emphasized the importance of looking for markers to identify
persons early on in the development of type 2 diabetes in order to preserve
? cells and ?-cell function He also
stressed the concept that there are
multiple factors that are responsible for the loss of ? cells in type 2
diabetes, which means that scientists need to start thinking outside the
box about how to handle the potential causes of reduction in ?-cell mass
that occurs in type 2 diabetes

Dr Kahn cited data from the UKPDS showing that people with type 2 diabetes
at time of entry into the study only had 50 percent of their ?-cell
function remaining as measured by the HOMA method During the 6-year follow-
up, ?-cell function continued to decline Assuming that the loss of ?-cell
function is linear, if one performed a linear regression and extrapolated
this data back, one could predict that ?-cell function was last normal over
a decade prior to the presentation and enrollment into the study Mr Kahn
noted that data such as that from the UKPDS and other studies is a basic
reason for the increased focus on ? cells

The acute insulin response to glucose, a measure of the ability of the ?
cell to release insulin in response to an intravenous injection of glucose
was used to highlight the deficit in individuals with type 2 diabetes Dr
Kahn demonstrated this with a slide showing the response of a
group of
healthy control subjects and a group of persons with type 2 diabetes who
were given a glucose injection In the control group, prior to the
injection, plasma insulin concentration was stable; then there was a brisk
increase in the plasma concentration in what is called first-phase
response, and then a second-phase response of decreased concentration In
individuals with type 2 diabetes, the first phase response was essentially
absent and the second-phase response was dramatically reduced compared to
the healthy controls, indicating deficient insulin secretion Dr Kahn said
that enhancing ?-cell function and lowering glucose in these patients
clearly would be useful, but it would be better to intervene prior to the
stage of diabetes progression of these individuals to try to preserve ?-
cell function and insulin secretion in general

Dr Kahn stated that understanding what modulates the ? cell is necessary
to address this issue Clearly, the ? cell is modulated by the nature of
the stimulus and the magnitude of the stimulus and by other factors For
example, the first-phase response is markedly diminished in patients with
impaired glucose tolerance IGT On the other hand, healthy
individuals
have a broad range of plasma insulin responses to glucose, thus raising the
question Why? Studies in the late 1980s and early 1990s tried to look at
the impact of insulin sensitivity on acute insulin response It was
recognized that when the ? cell is given a stimulus, it secretes insulin,
which then acts in a variety of tissues that are sensitive to its effect,
the major organ systems being the liver, the muscle, and adipose tissue
Because the insulin response seemed to be so well regulated in not only
bringing the glucose levels down to normal, but also shutting off
appropriately to ensure hypoglycemia does not occur after meals, it was
thought that there must be a feedback loop that controls the magnitude of
the stimulus, either through the bloodstream or through the brain, or
potentially through both systems

In following up the concept of a feedback loop, investigators in Seattle
looked at data from healthy individuals The investigators related the
acute insulin response to glucose as a measure of insulin response of the ?
cell to insulin sensitivity quantified using the minimal model of glucose
kinetics Using data from the 93 healthy subjects, males and females,
they
were able to show mathematically that the relationship between insulin
sensitivity and insulin response is not a straight line, as is commonly
applied to biological assessments, but instead, it is a curve, a hyperbolic
relationship Dr Kahn explained that this hyperbolic relationship means
that insulin sensitivity and insulin response are related in such a manner
that the product of the two-insulin sensitivity times the insulin response-
is a constant An example would be that an individual who had an insulin
sensitivity of 10 and fell on the line that represents the 50th percentile
or mean relationship for the group, for that individual, the insulin
response would be about 250, giving a product of 2,500 sensitivity index
of 10 times a response of 250 An individual with an insulin sensitivity
of 5 also would have a product of 2,500, because the insulin response would
be 500 Thus low sensitivity resulted in high responses This study
supported the concept of a feedback loop and a regulated system that was
dependent on a healthy individuals insulin sensitivity being a determinant
of the magnitude of the persons insulin response, assuming that the
healthy person had normal ?-cell
function

The study with the healthy subjects indicated that if there was insulin
resistance at the level of the insulin-sensitive tissue, because of the
feedback loop, either through the bloodstream or through the brain, the
islet senses that there is a change occurring at the site where insulin is
supposed to act, and it simply increases its insulin output in response to
the stimulus of the glucose injection In type 2 diabetes, Dr Kahn said it
is thought that what happens is either failure of the islet to respond to
the stimulus or failure of the feedback loop to be operating normally This
failure results in a reduction in insulin secretion and development of
hyperglycemia in individuals who have insulin resistance, as seen typically
with obesity

Dr Kahn asked how this understanding could help researchers develop
approaches to identify persons at high risk for type 2 diabetes who could
then be the subjects of intervention trials using therapies and compounds,
other than those from DPP, at early stages He also asked how could
biomarkers be identified, such as measures of secretion and sensitivity,
that could be used as endpoints instead of full-blown diabetes, which would
reduce
the need for large-scale, expensive clinical trials

To address the questions he had raised, Dr Kahn referred the audience
again to the data and curve from the study with the 93 healthy individuals
Researchers calculated percentiles for the relationship between insulin
sensitivity and insulin secretion based on a pair of numbers for those two
variables for any individual Based on these percentile plots and data from
other studies performed in Seattle and studies by others, Dr Kahn
illustrated the concept that diabetes is a disease where there is both
insulin resistance and a loss of the insulin response by showing that
individuals developing type 2 diabetes and those who are at high risk have
reduced percentile values for the relationship between insulin sensitivity
and insulin secretion

To illustrate how this measurement model and the calculated percentiles
could be used to identify those who are likely to progress to diabetes, Dr
Kahn presented data from several studies It was previously believed that
it was insulin resistance that begets type 2 diabetes and that persons with
impaired glucose tolerance did not have a ?-cell defect because they did
produce insulin Mr Kahn offered
data from a study at Emory University of
individuals with type 2 diabetes who had an insulin sensitivity index of 1
and an insulin response of 150 picomoles/liter and thus were very insulin
deficient He compared this study with a study in Chicago with individuals
with IGT who were as insulin resistant as the group from Emory but had an
insulin response of 500 producing only 20 percent of the normal product of
2,500 Based on their insulin sensitivity index and their insulin
response, the IGT persons already had severe ?-cell dysfunction and were
headed towards developing type 2 diabetes This was also true for a group
of elderly subjects in Seattle who had an insulin sensitivity of 3, an
insulin response of 250, giving a product of 750-again far below the norm
of 2,500, placing them on the 2nd percentile in the hyperbolic relationship
and thus progressing in the direction of full-blown diabetes Other groups
recognized as being at very high risk for type 2 diabetes are women with a
history of gestational diabetes GDM, who convert to diabetes at a rate of
approximately 10 percent per year, and women with polycystic ovarian
syndrome Studies with these groups and with a group of
relatives of
individuals with type 2 diabetes placed them at the 5th GDMs, 17th
polycystic ovarian syndrome, and 25th relatives percentiles,
respectively, showing that each group was at risk for developing type 2
diabetes

Another Seattle study of 34 first-degree relatives of persons with type 2
diabetes looked at a variety of parameters At baseline in 1994, their BMI
put them in the overweight category Over the 7 years of follow-up, they
gained weight and in 2001 were classified as being obese This weight gain
appeared to be central; waist circumference increased but hip circumference
did not change significantly Their fasting glucose and fasting insulin
concentrations also did not change dramatically Their fasting glucose was
well below 100 Dr Kahn noted that fasting glucose and progression to
diabetes is a late phenomenon; therefore, other biomarkers, possibly 2-hour
glucoses, are needed to diagnose diabetes risk and progression earlier
Over the 7 years of the study, the 34 subjects had a 7-percent reduction in
insulin sensitivity and a 16-percent decrease in acute insulin response to
glucose, placing them at the 15th percentile for relationship between
insulin sensitivity and
insulin secretion, in keeping with the progressive
loss of ?-cell function over the follow-up period Over the 7 years, there
was also deterioration in glucose tolerance as measured by an oral glucose
tolerance test OGTT In 1994, approximately 50 percent had IGT and 50
percent normal glucose tolerance In 2002, less than 50 percent were normal
and more than 20 percent had progressed to type 2 diabetes

Further information gained from this study of first-degree relatives showed
that those who initially had normal glucose tolerance measured by OGTT but
did not maintain this over the 7 years also initially fell into a lower
percentile based on insulin sensitivity and insulin response than those
who maintained their normal glucose tolerance In other words, they already
had an abnormality in ?-cell function even with normal glucose tolerance, a
point in time when no one would have considered intervening with them or
testing them in a clinical trial to prevent progression to impaired glucose
tolerance and later diabetes In the group that maintained normal glucose
tolerance for 7 years, ?-cell function barely changed according to their
insulin sensitivity/insulin response measurements and
percentiles Dr Kahn
suggested that in finding biomarkers of ?-cell function, there is a
potential to identify high-risk individuals much, much earlier than is done
currently with IGT and to intervene with them to try to preserve ? cells
and ?-cell function and thus hopefully prevent type 2 diabetes

Dr Kahn referred to a Pima Indian study Weyer C et al J Clin Invest
104:787-794; 1999 highlighting that pathophysiology of diabetes in Native
Americans is very similar to that of other US population groups Insulin
sensitivity was measured by the clamp technique Thirty-one persons
maintained normal glucose tolerance over the 5 years of follow-up, and
although they became more insulin resistant over time, their ? cells simply
increased insulin secretion to compensate, keeping them on their curves and
thus maintaining normal glucose tolerance In contrast, there were a group
of individuals who progressed, over the 5 years of follow-up, from normal
glucose tolerance to impaired glucose tolerance, and then on to diabetes
These individuals had a fall in insulin secretion over time resulting in a
deterioration of glucose tolerance and also development of diabetes Again,
these individuals at
baseline had a markedly disturbed relationship between
their insulin sensitivity and their insulin secretion, which Dr Kahn
believes indicates the presence of ?-cell dysfunction He repeated that
this marker of insulin sensitivity related to insulin secretion could
therefore identify persons with normal glucose tolerance who actually are
at high risk and who could be recruited for prevention studies
investigating a variety of agents that might preserve ?-cell function
before they reached the high-risk category of the DPP cohort who had
impaired glucose tolerance

In discussing the problems with the OGTT, Dr Kahn referred to data from an
American Diabetes Association study of first degree relatives of persons
with type 2 diabetes Of these 513 people given an OGTT at baseline, 100
were unaware that they already had diabetes, 191 had IGT, and 240 had
normal glucose tolerance From the early insulin response during the OGTT,
it became evident that ?-cell dysfunction was a characteristic not only of
type 2 diabetes but also of IGT Based on this and similar data, Dr Kahn
recommended using measures that are more sophisticated than the OGTT in
order to show subtle defects very early on
before hyperinsulinemia leads to
?-cell failure

Dr Kahn listed glucotoxicity, lipotoxicity, and loss of ?-cell mass as
possible causes of ?-cell dysfunction in type 2 diabetes A study of
autopsy samples of ?-cell mass from non-diabetic obese individuals based
on BMI criteria and non-diabetic lean individuals Butler, AE et al
Diabetes 52:102-110, 2003 showed that the obese persons had substantially
greater ?-cell volume compared to the lean persons, possibly as a
compensation mechanism by which the obese person increased insulin response
to insulin resistance On the other hand, obese persons with impaired
fasting glucose had decreased ?-cell volume compared to those with normal
glucose tolerance Both the obese and the lean persons with type 2 diabetes
had ?-cell volume lower than that of either group of non-diabetic subjects,
indicating that there is an association between diabetes and ?-cell mass

Why does this reduction in ?-cell mass occur? One hypothesis is that islet
amyloid deposits replace ?-cells in persons with diabetes In Alzheimers
disease, deposition of amyloid in the brain is a cause of the mental
changes in the disease The amyloid is deposited at a local site where
a
unique peptide component for those deposits is produced Similarly, in type
2 diabetes, in the islet amyloid deposits is the peptide islet amyloid
polypeptide IAPP, also known as amylin, which is a unique 37 amino acid
peptide This peptide has a critical amino acid sequence between amino
acids 20 and 29 that gives it the amyloidogenic potential in humans Dr
Kahn said that a problem in studying diabetes in animal models is that, in
rodents, amino acid substitutions in the 20 and 29 amino acid region of the
molecule result in an inability of the IAPP or amylin molecule to form
deposits; therefore, unless the animal is transgenic, it never develops
amyloid deposits as seen in humans with type 2 diabetes Dr Kahn said
another important answer to be found is why the peptide forms deposits in
diabetics and not in non-diabetics

Dr Kahn explained that his group has developed a microscope-based system
to quantify islet area, ?-cell area, and amyloid area and also developed
measures to show how much amyloid is being deposited and how much ?-cell
mass might be lost Using these measures, they can quantify for an
individual the number of their islets that have amyloid deposits, the
amount of
amyloid deposited in each islet, and thus the severity of the
amyloid deposition Dr Kahn said that the data generated to be shown at
the ADA meeting in June suggest that the development of amyloid is a
diffuse process that involves all islets, and as the degree of the disease
is progressing, the degree of amyloid deposition also increases and ?-cell
mass decreases in a strong inverse relationship to the severity of the
amyloid deposition Dr Kahn explained that what is not known is whether
the decrease in ?-cell mass occurs before or after the amyloid development;
however, studies in the transgenic mouse strongly suggest that amyloid
deposits develop long before hyperglycemia, which indicates that amyloid
may play a role in the loss of islet ?-cell function in type 2 diabetes

In the transgenic mouse, as in humans, amyloid deposition occurs profusely
and involves nearly all the islets before it starts to become severe and
replaces ? cells Increasing dietary fat in these mice increases amyloid
deposition, an interesting observation since the incidence of diabetes is
increasing and is related, at least partially, to the environment,
decreased exercise, and increased fat consumption Dr
Kahn added that,
unlike what has been suggested with Alzheimers disease and mouse models of
Alzheimers disease, apoE is not a critical component required for amyloid
deposition in islets in these mice

Dr Kahn said that studies with the transgenic mouse are very valuable
because equivalent studies in humans would be very difficult Other
information derived from the studies includes that in the transgenic mice
that are getting amyloid deposits, there is an increased rate of apoptosis
and the magnitude of amyloid deposition is positively correlated to the
rate of ?-cell death, suggesting strongly that amyloid formation in islets
increases apoptosis and ?-cell death The amyloid deposition also
suppresses the islets normal regenerative response to build ?-cell mass in
response to the apoptosis and ?-cell death Dr Kahn expects that these two
effects of amyloid deposition-suppression of regenerative response and ?-
cell death-also occur in human type 2 diabetes with, ultimately, loss of ?-
cell mass, which contributes to the development of hyperglycemia

Dr Kahn reviewed information from another transgenic mouse study in which
there were three groups: a control group, a growth group
given
rosiglitazone, and a group given metformin The mice were fed high-fat
diets for a year In the control mice, 32 percent had amyloid compared to
about 10 percent of the mice in the rosiglitazone and metformin groups,
indicating that the drugs did not prevent amyloid formation in these mice
but they did reduce it Both of the drugs also had dramatic effects on the
severity of amyloid measured by the number of islets containing amyloid
deposits and the amount of amyloid within these islets Dr Kahn
recommended that these studies be followed up

Dr Kahn pointed out that one of the difficulties of studying amyloid in
models of type 2 diabetes is that such studies take a year to produce data
Clearly, one wants to be able to test compounds that work earlier in the
diabetes cycle As an example, he presented a slide from an in vitro study
in which an islet from an hlAPP transgenic mouse that had been cultured in
167 mM glucose already showed amyloid deposition in just 1 week Using
this system, Dr Kahns group was able to test an agent that more or less
obliterated amyloid formation This compound, of course, is no where close
to being applied to type 2 diabetes There is still a great deal
of work to
be done both by the pharmaceutical industry and those in academia to
understand the ? cell, why its function declines, and how to preserve it
He suggested that amyloid inhibition might be one of the possible
approaches down the road

In conclusion, Dr Kahn acknowledged the work of outstanding post-doctoral
fellows and faculty members of the University of Washington with whom he
has collaborated, the researchers from around the world for their
contributions to the field, and those people who participate in clinical
trials He expressed his appreciation to ADA for their support and seed
money for the transgenic mouse studies, without which the field could not
be where it is today He also thanked NIDDK for support for clinical
studies and the amyloid studies; the VA for its career development grants,
and GlaxoSmithKline, which supported the studies in rosiglitazone

Discussion

To begin the discussion, Dr Irony asked Dr Palmer which he considered the
best approach to use to investigate products that would protect ?-cells in
patients with type 1 diabetes-C-peptide with a mixed meal tolerance test or
a glucagon stimulation test Dr Palmer
responded that part of the reason
for international collaboration being authorized as part of TrialNet is to
answer the crucial question of whether or not one gets differences in C-
peptide response with an MMTT versus a glucagon stimulation test The MMTT
usually takes 2 hours, but can take 4 hours The glucagon stimulation test
is classically done with a baseline measurement and then one measurement 6
minutes later, after a 1mg dose of intravenous glucagon Thus the tests are
dramatically different in terms of how the ? cells are stimulated The
small amount of data available suggests that in normal controls the tests
will give comparable responses What still needs to be asked is What is
the difference in people with diabetes? and As people progress toward
diabetes, does one of the tests give you a different answer?

Next Dr Irony asked Dr Kahn, With regard to the continuum of impaired
glucose tolerance and impaired fasting glucose as an individual moves
toward type 2 diabetes and with the availability of potential treatments in
the future for earlier conditions of ?-cell defects, will diabetes again be
redefined as tends to happen as treatments become available for diseases?
Dr Kahn
answered that, in fact, there has recently been a change in the
criteria for impaired fasting glucose from 110 to 100, which prompted that
weeks announcement about how many more people are at risk for developing
diabetes During DPP, the definition of diabetes as a fasting glucose level
was reduced from 140 to 126, which was clearly a challenge for a clinical
trial, but showed the potential in a clinical trial to adapt to changes
occurring in the outside world Dr Kahn felt this would continue to happen
down the road as he thinks the change in impaired fasting glucose was the
first step and he believes the criteria for diagnosing type 2 diabetes in
terms of fasting glucose is also going to be lowered, because there is a
disconnect between the fasting response and the 2-hour response In part,
this change also will be driven by clinical trials Dr Kahn recommended
that clinicians and investigators work with FDA to ensure that some of the
treatments that are being defined for diabetes are not limited to diabetes
but are moved into the general public health arena The metformin results
from DPP would be a good example as well as the lifestyle changes

Based on Dr Palmers presentation of
C-peptide as a good reflection of ?-
cell mass and Dr Kahns data that ?-cell function is reflected by dynamic
tests of insulin secretion, the question was asked if it was possible that
in the DCCT, adolescents in whom C-peptide was present were actually a
subgroup of patients with a different disorder, such as metabolic syndrome
or type 2 diabetes presenting at a younger age Or conversely, can people
with type 2 diabetes who progress to decreased ?-cell mass be reflected by
studies of on Dr Palmers presentation of C-peptide as a good reflection
of ?-cell mass and Dr Kahns data that ? function without measuring C-
peptide?

Dr Palmer replied that he would not want to leave the impression that C-
peptide is a good measure of ?-cell mass, but rather that there is a
correlation between ?-cell mass and all measures of ?-cell function ?-cell
function is really what is being measured by C-peptide, which is not
equivalent to measuring ?-cell mass He stressed that for type 1 diabetes,
and possibly also for type 2, part of the disease process is damaged ?
cells, not necessarily dead ? cells In animal models and increasingly in
humans, with aggressive treatment, especially glycemic treatment,
but also
with immunologic treatment in the animal models, there is a surprising
recovery of ?-cell function

Dr Kahn agreed that measuring ?-cell function is difficult and that C-
peptide has become the best way to do so in type 1 diabetes because those
individuals are being treated with insulin There are arguments to use C-
peptide in type 2 diabetes as well, since hepatic clearance, which can be
so variable, does not come into play The problem is the expense It is
easier to measure insulin, especially with ADAs move to have the insulin
assay standardized; therefore, it may be that insulin will be used in most
instances Dr Kahn also agreed that C-peptide is not truly a measure of ?-
cell mass Also, he did not wish to leave the impression that ?-cell mass
is all that is wrong with type 2 diabetes He suggested there is a
functional defect that might actually contribute to the amyloid formation
Amyloid formation and loss of ?-cell mass appear to go hand-in-hand in
contributing to the loss of insulin secretion

Dr Kahn continued that the issue of how best to assess this is a real
problem, because clearly the intravenous tests he described in his
presentation are not ones that can be
done in the clinic in large-scale
clinical trials, whether they are NIH-based clinical trials or
pharmaceutical-based clinical trials He did think that with the use of
more precise measures of ?-cell function, the number of individuals needed
in some of these trials could be reduced and it may even be possible to use
some of these measures, rather than glucose, as biomarkers when one is
making assessments in clinical trials aimed at preventing ?-cell loss By
reducing the number of subjects in clinical trials, Dr Kahn believes more
centers can do the studies, and, hopefully, in time the FDA and other
groups will look on tests and approaches like this as ways to assess early
disease and enable us to develop interventions He also felt that assessing
interventions early on in people with normal glucose tolerance to see if
this would prevent diabetes would require many years of follow-up, which
would be extremely difficult and expensive

As an aside, Dr Kahn noted that he and Dr Harry Shamoon and Dr Bill
Knowler have been involved in writing up the insulin secretion and
sensitivity data from the DPP and that data indicates that the lifestyle
intervention, which did best in preventing or
delaying diabetes, also had
the most effect in improving ?-cell function OGTT-derived measures were
used to measure this and could certainly be used in clinical trials to look
at compounds and how they might change sensitivity and ?-cell function

Dr Alan Moses, Novo Nordisk Pharmaceuticals, commented that he agreed
about the need to do better in terms of assessing both ?-cell mass and
function, particularly in looking to drugs to change the early natural
history of type 2 diabetes He asked if the UKPDS curve based on the HOMA
method was a linear curve or was it a combination of lipotoxicity, perhaps
glucotoxicity, at very mild levels of hyperglycemia, and perhaps amyloid
accumulation that made it something other than a linear curve Dr Kahn
said that it was possible that it was linear at that point in time In more
recent studies trying to measure secretory capacity by raising the glucose
to the maximum level above 450 mg/dl and then giving a stimulus like
arginine, to examine at ?-cell secretory capacity, it was found that the
relationship between ?-cell function and hyperglycemia is a curve as well
Individuals can lose 75 percent or more of ?-cell function before
developing
hyperglycemia

In response to a question about how the curves of insulin sensitivity
versus insulin secretion might vary for different categories of obesity in
early pre-diabetes and whether they would be shifted from those observed
in subjects with normal glucose tolerance, Dr Kahn answered that their
data with people of varying BMIs indicated that in older people and in
those with impaired fasting glucose, the curves, and they are definitely
hyperbolic curves in these other groups, are shifted down and to the left
Dr Kahn felt these curves indicate that, in people at very high risk,
simply using the product of the two measures-insulin sensitivity index and
insulin secretion-as a measure of ?-cell function might be a way of
following these individuals down the road

The question was asked whether the subjects in UKPDS who developed diabetes
might actually never have had normal ?-cell function and in relation to
islet volume measurements in those people who progressed to diabetes versus
those who did not, could the difference in the two groups been a defect in
?-cell volume to begin with in those who got diabetes Dr Kahn replied
that he believed that diabetes is certainly a
genetic and an environmental
disease If these subjects could have been studied at 2 years of age, he
thought that those who later developed diabetes at 65 probably already had
decreased secretion at 2 In other words, there was probably a genetic
component in those who developed diabetes, but that increased dietary fat
and other environmental factors that contribute to obesity have a very
deleterious impact on insulin secretion and thus, it was the environment,
in Dr Kahns opinion, that was the major player in what happened to
individuals who were genetically predisposed to develop ?-cell dysfunction
and diabetes

With regard to islet mass, Dr Kahn thought that islet mass might
genetically also be reduced Most of the genes that have been identified so
far for diabetes appear to be transcription factors, such as PDX1, which is
a major player in terms of islet development However these people had not
been studied in this regard In animal studies using systems with nuclear
staining and counting cells and looking at islet adaptation to higher fat
diets and obesity, there is ?-cell hyperplasia, but not hypertrophy or much
neogenesis Based on these studies, it is thought that there is
replication
occurring within the ? cell In mice, a very strong linear relationship has
been observed between the degree of adiposity in the mice and the number of
? cells The question again is that if this is a linear relationship, would
it have been monolinear up at the top in these animals? Dr Kahn said they
really do not know what is normal His guess would be that in humans ?
-cell mass might be genetically determined in part and then the environment
has a detrimental effect, restricting complete ?-cell adaptation, along
with other factors such as amyloids

Dr Amy Rosenberg, FDA, asked Dr Kahn if his group had dissected further
the amylin protein in the transgenic mice to target the particular amino
acids involved in the amyloid deposition She also asked why he felt fat
per se results in lipotoxicity If the mice had a high-fat diet but
calories were controlled, would there still be lipotoxicity and does the
kind of fat make a difference?

Dr Kahn replied that in terms of the amino acid sequence in the animals,
the transgenic mouse was created because normal mice have protein
substitutions in their 20 to 29 amino acid sequence that appear to be
critical Mice and rats never get
amyloid Monkeys, cats, and dogs do get
amyloid, so the sequence appears to be critical His group has not worked
further with this subject With regard to fats, in vitro studies have
clearly shown that fatty acids are deleterious in terms of islet function
and insulin secretion This seems to vary a bit, depending on the fatty
acid employed The high-fat diets in the transgenic mice were the high-fat
diets associated with obesity and what was seen was that insulin secretion
appeared to be disturbed A similar result was seen with dogs fed a high
fat diet These animals developed obesity, insulin resistance, ?-cell
dysfunction, and thus glucose intolerance Dr Kahn added that the
mechanism by which the high-fat diet is producing this effect in vivo is
unclear and this is one of the limitations of doing clinical physiology in
humans or animals

Session IV: Islet Transplantation
Moderators: Cynthia Rask, MD, Division Director, Office of Cellular,
Tissue, and Gene Therapies, Center for Biologics Evaluation and Research,
and Richard McFarland, PhD, MD, Medical Officer, Office of Cellular,
Tissue, and Gene Therapies, Center for Biologics Evaluation and Research,
FDA

Islet Transplants: Past,
Present, and Future
Bernard J Hering, MD, Director of the Islet Transplant Program, Associate
Director of the Diabetes Institute for Immunology and Transplantation, and
Associate Professor of Surgery, University of Minnesota; Co-Director, JDRF
Islet Transplant Center, University of California/University of Minnesota

Dr Hering pointed out that it is important to recruit many more
investigators to capitalize on the current opportunities for developing
islet translation to a viable and widely available treatment option for
people with type 1 and type 2 diabetes In the past, the challenge has been
to achieve and to restore insulin independence The challenge now is how to
implement what we have accomplished For the future, innovation will be
critically needed

The Past Dr Hering listed three barriers in the past that challenged
achieving insulin independence: low engrafted islet mass, high metabolic
demand, and immunologic graft loss It was felt that the islet mass
transplanted was inadequate, that the engraftment of islets was impaired by
hypoxia and immunity, and that the function of the engrafted islet mass was
compromised by insulin resistance and by impaired insulin secretion
caused
by diabetogenic drugs and possibly by underlying diabetes itself At that
time,
islets were subject to rejection and beta-cell toxic immunosuppressive
regimens

Dr Hering briefly reviewed the 30-year history of islet transplantation:

1974: First transplant was performed by Drs John Najarian and David
Sutherland Basic components of the 1974 protocol have remained much the
same Islets are still recovered from deceased donors, collagenase and
density gradients are used, islets are infused into the portal vein, and
anti-lymphocyte globulin or other T-cell antibodies are used for
recipient treatment
Late 1980s: Dr Ricordi made a significant contribution by developing a
new technique for islet isolation from the human pancreas
1990: First, well-documented case of insulin independence was reported by
Drs David Scharp and Paul Lacy using islets prepared from two donor
organs The type 1 diabetes patient achieved insulin independence 10 days
after transplantation and glucose control remained fairly stable
1990: Pittsburgh group reported on nine simultaneous islet liver
transplants in patients with surgical diabetes, using a prednisone-free

protocol Seven of nine patients became insulin independent, and at 1
year, five of the nine had remained insulin independent-a remarkable
success rate in patients with surgical diabetes
1991 and 1992: Edmonton group used islets from one fresh pancreas
together with cryopreserved islets from four additional donors 10,000
islet equivalents per kilogram and reported the first example of insulin
independence and euglycemia for more than 1 year duration after islet
transplantation in Type 1 diabetes
1992: Dr Hering and others developed the Geissen protocol that
successfully prevented islet graft failure in most of their patients
Outcome was measured in basal C-peptide levels exceeding 1 nanogram per
ml Insulin independence was achieved in about one-third of patients
treated with high-dose cyclosporin and prednisone after a single-donor
islet transplantation
1993: Dr Paul Gores reported on insulin independence in type 1 diabetes
after a single donor transplantation using unpurified islets
1998: First type 1 diabetic islet recipient remaining insulin independent
for more than 5 years, was reported by Washington University, St Louis
2000: Dr
Shapiro reported an 85-percent success rate for insulin
independence at 1 year post-transplant using a modified Edmonton protocol
with a new streptomycin-based, steroid-free, immunosuppressive and islets
from two to three donor organs

Dr Hering stated that the Edmonton protocol changed the field He felt the
high rate of insulin independence achieved was probably due to the
increased islet mass engrafted, the lowering of metabolic demand, and the
new protocols prevention of graft loss due to autoimmunity and allo-
immunity More than 300 patients have received transplants following the
Edmonton protocol, with a number of groups achieving success rates as high
or nearly as high as at Edmonton

The Present Dr Hering named several current concerns in making successful
islet transplantation available to more persons who suffer from difficult-
to-manage diabetes These included the low efficiency of the procedure,
safety issues, limited availability, and uneven integration of the
procedure into the diabetes care community Specific questions within these
concerns are: What is the cost utility, what is the duration of successful
islet transplants, do we need multiple donors, is the
academic setting
adequate to deliver against demand, how do we resolve the logistics of
pancreas allocation, will third-party reimbursement bear the cost, what are
the risks of the procedure, and importantly, what are the risks of long-
term immunosuppression, are those risks known, and what would be the most
adequate approach? Dr Herings priorities to address these issues were to
focus on single donor islet transplants, steroid- and calcineurin inhibitor-
free regimens, the FDA biologics license application, and randomized
clinical trials to determine when to use islet transplantation versus
insulin therapy

Single-Donor Islet Transplant Approaches Dr Herings rationale for single-
donor islet transplantation was based on the fact that a second transplant
increases cost by 75,000, which cannot be handled easily; single-donor
transplants allow ultimate validation of islet potency assays, which is
important to move the field forward and to improve islet processing
techniques; and single-donor transplants facilitate evaluation of
immunotherapeutic protocols He added that adopting single-donor
transplants will promote FDA approval and insurance coverage, promote donor
pancreas
allocation to islet patients, and therefore promote overall
availability of islet transplantation

A new approach and protocols have been developed by Dr Hering and his
colleague, Dr Jeffrey Bluestone, for successful transplantation of
cultured islets from two-layer, preserved pancreases with anti-CD3 antibody
immunotherapy Four of six recipients achieved and maintained insulin
independence after single-donor transplantation The basic approach uses
maintenance treatment as described by the Edmonton protocol Dr Hering
used two additional protocols, one of which involved the addition of a
soluble TNF tumor necrosis factor receptor blocker to mitigate early
inflammatory responses to the transplant islets and rabbit antithymocyte
globulin ATG Dr Hering stated that immunotherapy with a new generation
anti-CD3 antibody may facilitate minimization of maintenance
immunosuppression Hering et al, Am J Transplantation 4:390-401, 2004

Patients with sustained insulin independence after single-donor islet
transplantation showed acceptable metabolic control with normal HbA1c
levels, normal OGT responses in 8 of 10 recipients, and acceptable acute C-
peptide and insulin responses to arginine and
insulin Hypoglycemia was
avoided in all recipients who suffered from recurrent episodes of severe
hypoglycemia pre-transplant There were no prolonged serious adverse
events, procedural complications, or opportunistic infections Dr Hering
explained that studies indicate that different induction protocols may
produce a different engraftment index ie, the acute C-peptide response
to arginine, divided by the transplanted islet mass per kilogram
Preliminary data suggest that the addition of soluble TNF-receptor blockers
could promote engraftment of transplanted islets Based on successful use
of this protocol in a series of 20 recipients, Dr Hering believes it
possible to build on the achievement and make it available to more centers
for single-donor transplants

Dr Hering suggested the following as other opportunities to achieve single-
donor success on a more consistent basis: improvement of islet mass and
potency by working on donor pre-treatment, pancreas preservation, using
recombinant enzymes, process engineering, and gene transfer and protein
transduction for the purpose of protecting islets during processing For
example, in islet processing what will be important is having a
validated,
reliable, preferably real-time assay of islet ?-cell mass and potency,
which is an area in which Dr Hering and others have been working Dr
Hering presented a slide showing there are now real-time release assays
that show very good correlation with post-transplant function, the ?-cell
mass per kilogram, oxygen consumption rate OCR per DNA, and ATP
adenosine triphosphate His example from work done by Drs Papas,
Koulmanda, Weir, Colton, Ikle, and Nelson showed that in the rat-to-mouse
model, the assay had a predictive value of 89 percent, a sensitivity of 93
percent, and a specificity of 94 percent By plotting OCR per DNA as a
measure of the fraction of viability of tissue and the implanted viable
islet equivalents, then, with a very low dose of islets, just 75 islet
equivalents per mouse, diabetes can be reversed with a high fraction of
viability As the fraction of viability decreases, probability will
decrease The example also showed that even a very high number of islets
will not reverse diabetes if the fraction of viability is below 75 nanomole
per minute per milligram DNA Dr Hering said there is more and more
information from human islet transplants and pig islet
transplants
suggesting that this probability of transplant success based on OCR per DNA
and viable islet equivalents per kilogram is also present in pre-clinical
and clinical situations

Dr Hering suggested an islet engraftment can be optimized by targeting
immunity through developing new islet delivery techniques using
biodegradable scaffolds or using pro-angiogenic, anti-apoptotic, anti-
inflammatory, and immunoregulatory peptides One islet implantation site
that his center has become interested in is the small intestine subserosal
space, a highly vascularized space In a pig islet transplant model,
diabetes was reversed and outcomes were comparable with an intraportal
islet transplantation site Local immunotherapy can possibly be easily
performed at this site and promote engraftment and survival

Steroid and CNI-Free Regimens According to Dr Hering, lower metabolic
demand can be achieved by avoiding both corticosteroids and calcineurin
inhibitors Two protocols have recently been developed: one based on CD28
blockade using LEA29Y, a CTLA4 IG mutant, and a second one based on FTY720
Compared with the Edmonton protocol, the protocol published by the Emery
group basically replaced
the calcineurin inhibitor, FK506, with LEA29Y
Work done at Dr Herings institution, in collaboration with Miami, used
FTY720 instead of FK506 This approach lacked islet, kidney, and
cardiovascular toxicity The impact on protective immunity is unknown, but
Dr Hering considers this a very promising development With LEA29Y, it was
possible to reverse diabetes and protect transplant islets, whereas in the
control group, all animals rejected the islets With FDY720, basiliximab,
and RAD a rapamycin derivative, again it was possible to prevent
rejection in a non-human primate transplant model It was also possible to
reverse diabetes with a very low islet dose of 5,000 islet equivalents per
kilogram, and animals became insulin independent and remained euglycemic
after discontinuation of insulin, suggesting that avoiding calcineurin
inhibitors may promote engraftment and may improve insulin secretion

FDA Biologics Response Modifiers Advisory Committee In October 2003, FDA
hosted a meeting focused on islet transplantation and addressing
manufacturing and clinical study design issues related to clinical trials
designed to support a biologics license for human islets The Biological
Response
Modifiers Advisory Committee was asked to review the status of the
field Dr Hering thought the consensus in the field was that control and
consistency of islet manufacturing has progressed to the point that a
license could possibly be considered More work will be necessary in the
area of islet potency assays, and it was unclear whether substantial
evidence of safety and effectiveness are available A proposed indication
on labeling also was discussed Restoring euglycemia in type 1 diabetes as
a clinical endpoint was also considered

Dr Hering emphasized that for a small subgroup of people with type 1
diabetes who suffer from recurrent episodes of severe hypoglycemia, islet
transplants can achieve remarkable improvement He added this is important
in relationship to the DCCT findings that risk can be reduced but not
without increasing the rate of hypoglycemia He presented several slides
supporting his statement

Randomized Trials and Islet Transplantation Vs Insulin Therapy Dr Hering
said the current overall question is whether the field has developed to the
point where randomized clinical trials should be considered Other
questions include whether to focus on hypoglycemia-associated
autonomic
failure, whether costs per quality-adjusted life year can be approved, and
whether to focus on chronic complications and ask if microvascular lesions
in type 1 diabetic patients with, for example, microalbuminuria treated
with renin angiotensin system blockers RASB, will continue to progress if
normal glycemia is not restored There is emerging consensus in the field
that randomized clinical trials are probably needed to document the
benefits of islet transplantation Dr Hering noted that a lot of support
has been provided by NIH and the field has clearly benefited from this
support and by FDAs interest He felt additional Federal agencies will
need to be involved in the trials Pancreas allocation and health insurance
coverage are two very important issues In support of initiating trials,
Dr Hering stressed that progress has been made in islet transplantation;
efficiency and safety have improved He cited integration and availability
as important areas requiring further work

The Future Dr Hering emphasized that innovation is needed, for example to
develop a state of immunologic tolerance and to provide an unlimited ?-cell
source or possibly ?-cell replication in
situ

Immunologic Tolerance The current paradigm suggests depletion of
pathogenic T-cells and establishment of a state of regulation is necessary
to achieve stable and robust tolerance This has become possible, as
reported by the Alabama group, with anti-CD3 immunotoxin combined with
deoxyspergualin 15-DSG, which inhibits allo-immunity, dendritic cell
maturation, and antigen presentation Dr Terry Stroms group developed
another apparently successful approach in a very difficult NOD mouse model
and also in non-human primates, involving three different strategies-
rapamycin, agonist interleukin 2, and antagonist interleukin 15-promoting
deletion and regulation

With support provided by the Immune Tolerance Network, Dr Herings group
will begin testing anti-CD3 immunotherapy with rapamycin to see if it can
achieve tolerance in type 1 diabetic islet recipients It has been shown
that this antibody can actually lead to a contraction of 85 to 01 percent
of the anti-T-cell repertoire in the peripheral circulation A striking
increase in the percentage of regulatory T-cells after immunotherapy with
this antibody has been noted, suggesting that tolerance could possibly be
accomplished A paper
published on-line suggests a 40,000-fold expansion of
CD25CD4 T-cells ex vivo over a period of only 3 or 4 weeks

?-Cell Source A number of different strategies have been proposed to
develop a ?-cell source including maximization of decreased donor pancreas
utilization, living donor islet transplants, xenogeneic islet transplants,
precursor cell-derived islet beta cell transplants, and beta cell
replication in situ Dr Hering believes ?-cell mass and supply for
transplantation can be increased Pig islets are already being tested in
animal studies

In the area of xenotransplantation, Dr Herings center transplanted pig
islets into immunosuppressed diabetic monkeys and demonstrated reversal of
diabetes Normal glycemia was achieved for more than 100 days A liver
biopsy showed 90 percent of islets without any evidence of infiltration
Dr Hering stated a number of strategies are becoming available to decrease
immunosuppressive risks It was his opinion that adult stem cell-derived
islets probably would not become a source A paper by Dr Douglas Melton
Nature 429:41-46, 2004 suggested that new ?-cells are formed by self-
duplication of pre-existing ?-cells and are not formed by stem
or
progenitor cells during adult life Dr Hering thought the other important
message from the paper is that there is a very high proliferative capacity
and turnover of terminally differentiated ?-cells The question is, Can
this capacity be exploited for expansion to a clinically useful mass?
Also, with respect to islet transplantation, Is the longevity of islet
transplants determined by the proliferative potential of transplanted ?-
cells? Dr Hering continued that Dr Peter Butler keeps reminding him
that, based on mathematical modeling, transplants can only last for 5
years, unless there is replication of transplanted ?-cells Dr Hering
believes, from clinical observations, that replication happens He gave as
an example an islet auto-transplant patient with chronic pancreatitis who
has been insulin independent and normal glycemic for 20 years, suggesting
islets can survive long-term; this may also be evidence of intrahepatic
islet replication more than neogenesis

In conclusion, Dr Hering said cell-based therapeutics will soon play an
increasingly significant role in diabetes care, particularly if
documentation of benefits of islet transplants using clinically relevant
endpoints is
possible Considerable effort and new concepts will be needed
to overcome translational obstacles in the implementation and integration
of cell-based therapeutics into the healthcare system

Obstacles and Hurdles Facing the Clinical Application of Islet
Transplantation
Robert S Sherwin, MD, CNH Long Professor of Medicine and Director,
Diabetes Endocrinology Research Center and General Clinical Research
Center, Yale University School of Medicine

Dr Sherwin explained that he became interested in the issues of islet
transplantation as a diabetologist and an ad hoc member of the Biological
Response Modifiers Advisory Committee As Dr Hering said, the Edmonton
study was the turning point in the story of islet transplantation Today
there are remarkable improvements, but we still cannot ensure normality for
people with islet transplantation, only about 50 percent of whom become
insulin independent over the first year Although considered clinically
successful, normal glucose tolerance is extremely rare in these patients
About a third of the insulin-independent patients resume insulin therapy
within 2 years, although they often require less insulin, have less
hypoglycemia, and are more
stable metabolically In other words, clinically
they are greatly improved One can anticipate, given the numbers today,
that there are quite a few patients who will resume insulin over time
However, the majority of transplant patients self- report improved quality-
of-life At present there is little data regarding microvascular and
macrovascular complications in islet transplant patients

Regarding the mechanism for the loss of ?-cell function post-transplant
over time, Dr Sherwin feels there are multiple factors involved Chronic
rejection undoubtedly contributes, since it is unlikely that there is no
allo-response in these patients In many cases, there is the recurrence of
autoimmunity, as demonstrated by the formation of antibodies in some
patients who required insulin The immunosuppressive drugs themselves have
adverse effects on ?-cells Tacrolimus, which is the part of the Edmonton
protocol, clearly reduces ?-cell function, and rapamycin, another
component, inhibits the mTOR signaling pathway involved in protein
synthesis and probably has a role in reduced ?-cell proliferation, which
may be an important factor An article in Diabetes Care Davidson, Diabetes
Care 24; 2004 reported
that there is a high rate of incidence of diabetes
with tacrolimus compared to cyclosporin, which also had some adverse
effects In the best of circumstances, even immediately after
transplantation, there is probably only about 20 to 30 percent of ?-cell
mass present, thus only marginal ?-cell function One thing that little is
known about is whether there is insulin resistance, a critical factor in ?-
cell function

On the positive side, Dr Sherwin reported pooled data compiled by Dr
Hering showing that progress was being made The pooled data on cultured
islet transplants from three centers where 75 patients received transplants
since 2000, showed that 74 of the 75 99 demonstrated primary function
based on C-peptide post-transplant, 72 96 were C-peptide positive after
1 year, and 64 85 remained insulin independent at 1 year

Dr Sherwin noted that there are complications associated with the Edmonton
experience, which is critical when asking FDA to consider instituting this
kind of therapy and licensing it Safety is a key element in such
deliberations The major acute islet-related complication was bleeding,
although generally it was modest 10 percent incidence but this often
requires
transfusion There was also occasional thrombosis at the injection
site 4 percent incidence Chronic islet-related complications included
fatty liver A host of side effects and drug-related complications also
occur, some modest, some significant Certainly mouth ulcers are a problem
for patients as well as increased cholesterol, increased blood pressure,
and diarrhea

Dr Sherwin reported that the major questions at the FDA meeting of the
Biological Modifiers Advisory Committee in October 2003 were What
manufacturing requirements and clinical evidence should be needed for FDA
approval of allogeneic islets as type 1 diabetes treatment? In Dr
Sherwins opinion, the outcome from the meeting was that there are still
many basic and clinical questions that need to be resolved However, some
centers have made substantial progress and therefore may ultimately be able
to provide sufficient data for FDA approval for islets as a licensed
product

Next Dr Sherwin listed the following obstacles and hurdles to be overcome
for FDA approval, noting there are probably others he did not list:

Islet procurement is a major problem Islet transplantation centers have
tremendous difficulty getting islets
for islet transplantation
Optimization of islet production and culture methods needs to be refined
There needs to be development of islet viability and function tests in
vitro that relate to clinical outcomes Although there is progress in
this area, there is not a gold standard yet
Optimization of immunosuppressive regimens are needed
The preferred site for islet engraftment needs to be studied and
determined
Methods to reduce implantation local phenomena, such as inflammation,
clotting, and perfusion deficits need to be developed
Appropriate clinical outcome measures must be defned
Data is needed to assess the risk-benefit ratio for approval
Methods to detect early islet rejection must be devised This is a major
problem, because currently rejection is detected by hyperglycemia, which
is too late

Pancreas Allocation Dr Sherwin pointed out that the pancreas allocation
process is an issue of importance and a major obstacle to islet
transplantation The vast majority, probably over 95 percent, of pancreas
organs from obese and older 50 years of age patients are not used and
yet they are not offered in a timely manner to the islet transplant
community
This is important since cold ischemic time is highly critical
for islet transplantation, much more critical than for pancreas
transplantation Dr Sherwin added that, surprisingly, the United Network
for Organ Sharing UNOS kidney-pancreas allocation committee, which is not
under FDA, has no representation from either the islet transplant community
or the diabetes community Dr Sherwin recommended that the pancreas
allocation policy be amended to include 1 limiting time to less than 4
hours for offers for pancreas transplantation or provide pancreases
directly for islet transplantation from donors with a BMI greater than 30
or older than 50 years of age; and 2 involve the islet transplant and
diabetes communities in the pancreas allocation process

Clinical Outcome Measures The current clinical outcome measure for
successful islet transplantation is insulin independence The criterion for
insulin independence is HbA1c less than 65 percent when off insulin
Dr Sherwin recognized that this means many of these insulin-independent
patients obviously have pre-diabetes or diabetes He suggested that
although insulin independence is obviously important to the patient,
clinical outcomes would be
better defined on the basis of ADA criteria of
glycemic control, such as normal glucose tolerance, IGT, IFG, and non-
insulin-requiring diabetes

For partial success in islet transplantation, the current clinical outcome
is C-peptide secretion and reduction in insulin dose Dr Sherwin said it
is important to keep in mind that the studies of islet function that are
used in the transplant community are largely based on arginine stimulation
or mixed meal tolerance tests, rather than the gold standard used by
diabetologists to assess diabetic state, namely glucose-stimulated
insulin/C-peptide secretion

Referring to the NIH Roadmap Initiative, Dr Sherwin said that what was
needed to move forward is an in-depth assessment of islet transplantation
with multi-disciplinary centers such as General Clinical Research Centers
GCRCs able to conduct state-of-the-art physiological, end organ, and
behavioral outcomes studies on islet graft recipients, who, he added, are
not an enormous population

Clinical Assessment of ?-cell Function, Glycemic Control, Hypoglycemia, and
Complications Dr Sherwin presented two suggestions for clinical
assessment of ?-cell function in islet transplant patients-one
for insulin-
independent patients and one for insulin-requiring patients For him, the
gold standard for the insulin-independent patient is an oral glucose test,
preferably OGTT, with early insulin and C-peptide sampling to better
characterize secretory responses Second, as a crude measure of ?-cell
mass, he recommended stepped glucose infusion, possibly with arginine
added Third, as a measure of insulin sensitivity to assess ?-cell function
insulin secretion data, he suggested the euglycemic insulin clamp
Lastly, Dr Sherwin said there needs to be more direct measures of islet
cell mass, which we do not have yet Insulin-requiring patients will
obviously not have much glucose-stimulated ?-cell function; therefore Dr
Sherwins suggestion for clinical assessment of them was mixed meals,
focusing on C-peptide; maybe a stepped glucose infusion with arginine; and
again, the ?-cell mass

For clinical assessment of glycemic control and hypoglycemia in islet
transplant patients, Dr Sherwin would do an OGTT, with 24-hour glucose
monitoring in the hospital to monitor glucose excursions and hypoglycemia,
especially in the insulin-independent patients Additionally, he would want
monthly profiles
of these patients pre- and 2-hour post meal, bedtime, and
3 am, including glucose meter measurements; a continuous glucose
monitoring system CGMS for postprandial hyperglycemia and lability; and a
validated hypoglycemic scoring system

Dr Sherwin proposed clinical assessment of complications in islet
transplant patients should include fundus photos and checks for
microalbumin excretion and glomerular filtration rate GFR, essentially as
done in the DCCT; sensory testing, nerve conduction, RR interval;
endothelial function studies; carotid IMT and perhaps coronary perfusion
studies; measurement of hypoglycemic counterregulation and awareness; and
potential complications related to therapy

Risk-Benefit Assessment Dr Sherwin stated a risk-benefit assessment also
is needed On the benefit side would be insulin independence, which is
everyones dream for patients with type 1 diabetes, or at least sufficient
C-peptide secretion to make glucose control easier without hypoglycemia and
to have better glucose control than is achievable with current methods
Another major benefit would be the potential decrease in diabetic
complications On the risk side, Dr Sherwin identified the risk of
acute
complications of the procedure, the side-effects of the anti-rejection
regimens, and the potential for neoplasia, infections, poor wound healing,
pneumonitis, and so forth Remaining questions raised by Dr Sherwin
included uncertainty about the diabetic nephropathy benefit; potential
adverse effects with respect to cardiovascular disease, since other kinds
of transplantation clearly accelerate cardiovascular disease and produce
hypertension and hypercholesterolemia; and uncertainty about the duration
of islet function with these grafts being sufficient to have a clinical
long-term outcome

One of the key questions for Dr Sherwin was, Will islet transplantation
prevent or reverse nephropathy? The pros are that the University of
Washington, Seattle, group showed reversal of mesangial accumulation and
base membrane thickening, 10 years after successful pancreas
transplantation Robinson et al NEJM, 2004 On the other hand, in 2003
the New England Journal of Medicine reported development of renal failure
in 3 years in 17 percent of non-kidney graft recipients Ojo et al NEJM,
2003 Transplantation Majur et al Transplantation, 2004 reported a 38-
percent decrease in GFR in patients who
had bladder drained pancreas
transplants one patient actually required a kidney transplant; granted
bladder drainage produces dehydration, which probably contributed to this,
but it is something to consider Dr Sherwin also pointed out that pancreas
transplantation currently produces better and more sustained glycemic
control than islet transplantation

Dr Sherwin also cited the report of Dr David Harlan JAMA, 2003, who
looked retrospectively at studies Using the UNOS database 1995 through
2000, Dr Harlan divided patients according to procedure pancreas alone,
pancreas after kidney, or simultaneous pancreas/kidney He then compared
these patients to a control group, based on 4-year follow-up period from
the database Dr Sherwin admitted it could be argued that those in the
control group, such as people on a waiting list who did not receive a
pancreas, might not have been in as desperate circumstances as those who
did get pancreas grafts Nevertheless, the data showed that those who
received simultaneous pancreas/kidney transplants clearly benefited
However in the other categories, 4 years out, there was not much benefit
compared to the control group who received conventional therapy
Dr
Sherwin concluded that, although retrospective studies that compare
different populations can be questionable, this one does raise issues
regarding the risk-benefit ratio

Islet Transplantation or Insulin Therapy? Comparing intensive insulin
therapy in 2004 with islet transplantation, Dr Sherwin scored glycemic
control generally better; hypoglycemia, much better; central nervous system
CNS function in patients who have severe hypoglycemia, unknown; quality
of life, most say better; retinopathy, probably better; nephropathy,
unknown; neuropathy, probably better; cardiovascular disease; unknown;
malignancy, probably worse; and long-term survival, unknown Based on his
scorecard, Dr Sherwin concluded there are only two current indications
for islet transplantation: 1 patients with severe recurrent hypoglycemia
and hypoglycemia unawareness, which is the major clinical problem
encountered with insulin therapy in a subgroup of type 1 diabetes patients;
and 2 patients who have had a kidney transplant and are already receiving
steroid-free regimens that are like the ones used for islet
transplantation Dr Sherwin said that only rarely should poorly controlled
or labile type 1 diabetes
patients be considered for islet transplantation
because these patients are doing reasonably well today compared to the
past Survival and quality of life have improved, largely due to DCCT/EDIC
and to the newer insulins and insulin delivery systems, the statins, lipid
control, improved diets, and so forth Dr Sherwin concluded that due to
these improvements in standard of care, judging the need for islet
transplantation is different today than it was 10 or 20 years ago

Dr Sherwin noted that severe hypoglycemia remains a problem and is far
more common than appreciated Sympathoadrenal responses and cognitive
awareness are markedly reduced in these patients and 50 percent of severe
events occur while people are sleeping In most patients treated
intensively, the fear of hypoglycemia exceeds their fear of complications,
which is anxiety promoting and leads to decreased commitment to treatment
in patients, their families, and their physicians Dr Sherwin stated that
patients with severe recurrent hypoglycemia with unawareness, who fail to
respond to modern multiple injection and insulin pump therapy delivered by
a diabetes specialist for a period of time and this is arbitrary are
very
good candidates for islet transplantation He added that severe
hypoglycemia and unawareness needs to be well-defined and documented
Basically, it is considered a history of two serious events a year such as
coma, hospitalization, or requiring help from another person, with
documented glucose meter readings and, ideally, hypoglycemia clamp studies
or some form of study to evaluate function Dr Sherwin said that these
measurements are important because sometimes improved management can reduce
iatrogenic hypoglycemia and improve responses, and although this can be
difficult and may not be practical in many settings, it s worth considering
prior to undergoing transplantation

For Dr Sherwin, an acceptable outcome in the patients with severe
hypoglycemia could be both insulin-independent and insulin-requiring, C-
peptide-positive patients, with insulin independence obviously more
acceptable In patients receiving islet transplants after kidney
transplant, again, insulin independence and insulin requiring C-peptide
positive secretion would be acceptable outcomes because better control
would probably be achieved in those patients since they would be on the
same regimen Dr Sherwin
questioned there being an acceptable outcome in
patients with impaired renal function, especially if they would be insulin-
requiring, C-peptide positive, given his concerns about presently available
regimens He was uncertain about an acceptable outcome for patients with
poor control of their diabetes

Cautioning that clinical trials are expensive, Dr Sherwin recommended the
following kinds of clinical trials to further examine the potential
benefits of islet transplantation for certain patients with type 1
diabetes:

Patients with severe hypoglycemia: relatively short-term 1 to 2 years
observational studies
Patients for islet transplant after kidney transplant: matching of
patients with historical controls and data with 2 or 3 years of follow-
up
Patients with poorly controlled labile diabetes: a 5-year, DCCT-type
randomized trial to assess the long-term impact of this treatment

Discussion

In response to a question about the regulatory pathway to approval of
manufacturing of islets, Dr McFarland said that there are nuances since
one islet preparation is not the same as another islet preparation;
however, the principle under
which the Center for Biologics Evaluation and
Research CBER grants licenses, at least going back to the granting of the
first biologics license for monoclonal antibodies, is that processes are
very important in the development of the product Islets are regulated at
the level of the cellular product, but the process to make that product is
evaluated as part of the application This is also true at the level of the
investigational new drug IND applications for investigational products
As islet technology improves and changes occur, FDA will be informed and
also will have bridging studies to show that the lot release tests are
similar and that the products are similar in function

Dr David Marrero, Indiana University School of Medicine, Indianapolis,
stated that quality of life is a key phrase in considering the potential
for new treatments and targets for treatments It is important to consider
a patients quality of life and the trade-offs that are involved with
decisions to invoke certain treatment, not only for transplantation, but
for virtually anything, be it a drug or device, or whatever the technology
under discussion Dr Sherwin said that for patients and their families,
severe
hypoglycemia is a dominant player Avoiding this phenomenon has an
enormous impact on quality of life for that group One of the purposes of
islet transplantation is to improve quality of life and if there is anybody
whose quality of life is going to be improved the most, it will be the
patient with severe hypoglycemia, provided that the side effects of the
drugs are minimal Given the fact of very limited resources, Dr Sherwin
would give priority to the patient with recurrent severe hypoglycemia

Dr Marrero, a type 1 diabetes patient of 26 years, followed up by saying
that what was of interest to him about hypoglycemia was that many of the
therapies that have evolved in his lifetime have a dual-edged component,
where initially there is an increased risk but over time or exposure or
experience with the treatment, the results become better He said FDA and
NIH may need to plan on how to balance the risk-benefit ratio between an
acceptable level of risk versus what in fact may turn into a benefit over
time

Another participant, commenting on the Edmonton protocol and the importance
of non-immune factors in progressive ?-cell mass loss and loss of
secretion, asked Dr Hering what is being
done with human islet
transplantation in terms of biopsies or such to learn what is really
happening to ?-cell mass from non-immune processes He also asked how the
acute and long-term or chronic effects might be dealt with in the future if
only about 25 percent of the ?-cell mass that has been transplanted is
functional

Dr Hering agreed this is currently a problem of increasing importance
Most centers see their patients with initially successful islet transplants
later experience failure The reason or reasons are not really known
Biopsies will help in the short-term A major focus of the new islet
transplant consortium that is being established in 2004 will be mechanistic
studies with respect to pre-transplant evaluation of islet mass potency and
also post-transplant immune monitoring using the most sophisticated and
developed technology that is available to monitor allo-immunity,
autoimmunity, and innate immunity after transplantation This will be very
sophisticated metabolic monitoring involving studies looking at insulin
sensitivity, insulin action, and so forth Dr Hering also expected to see
progress in the field of islet bioimaging to monitor islets post-transplant
using
non-invasive technology There is not just one approach to the
problem of why some transplants fail Maybe it is because a marginal mass
was present initially Maybe it is a failure of replication Maybe it is
autoimmune recurrence There are many possibilities for studying this
question

Dr Sherwin agreed that the basic problem is starting out with a marginal ?-
cell mass and then a number of factors contribute to the loss of function,
be it failure to replicate, apoptosis, or core perfusion It is not really
known if the islet normally is perfused inside-out or how it is perfused
More information also is needed on amyloid production The fact that mild
hyperglycemia develops with time, probably doesnt help the ?-cell
function; therefore, if even a successful transplant has not more than 30
and maybe only 20 percent of ?-cell mass, it is not difficult to see how,
over time, small effects quickly add up to produce insulin requirement

Referring to the suggestion from Dr Sherwin about using islets from obese
individuals whose pancreases are otherwise not used, the comment was made
that one thing that happens with obesity is that there is an adaptation
that clearly includes an increase in
?-cell mass Using the obese persons
islets that have more ?-cells actually may be a better answer than taking
people who have been sick, who are on drugs, and who are insulin resistant,
and transplanting them with an islet equivalent mass of what are thought to
be healthy islets, but in which the ?-cell is not able to replicate quickly
enough

Dr Hering said he thought most programs do isolate islets from obese donor
pancreases because they are available In his opinion, the reason for late
failure in transplantation is more immune-related than islet mass-related
The experience in islet autotransplantation indicates that patients who
received a very low ?-cell mass 2,000 or 3,000 islet equivalents per
kilogram, or one-third of what an islet autograft recipient would receive
showed stable function long-term In the Minnesota islet autograft data,
late failure was seen in no more than one or two patients out of 110
transplanted so far; thus it was a rare occurrence

In answer to Dr Sherwins question about allocating human donor islets to
islet allograft recipients based on matched tissue antigens, Dr Hering
replied that it is probably helpful, but not very practical If possible,
Dr
Hering would do it, but it is difficult to accomplish Most programs
have a very small list of islet recipients and finding a patient with a 6-
antigen match pancreas is very unlikely, so that is the limiting factor

Dr Jose Caro, Eli Lilly and Company, asked if there was a plan to develop
collaborative arrangements among the transplant centers, employ a common
protocol, and jointly accrue enough patients to obtain a reasonable amount
of outcome data and then modify the protocol based on that outcome data
The question was based on the seeming lack of adequate outcome data
possibly being related to the number of different centers that are using
different protocols and the relatively small number of patients that each
one of those centers had

Dr Hering responded that progress in any field in medicine is only
possible if well organized and carefully designed multi-center clinical
trials are organized to address clinically important questions The very
first multi-center trial has just been more or less completed, testing
whether the Edmonton data can be confirmed at a number of additional sites
Results will be presented at the ADA meeting and at the American Transplant
Congress later
this year One question is how to standardize and address
roadblocks With NIHs establishment of the islet transplant consortium,
there will be many opportunities to promote collaboration between centers
and address important questions Dr Hering added that designing an islet
transplantation mega-study, involving a few hundred patients, as has been
done in hypertension or in diabetes intervention, requires substantial
resources not readily available Dr Hering recommended using a multi-
disciplinary approach and focusing on a small subset of people with
difficult-to-manage diabetes such as those with severe hypoglycemia-related
problems Well-defined, controlled, and consistent islet manufacturing
processes would have to be in place Once a process is licensed for this
very defined subgroup of patients, additional resources through third-party
reimbursement may become available so other clinical trials can be
performed Dr Hering pointed out that the per patient cost for the type of
trial under discussion is 100,000 to 150,000, which is difficult for even
NIH or JDRF to sponsor

Dr Caro asked what FDAs position was about using a multi-center,
collaborative arrangement with a defined
patient population and agreed-on
protocols to establish a defined starting point and then modify the
protocols based on outcomes Dr McFarland answered that he thought FDA
would support such an attempt, in general, if it provided them with more
clinical information He reminded the group that an important point is the
quality of the islets that would be used by the collaborative FDA is
currently involved in the INDs Investigational New Drug Applications
process with the ITN multi-center trials

In response to a question about the possible benefit of expanding the mass
of the islets that are transplanted or supporting them after transplant
with, for example, GLP or exendin-4 or DP- IV inhibitors, Dr Hering said
that any strategy that would accomplish this would be very helpful
Dr Gordon Weir and his group at the Joslin Diabetes Center studied this in
an animal model using GLP-1 and did not find evidence of a beneficial
effect in the first study Dr Hering was not aware of any other studies

Dr Marcel Salive, Centers for Medicare Medicaid Services CMS, stated
that CMS was very pleased to be directed by Congress to participate in the
islet cell transplant trials under the Medicare
Modernization Act CMS has
begun the process in coordination with NIH, FDA, and other agencies
Currently, CMS is providing coverage for Medicare-eligible patients who are
participating in the clinical trials In order to provide future coverage
to Medicare patients, CMS needs to see clinical evidence of effectiveness
rather than surrogate markers as endpoints Dr Salive asked Dr Sherwin if
the types of clinical trials he proposed would be designed to provide such
data

Dr Sherwin said they would A problem in clinical trials is the amount of
duration required to show benefit For people with severe hypoglycemia who
are nearly incapacitated by that complication, Dr Sherwin thought the
answer would be easy and straightforward These patients do not do well
long-term and consequently would benefit The patients who have kidney
transplants can be followed for kidney outcomes and to see whether the
islet graft prolonged kidney graft survival, which presumably would have an
impact from the standpoint of Medicare That is why Dr Sherwin proposed
trials with those two groups of patients For the general patient with type
1 diabetes, longer trials would be required to validate that
islet
transplantation was an improvement over insulin therapy Longer trials are
more expensive Dr Sherwin expressed the idea that the short-term trials
with the specialized subgroups would provide a valuable learning process
and to help design a longer, more expensive trial At this point in time,
Dr Sherwin said he doubted that one could prove that islet transplantation
can provide a better survival benefit and any major complication
differences for the majority of type 1 patients

Dr Hering agreed The islet transplant community at this time is not
expecting coverage of islet transplantation for just any patient with type
1 diabetes Granted, coverage would be very helpful, for the patients and
for the field, for patients that present with diabetes that cannot be
managed satisfactorily by any other available treatment This is the place
to start Then, as treatments improve with respect to islet manufacturing,
or in particular, immunosuppression, and data from randomized clinical
trials becomes available, additional patient groups could be considered

The comment was made that diabetes and its treatment is more complex than
dealing with a malignancy To begin with, defining the patient
at-risk is
very subjective The speaker liked Dr Sherwins suggestion of having a
patient cared for by a committed diabetes care team for 6 to 12 months
before deciding that this person had uncontrollable diabetes Treatment
advances in diabetes are happening all the time There is uncertainty as to
which patients to study; there is uncertainty as to what a good islet
quality is; there is uncertainty about how to monitor outcome; and there is
uncertainty in the immunosuppressive protocol selected Designing a multi-
center study that might be the very best design one can come up with today
would very likely be quite different if designed 6 months later This
presents a very difficult conundrum

Dr William Tamborlane, Yale School of Medicine, said that the problem with
long-term clinical trials is that by the time one arrives at an answer, the
therapy is outdated Dr Tamborlane thought that a network of transplant
centers collaborating on targeted trials was a good idea A single study
cannot respond to all the transplantation issues A multi-site effort would
be more effective, in his opinion

Dr Caro added that the idea is not to get a protocol that is going to
answer all the questions,
but rather an evolving protocol that changes over
time Given the amount of information that is not known, it would be good
to at least have a starting point and then, as more is learned, modify
accordingly

Session V: Devices
Moderator: Patricia Bernhardt, Office of In Vitro Diagnostics, Center for
Devices and Radiological Health, FDA

Device Issues: Glucose ]Monitoring
William V Tamborlane, MD, Professor and Chief of Pediatric Endocrinology
and Diabetes, and Deputy Program Director, General Clinical Research
Center, Yale University School of Medicine, New Haven, CT; Steering
Committee Chair, DirecNet

Dr Tamborlane, whose background includes 25 to 30 years of working to
achieve good control of type 1 diabetes in children and adolescents as well
as being the current Steering Committee Chair of DirecNet Diabetes
Research in Children Network, noted that DirecNet is an NIH-funded
collaborative study group of five centers, similar to what Dr Caro
suggested for islet cell transplants DirecNets objective is to critically
evaluate the clinical usefulness of current and future glucose sensors in
youth with type 1 diabetes Dr Tamborlane stated that one of the great
strengths of the network
is its outstanding coordinating center in Tampa,
Florida, the Jaeb Center for Health Research

Dr Tamborlane explained that his presentation would try to answer the
following two questions:

What criteria should be used for approval of new glucose monitoring
sensors?
Can data from continuous glucose monitoring sensors be used as outcome
measures for evaluation of the safety and efficacy of new diabetes
treatments?

Dr Tamborlane said the answer to both of these separate, but related,
topics depends on sensor accuracy This was the conclusion derived by the
DirecNet study group when they designed their first study that focused on
the accuracy of the two FDA-approved continuous sensing systems-the Cygnus
Glucowatch Biographer II and the Medtronic MiniMed CGMS For the DirecNet
study, the investigators planned to recruit 90 youngsters ranging in age
from 1 to 17 years, and were successful in recruiting 89 ages 3 17 years
in the record time of only a few months Dr Tamborlane explained that each
patient was admitted to one of the inpatient clinical research centers
CRCs participating in the study for a 24-hour admission process that
included serum samples for reference
glucose measurements collected every
hour during the day and every 30 minutes during the night The samples were
processed and mailed to Dr Mike Steffes lab, which was also the central
laboratory for DCCT The study participants wore at least one Medtronic
MiniMed CGMS and one Glucowatch simultaneously, and some wore two
Glucowatches and two Medtronic MiniMed CGMSs simultaneously In addition to
noting spontaneous fluctuations in glucose, there was the intent to stress
the sensor systems by looking at their performance during acute
hyperglycemia and acute hypoglycemia The hyperglycemia subprotocol to
cause a rapid increase in glucose involved a high carbohydrate liquid meal
without a pre-meal bolus of rapid-acting insulin In the older children,
the equivalent of an insulin tolerance test also was done

Dr Tamborlane remarked that one of the wonderful advantages of working in
pediatrics is how the children respond to these kinds of studies The
principle outcome of the DirecNet study was fairly standard point-to-point
differences between the sensor and reference glucose values Dr Tamborlane
pointed out that the differences can be looked at in multiple ways: simple,
absolute, relative,
and relative absolute difference Looking at the simple
difference, if there is random error on either side of the reference value,
then the difference should be close to zero If there is a systematic bias,
then there will be a consistent mean difference between the sensor and the
reference values Looking at the relative difference, which is the
difference divided by the reference value expressed by a percent, one
obtains a relative absolute difference, or RAD, which was the primary
accuracy metric used in the DirecNet studies

Dr Tamborlane continued that another way to look at the performance of
sensors as well as meters is by International Standards Organization ISO
criteria, which says, If the reference glucose is greater than 75 mg/dL,
then the sensor reading should be within 20 percent If the reference
glucose is less than 75 mg/dL, rather than a percentile, the sensor glucose
value should be within 15 mg/dL DirecNet data were expressed as a
percent of paired values meeting these ISO criteria

Main results of the DirecNet trials as presented by Dr Tamborlane were
fairly consistent with published results for these sensors; however, the
data do support the argument that these
are first-generation devices Their
accuracy could be said to be analogous to the accuracy of the original
glucose meters that were introduced 20 years ago The Glucowatch reports
glucoses every 10 minutes and the Medtronic MiniMed CGMS every 5 minutes
The mean relative absolute difference in the percent error for the
Glucowatch was about 22 percent, and for the original Medtronic MiniMed
CGMS, it was about 26 percent Dr Tamborlane said that, in looking at the
overall dataset, the study investigators decided that mean was not the best
metric to use, that median was a fairer test of the accuracy of these
meters, because a few sensors were outliers that pulled up the average
value The median value RAD data was better: 16 percent for the Glucowatch
and 19 percent for the original Medtronic MiniMed CGMS, with neither meter
meeting ISO criteria consistently Dr Tamborlane explained that about 80
percent of the way through the study, Medtronic MiniMed modified the sensor
matrix that they used, giving DirecNet the opportunity albeit with a
smaller number of subjects to look at the accuracy of the modified sensor,
which was much better 16 for mean RAD, 11 for median RAD, and within 72
of ISO
criteria Correlations between sensor and reference values also
were better Since the data for the later model was from only 1,120 paired
reference and sensor values and only from one or two lots, Dr Tamborlane
recommended further confirmation of these encouraging results While the
children were on the research unit, Dr Tamborlane explained that to make
decisions regarding their therapy, the One-Touch Ultrameter, a more mature
technology, was used In 1,200 pairs, r-values between reference glucose
and the Ultrameter values were 097, and the accuracy was between 6 and 7
percent

In looking at the data, Dr Tamborlane cautioned the audience to keep in
mind that there is error involved with obtaining a reference value and
sending it to a central lab, where there is the possibility of error as
well During the IV insulin test, the study measured and compared the
Ultrameter measurements with measurements from YSI and Beckman instruments,
which they had bedside for safety Both sets of measurements were sent to a
central lab during acute hypoglycemia, and there was no difference in the
relative error between the instruments Dr Tamborlane stated that this was
an impressive performance and
indicated what the meter industry is
currently able to produce for patients

Looking at error as a function of plasma glucose level, both the Glucowatch
and the Medtronic MiniMed CGMS had problems in the hypoglycemic range 25
to 40 percent error in glucoses under 60, which is an important issue
related to FDA using continuous glucose monitoring as a safety index The
Ultrameter did fairly well even in the hypoglycemic range

Dr Tamborlane stated that, instead of just looking at point-to-point
comparisons, the sensors were compared for ability to pick up a real
hypoglycemic event and for incorrectly reporting a hypoglycemic event that
was not real The data collected during the IV insulin infusion test, where
reference glucose dropped to values lower than 60 and hypoglycemia was
usually achieved, the modified Medtronic MiniMed CGMS appeared to do best,
although there were too few events to ensure the results; the original CGMS
did the next best; but only 12 of the 48 Glucowatches detected the episode

The DirecNet study group was particularly interested in detection of
hypoglycemia at night With the Glucowatch, there were 18 events where the
sensor said the patient had a night where
the glucose levels fell below 60,
but only 10 of those were confirmed by the actual reference glucose The
Medtronic MiniMed CGMS reported 26 events and only 8 were confirmed, and
the modified Medtronic MiniMed CGMS was accurate with 3

False alarms, either for hyper- or hypoglycemia, were considered a very
important function for the sensors in relation to their use with children
A selling point of the Glucowatch is that it has both hypo- and
hyperglycemic alarms With the alarm set for a glucose under 60, the
Glucowatch only picked 23 percent of actual hypoglycemic episodes, and had
a 51 percent false alarm rate Sensitivity was better at a setting of 120
92 percent of real events but the false alarm rate rose to 85 percent
Dr Tamborlane reported that, in practice, patients tend to quit using the
sensor at night after they, and their families, are repeatedly awakened
with so many false alarms The Medtronic MiniMed CGMS does not have an
alarm system built into it; its sensitivity for real events was better at
49 percent, but it also had a high false alarm rate 58

In discussing metrics to use for analyzing the sensors, the DirecNet study
group chose not to use the Clark error grid
analysis or correlation
analysis with R values for a number of reasons In the Clark error grid
analysis, there are zones, good and bad, and a reference glucose plotted
against the meter or sensor glucose The different zones are intended to
distinguish clinically meaningful versus less important errors in glucose
measurements For example, when the grids were set up, if the blood glucose
was between 50 and 250, treatment was not required, an easy decision The
correlate was that the grid divided glucose measurements into zones that
distinguished increasing clinical significance of error, to ensure not
mistaking hyperglycemia for hypoglycemia, and treating the patient with
insulin Sensor accuracy with the Clark error grid is usually measured by
percentage of values within the A and B zones The problem with this,
Dr Tamborlane explained, is that zones A and B are large enough that even
inaccurate sensors will hit them the majority of times Secondly, current
insulin dosage adjustments are based on much smaller variations in glucose
than when the grids were initially set up eg, there is now a difference
between a 50 and a 250 and a correction dose is administered at 250
Third, one can get
a misleading notion of sensor accuracy through chance
agreement as in Dr Tamborlanes example of randomly shuffling sensor and
reference glucose pairings, which a statistician at the Jaeb Center did as
a test, with 10,000 simulations Even with these random pairings, the
result was the average A and B zone accuracy was still 76 percent

Dr Tamborlane next discussed the problems with correlation analyses of r-
values, beginning with the fact that r-values are so sensitive to the
amount of variation in glucose levels that their reliance is limited In
correlation, variability is required The DirecNet study group used the
example of four hypothetical simulated sensors, each with identical
accuracy, and 10,000 data pairs per sensor Sensor value was equal to the
true value or the reference value plus a normally distributed error with
a standard deviation of 25 mg/dL The actual mean of all the glucoses was
200 For the analyses, the range of true glucose values for each sensor was
varied The results were that if the reference values ranged between 175
and 225, the Pearson correlation R value was 05 With the same accuracy,
if the range wais 50 to 350, the R value was 096

Other limitations of
point-to-point assessments of accuracy listed by Dr
Tamborlane included that methods developed for meters are single-point
tests, which cannot capture the dynamic nature of continuous glucose
sensors Also, it is difficult to assess trends and there are issues about
how to do accurate trend analyses to determine how well sensors
characterize acute changes in glucose Dr Tamborlane stressed that these
are very important questions that, hopefully, smart mathematicians can
address

Dr Tamborlane next discussed potential physiologic contributions to so-
called error between reference values of plasma glucose obtained by a meter
and sent to a central lab and sensor glucose values measuring interstitial
glucose concentrations It has been demonstrated that there is undoubtedly
variability in the plasma and interstitial glucose gradients during the
day In a Yale study, euglycemic-hyperinsulinemic clamps were used at
baseline and a sensor calibrated against baseline plasma glucose levels
where nothing was infused In this process, basically, the sensor is told
what the plasma glucose level is, it measures a current coming off the
interstitial glucose, and comes up with a ratio to account for
the gradient
between plasma and interstitial glucose Next a euglycemic clamp was done
with an infusion of high doses of insulin while maintaining plasma glucose
unchanged, which lowered interstitial fluid glucose concentrations
dramatically, measured by microdialysis, and the sensor followed the
interstitial This demonstrated that there are possible physiologic reasons
why there is going to be some discrepancy between the reference blood
glucose, or serum or plasma glucose, and the sensor glucose, which may
actually be very important Dr Tamborlane said currently how to interpret
these differences is unknown In addition, in comparing a reference plasma
glucose and an interstitial glucose, the interstitial is going to lag 10 to
20 minutes behind the plasma If doing point-to-point assessments, one must
find a way to account for that lag time

For future studies of sensor accuracy, Dr Tamborlane stressed the
importance of studying children from diverse populations, especially type 1
diabetics post-transplant, those with hypoglycemic disorders, as well as
type 2 diabetics and non-diabetics When the Glucowatch and Medtronic
MiniMed CGMS originally came out, there was a lot of interest in
pediatrics
to use these sensors to diagnose and manage hypoglycemia-related disorders
Unfortunately, the accuracy was insufficient, but there was still interest
in seeing how well they performed with non-diabetic as well diabetic
individuals When these sensors, particularly the Medtronic MiniMed CGMS,
were used with non-diabetic individuals, it was discovered that the
algorithms developed to convert electrical current coming off the sensor
into a plasma glucose level were based on type 1 patients with wide
fluctuations, and those algorithms did not work in non-diabetic individuals
where the fluctuations were much more modest, so algorithms had to be
redone for non-diabetic studies

Other areas for future studies recommended by Dr Tamborlane would be
frequent sampling in an inpatient study with Clinical Laboratory
Improvement Amendments CLIA-certified laboratory methods and also an
outpatient study to investigate the accuracy of outpatient data using well-
characterized meter methods as reference values Beyond accuracy, Dr
Tamborlane called for testing the efficacy of using glucose sensors in
clinical management to lower HbA1c levels, including whether this would
lower or increase
the risk of hypoglycemia Dr Tamborlane referred to a
plan to do this in an outpatient study with one sensor as the therapy and
the Medtronic MiniMed CGMS as an outcome measure, because one could mask
the patients to the CGMS data However, the CGMS is not a good outcome
measure to determine the frequency of hypoglycemia in clinical trials due
to insufficient accuracy in measuring glucose in the low glucose ranges
He added that the continued obstacle in looking at safety related to
hypoglycemia that goes beyond clinically important events is that there is
no simple test There is no HbA1c for hypoglycemia, just as there was no
HbA1c for hyperglycemia until 1980 Dr Tamborlane noted that this
inability to have a simple outcome measure for hypoglycemic exposure in
patients obviously has important implications for islet cell
transplantation as well as other therapies

Another issue raised by Dr Tamborlane was that not only do sensors need to
be accurate and effective, they also need to be user friendly or patients
will not use them Also, how will patients and clinicians deal with the
reams of data from 24×7 sensors? Who will provide the support to assess
this data? Will the cost be
reimbursed?

In responding to the question of whether current sensors are accurate
enough to be used for outcome measures for diabetic therapy, Dr Tamborlane
said the answer depends on what is being measured

For mean glucose values, the average difference between the Medtronic
MiniMed CGMS profile and the actual reference was 2 mg/dL, so the answer
would be Yes However, the HbAlc values are still easier and better

For hyperglycemia, the answer would also be Yes since current sensors
are reasonably accurate in the hyperglycemic range With the CGMS, one
can mask the patients to the sensor data, and a number of different
metrics to do analyses can be used, such as meal-related excursions, AUC
area under the curve, or amount of time during the day above cut-offs

For glycemic variability, again Yes, using day-by-day profiles, MAGE
values, M-values, standard deviation scores, and so forth The
therapeutic question of particular importance to FDA is Is postprandial
hyperglycemia an independent risk factor beyond HbA1c for diabetic
complications? The answer is not known

For hypoglycemia, the answer is No They are not accurate enough

According to Dr
Tamborlane, the real excitement about continuous
monitoring is not only the present, but the promise for the future,
especially the potential to combine sensors and pumps and develop a closed-
loop artificial pancreas Studies completed at the University of California
at Los Angeles tested the Medtronic Guardian system, which is a wireless,
continuous glucose monitoring system that sends real-time glucose readings
from a sensor via wireless transmission to a computer that then drives a
pump to respond to high and low glucose alarms Ultimately, the sensor
connected to the pump will have a computer in the unit itself

In using such a closed loop system to regulate overnight insulin delivery
to a patient with type 1 diabetes, the concern would be the sensors
reading higher than the true plasma glucose level, and therefore extra
insulin would be infused when the plasma glucose was normal Dr Tamborlane
said the solution is to set the target at 120 at night so that, even if the
sensor is mis-reading plasma glucose by 50 percent, the pump will go back
to basal insulin infusion when the glucose hits 80 If the error is 100
percent, there will be a back-to-basal insulin infusion when the
glucose
gets to 60 He stressed that such an overnight insulin delivery to control
glucose in the type 1 patient would be a tremendous therapeutic
advancement

Pumps: Hopes and Expectations
Christopher D Saudek, MD, Hugh P McCormick Family Professor of Medicine;
Director, Johns Hopkins Diabetes Center; and Program Director, General
Clinical Research Center, The Johns Hopkins University, Baltimore

Dr Saudek suggested that, broadly speaking, a cure for diabetes could be
considered achieved if the person were able to forget that he or she has
diabetes, and were able to live life normally, free of the complications of
diabetes Dr Saudek said he thought it reasonable to consider approaches
to cure as either biological approaches or mechanical Today those
present had heard about organ transplants and islet cell transplants as
therapies and, although not mentioned, embryonic and adult stem cells also
were possibilities As a mechanical approach, open loop pumps have been
around for a long time There is an external open-loop pump and an
implantable open-loop pump With continuous sensing, the ultimate answer
will be a closed loop external or implantable pump All the approaches have
to be
assessed for efficacy and effectiveness within particular
circumstances and timeframes

The current conventional treatment of diabetes is multiple daily injections
of a long-acting glargine and short-acting insulin preparations, which are
adjusted according to meals and bedtime Dr Saudek said that
subcutaneously delivered insulin response is affected by a whole series of
variables such as the depth, the location, the surrounding tissue, heat of
the tissue, and so forth, all of which contribute to making injectable
insulin imperfect

The theory behind external pumps and, in fact, implantable pumps is to
establish a known basal rate that can be varied, but is relatively
constant, as an infusion and to supplement that by specific boluses that
are given by the patient choosing the dose and given precisely in the same
spot as a relatively exact amount of insulin The currently available
external pumps have developed from the Continuous Subcutaneous Insulin
Infusion CSII first accomplished with the Mill Hill Infuser The new
models of CSII are small, relatively convenient, but still injecting from a
syringe housed in the external device, through a catheter into subcutaneous
space In the
last year or so, Dr Saudek said that telemetry from a
glucose monitor has been one newly available approach, the pump then doing
some of the arithmetic that patients ordinarily do when they calculate a
bolus dose This telemetry system, available as the Medtronic MiniMed
Guardian device, can suggest an insulin dose based on the blood sugar As
mentioned by Dr Tamborlane, Medtronic MiniMed has also developed- and had
approved recently-the Guardian System, a telemetry system that takes a
sensor reading and telemeters it to an alarm system There are, then,
continual improvements being made on the available external delivery and
sensing systems

External pumps are now a viable business and have been an available option
since the 1980s for treatment of type 1 and unstable type 2 diabetes
Regarding indications for using a pump, Dr Saudek commented that the
distinction between type 1 and type 2 diabetes is, in some clinical
respects, artificial since beta cell secretory capacity in type 2
deteriorates, and patients can end up so insulin-deficient as to be
metabolically similar to type 1 diabetes Insulin pumps may be indicated
for unstable, labile diabetes, regardless of whether type 1 or
type 2
diabetes is the underlying diagnosis Well over 100,000 have been sold,
produced now by at least four manufacturers Medtronic MiniMed,
Roche/Disetronic, Deltech, and Animus

Dr Saudek listed advantages and disadvantages of the external pumps The
external pump offers flexibility of meal and activity timing The patient
can choose a meal time, even skip a meal, and theoretically, with the right
basal rate going, not have to worry about eating on time Other advantages
are freedom from multiple daily injections, more precise insulin delivery
patterns, and true basal/bolus insulin delivery Most of the evidence
suggests improved glycemic control A major limitation of external insulin
delivery is that the patient must wear the device at all times, and some
people do not like that, are truly phobic about it Other disadvantages
include occasional skin irritation, infection, need to change the site
regularly, poor skin insert sites, and peripheral insulin delivery Dr
Saudek stressed that therapies such as injectable insulin, external pumps,
and even whole pancreas transplants deliver insulin peripherally, not
hepatic portally

When implantable insulin pumps IIPs were invented, the
potential
advantages included that there was none of this externality that many
patients find very inconvenient The maintenance or refill procedure is
done only every 3 months, rather than every 3 days or so as required by
external pumps The implantable provides the more physiologic, hepatic
portal insulin delivery, with the potential advantages of that for hepatic
glucose handling, lipids, and so forth Dr Saudek referred to the latter
as potential advantages because while the exact effects of portal delivery
of insulin is an area of science he thinks is under-tapped, it does appear
to have beneficial clinical effects

Dr Saudek noted that the history of the implantable pump is almost as long
as that of islet cell transplantation Dr Buchwald started in the 1970s
with the continuous rate pump NASA in the late 1970s developed a little
pump that landed on the Mars surface and became the basis of a so-called
Programmable Implantable Medication System PIMS developed at the Johns
Hopkins Applied Physics Laboratory, which then became the basis of todays
implantable pump There have been a couple of other manufacturers of
implanted pumps, but the present day Medtronic MiniMed pump is the
one that
has linearly descended from the PIMS

Preclinical dog trials conducted by Dr Saudek in the mid-1980s led to a
proof-of-concept set of human implantations done in the late 1980s, with
about 21 implanted pumps These studies showed that a variable rate pump
could work and could manage type 1 diabetes The trials were greatly
expanded in the 1990s and the incidence of pump implantations during the
mid-1990s increased dramatically

Between 1990-2000, Dr Saudek said it was shown that IIP therapy was safe
and effective on a large scale, that the refills were practical and safe,
and that metabolic control and lipid metabolism could be improved with the
IIP and hypoglycemia could be lessened It also was found that the
catheters and the insulin are vulnerable points that have to be taken very
seriously in the evaluation process Autoimmunity, pocket complications,
refills, and flushes were manageable, but they also were issues, and
battery programming needed to be improved Dr Saudek presented information
on each of these positive points and areas of concern

IIPs are feasible on a large scale The number of IIP implants per year
grew worldwide in the early 1990s In the mid-1990s, there
was a brief
period of decline due to an insulin problem, which has been resolved, and
now the field is back to more and more implants Most active centers are in
France because the French government chose to support and pay for pump
implantations and the pumps; therefore, MiniMed spent a lot of its time
working in France to develop the technology In 2000, there were 340 active
patients and in 2003, there were 365 in France and 59 in the United States
for a total of 424

Refills are practical and safe The refill procedure involves a little
scrubbing of the abdomen, some xylocaine in the skin, an introducer needle,
and then a thinner needle going into the refill port of the pump, pulling
the old insulin out, and then, with another syringe, putting new insulin
in Dr Saudek explained that one of the key safety features of these
Medtronic MiniMed pumps is that the pressure of the reservoir is negative
relative to atmosphere, so that when the insulin is replaced, the old
insulin must be pulled out but when the needle with new insulin is
inserted, because of the negative pressure, the insulin is drawn into the
pump, not pushed This is a major safety feature when introducing about
6,000
units of insulin in the refill procedure; if the needle is not
actually in the pump reservoir the insulin will not be injected; it will be
drawn in only if the needle is properly in place The refilling procedure
is now routine, and takes about 10-15 minutes, done every 3 months

Metabolic control can be improved with IIP Dr Saudek expressed some
skepticism about the ability to prove superiority of any one method of
insulin delivery over another, perhaps excepting fully closed loop
delivery, noting that metabolic control can be improved with any variety of
insulin delivery approaches It can be improved by a diabetes team, an
attentive endocrinologist, an external pump, an implanted pump, a
transplant, and so on It is not so much that measures of metabolic control
are not important-they are But in considering relative approaches to the
management of diabetes, regulators should not consider improved blood
glucose control the only parameter, since it is such a manipulateable
feature, subject to all levels of bias in study design and investigator or
patient involvement This said, Dr Saudeks Johns Hopkins data suggest
that HbA1c is reduced and mean plasma glucose is reduced
significantly
Udelsman R, H Chen, K Loman, HA Pitt, CD Saudek 1997 Implanted
programmable insulin pumps: 153 patient years of surgical experience
Surgery 122:1005-11

A number of other studies of implanted insulin pumps also showed a decrease
in mean blood glucose with IIPs and a drop in HbA1c and introduced the fact
that the standard deviation of blood glucose came down very significantly
in this study The French consortium, Evaluation dans le Diabete du
Traitement par Implants Actifs EVADIAC, has collected very good data on
implanted pumps, comparing subcutaneous and multiple dose insulin with
external pump insulin and with implanted pump insulin Their experience
also showed reduced HbA1c and a marked reduction in severe hypoglycemia

Hypoglycemia can be lessened A large, randomized, company-independent
trial in the VA system was, in Dr Saudeks opinion, the best and largest
randomized trial done The initial goal was to achieve equal glucose
control with multiple dose therapy and implanted pump therapy The goal was
stated prospectively, to get equal measures and to look at other
parameters Dr Saudek stressed to those who are involved in regulation of
devices and evaluation, that
if mean blood glucose is lowered without
lowering the standard deviation, the result is what happened in the DCCT,
there is an increase in hypoglycemia If the mean glucose and the standard
deviation are both lowered, then it can be proven medically or
statistically that people are not driven into hypoglycemia This can be
seen in downloads of glucose meters and so on He emphasized that in
managing diabetes, it is very important to look at how variable the blood
glucose is, whether you call it MAGE or whether you call it measure of
standard deviation Results in the VA trial demonstrated significantly
decreased definite and suspected mild hypoglycemia Results also showed
decreased severe hypoglycemic reactions, although the number of events was
not large enough to be significant

Lipid metabolism can be improved Dr David Kelley measured free fatty acid
data showing a more finely tuned regulation of fatty acid metabolism for
patients on the implanted pumps than on subcutaneous insulin Dr Barbara
Howard also published favorable changes in lipid status with IIP therapy

Portal absorption of peritoneal insulin delivery Dr Saudek presented
older data from Schade to show that there is a
portal peripheral gradient
of tagged insulin, when you infuse insulin into the peritoneal space This
indicates, at least to some extent, that this insulin is absorbed into the
hepatic portal system and there is a hepatic portal gradient established by
peritoneally delivered insulin Another study of Micossi et al showed that
the different routes of delivery-upper peritoneal, lower peritoneal,
intramuscular and subcutaneous-all had different pharmacokinetic
characteristics Dr Saudek commented that the millimeter differences
between intramuscular and subcutaneous insulin can be a significant factor
in the variability seen with glucose in response to conventional insulin
injections With IIP therapy, the free-floating intraperitoneal catheter
tip may vary in its lower-versus-upper peritoneal cavity insulin delivery,
although this has not been studied

Catheters and insulin are a vulnerable point Dr Saudek explained that in
the first dog implantation, there was a vicious attack on the catheter by
the peritoneum The Johns Hopkins study group worked on catheter materials
and came up with a much better result Today catheter blockage is occurring
at about 10 to 15 percent per year A
side-port catheter is used now that
can be pushed through blocks

The early dog trials showed that insulin precipitation in the catheter
meant that the insulin was not going to go very far with a clot right in
the middle of the catheter A stabilizing factor worked; polyethylene
polypropylene glycol stabilized the insulin very well It was first used in
vitro and then in vivo for upwards of 8 years without any indication of an
insulin problem Then, all of a sudden in the mid-1990s, the EVADIAC group
noted that there was a systematic increase in the pump slow-down rates and
problems such as catheter survivals that did not relate to how long the
pump was going, but related to the stability of the insulin being used Dr
Saudek explained that what happened was that, in the mid-1990s, Hoechst
changed its insulin manufacturing technique, causing serious problems The
insulin was aggregating in the catheter and precipitating on the pump
valves, causing some backflow and under-delivery of the insulin Catheter
flush and pump procedures were developed to handle the problem temporarily
Then Van Entwerp at MiniMed developed a technique for the rapid assessment
of insulin stability, so it was not
necessary to wait months to assess the
stability of insulin preparations In the meantime, work was done to
improve the insulin, so that the newer Aventis HOE 21 PH seems to be stable
at this point Today, the insulin being used is much better than in the mid-
1990s

Autoimmunity, pocket complications, and refills/flushes are manageable
Reported data indicate that the incidence of pump pocket infections varies
from 0 to 28 percent per patient year, which is a very wide range The mean
was 7 percent Dr Saudek said the importance here is that it is difficult
to clear if it happens Usually, the device has to be explanted or changed
entirely

Autoimmunity has also been a long-time concern, sometimes bordering on
obsession regarding anti-insulin antibodies in IIPs One study showed an
increase in insulin antibody titer The amount of total antibody increase
was divided up into so-called responders and non-responders, and obviously,
the responders responded and had much higher insulin antibody titer Dr
Saudek said he did not favor this type of study design Over the years, the
responders levels tended to come back down, possibly indicating regression
to the mean; however, in looking at the
data, a wide range of insulin
antibody levels were found Then a syndrome appeared that seemed to suggest
what were called fasting lows Even cutting the infusion rate way down
overnight, people were still low in the morning On looking at the antibody
titer of people who were suspected of the syndrome clinically, it was, in
fact, the people who were at the very high end of the antibody syndrome who
had the fasting lows, indicating that antibodies can be induced in persons
with a high affinity There were no metabolic consequences overall, but Dr
Saudek said he thought that IIPs do occasionally cause high antibody titer
and a prolonged insulin action that is rarely clinically significant

Dr Saudek remarked that when MiniMed became Medtronic MiniMed, the
implants slowed down while the company went through its consolidation
period, before resuming implantations in 1993 Now Johns Hopkins is
implanting the new IIP model 2007, which Dr Saudek showed in a slide The
new model has a much smaller and more efficient communicator, and the
battery life is now up to 8 years

In discussing the future of insulin pumps, Dr Saudek stressed that he
certainly hoped patients did not have to wait too long
for a closed-loop
system, but cautioned that it will take time to develop because it requires
very high levels of safety and reliability of both the sensor and delivery
systems Nevertheless, it is too limited to think of the closed loop system
only as entirely implanted It could be developed as an external-to-
external system, with an external pump and a subcutaneous sensor; or it
could be a combination of an external sensor and an implanted pump; or
implanted sensor with external pump; or both implanted Dr Saudek stated
that developing the software to link the glucose monitoring with the
insulin delivery will not be easy, but is do-able Initial forays and
initial trials into developing such a closed loop system are beginning, but
Dr Saudek sees the successful development of a safe and successful system
as being some years away

Dr Saudek acknowledged the contributions of his collaborators at Johns
Hopkins, the founding fathers and young contemporaries in the field, and,
in particular, the research subjects who have been such an important part
of the study projects to develop and test insulin pumps

Discussion

Ms Bernhardt opened the discussion
period by asking if Dr Tamborlane and
Dr Saudek thought that before a closed-loop system could actually be used
clinically that management of diabetes would have to change to be based on
interstitial values rather than blood glucose values Her question was
based on taking into account the physiological differences between the
interstitial glucose and the blood glucose, and the fact that current
diabetic management is based on blood glucose measurements

Dr Tamborlane responded that he had raised the issue of interstitial
versus blood glucose values because of small differences in accuracy
Another physiologic observation that may or may not have real clinical
importance is that 10 minutes off may not make a big difference in how a
patient is treated, but it may make a big difference in the error of the
method used For example, his group did a more complicated clamp study
where there was a measurement at baseline and then at an acute euglycemic
phase, a hypoglycemic phase, and an acute hyperglycemic phase, and there
was a discrepancy If all calculations were done at basal, aligning the
gradient between the plasma and interstitial resulted in an abnormal sensor
value On the other
hand, if measurements were calibrated throughout the
four different phases of study, and the small changes in gradients were
averaged out, the numbers came out quite well Dr Tamborlane added that
this is something to consider, but it should not have a major impact on use
of the closed loop system

Dr Saudek commented that his group had done some studies of time-lag
between subcutaneously measured glucose and blood glucose, finding also
that there is a gap of between 9 and 12 minutes They did not find a
consistent difference dependent on whether the blood glucose is increasing
or decreasing under insulins effects, contrary to the findings of some
others In driving a closed-loop system, what may be more significant than
the GLP issue is whether reproducing a cephalic phase of insulin
secretion ie, the anticipation of an up-coming meal is needed to
normalize postprandial glucose The patient would have to somehow signal
the pump that he/she was going to eat, because the pump would have no way
of knowing that ie, no way of reproducing a cephalic phase of insulin
secretion Dr Saudek said that he doubts, however, that this is
clinically significant, and emphasized that absolute normality
of glycemic
response is not necessary to control blood glucose between 90 and 110
Diabetic complications should be preventable with something a lot less fine-
tuned than that

Dr Tamborlane added that the point is particularly relevant to the
external-external model, where insulin is infused subcutaneously Between
the time the glucose is rising on the sensor and insulin is being augmented
and delivered subcutaneously, there is that lag time Two separate issues
with the external-external are How well can postprandial excursions be
controlled and then what about overnight? The overnight does not have to
be extremely accurate Gains on the algorithms can be adjusted fairly
quickly to tell the pump how fast to infuse the insulin, so that even if
there is not a perfect glycemic excursion-the peak values may go up into
the low 200s-but 2 or 3 hours later they will be back to basal Looking at
postprandial hyperglycemia data in 56 youngsters with HbA1c of about 75,
which is outstanding for children, 50 percent of postprandial glucoses were
over 300

Asked to expand on his concern about control of variability, particularly
as it relates to postprandial glucose, and why this happens, given
the
tools available, Dr Tamborlane answered that he supposed the normal
pancreas does respond to cephalic phases He related an anecdote about when
he was a student in medical school The students were required to fast for
24 hours, taken into a room and shown a big meal, and then had blood drawn
to measure the increase in their insulin levels based on seeing the meal
That is probably the cephalic phase where the pancreas is primed to secrete
insulin even before meal ingestion Portal delivery may affect the post-
meal excursion, but Dr Tamborlane said he doubted this was clinically
significant

Dr Fradkin asked Dr Saudek for more detail about the differences in
lipids that he saw when delivering the insulin portally versus peripherally
and also, did he look at any inflammatory markers such as CRP or
plasminogen activator inhibitor-1 PAI-1 Dr Saudek said they have not
looked at inflammatory markers In the VA study, Dr Kelly did look at
fatty acid metabolism and found free fatty acids to be more finely tuned
with the implanted pump Dr Barbara Howard also has shown there is less
atherogenic LDL with the implanted pump A thorough fractionation of lipids
has not been done, but he thought
it would be interesting to see whether
portal delivery makes any difference

In reply to a question about whether anyone had put GLP-1 in a pump to
treat type 2 diabetes, Dr Saudek had not heard of this being done He had
received a call at one time about putting growth hormone in a pump for
cattle, but to do this was too expensive The regulatory process takes a
long time, which is reasonable

Asked if he thought the current sensor devices were accurate enough to be
used to manage hypoglycemia unawareness, Dr Tamborlane said he thought
this would certainly be worth a study, especially in patients who suffer 5
or 10 treatable episodes a week that lead to serious defects in their
regulatory responses

Related to the issue of quality of life, as came up earlier in the islet
transplant discussion, Dr Tamborlane asked if the FDA ever put on the
label, information about quality of life For instance, given two
hypothetical therapies, a standard therapy and a new therapy that had a non-
inferior efficacy but superior quality of life, would this information be
reported on the label? The reason for the question was the reimbursement
problem that concerns most everyone Fortunately, pumps in
children are not
a big problem, but there are artificial barriers put up by insurance
companies unless one can show that the patient has failed every other
therapy

Dr Orloff answered that a group at FDA is working intensely on quality of
life issues and instruments to measure it Within CDER, institutional
procedures and policies are being developed to give guidance, essentially,
to industry for developing products with quality of life measurements and
thereby labeling them If two products had non-inferior efficacy, or had
equivalent efficacy, but there was a difference in some other aspect, then
in that instance, to some extent, the quality of life would fall under the
rubric of safety The reason for this would be because, as an example,
refractory problems with repeated hypoglycemia are ultimately a safety
issue Clearly, there is a quality of life aspect in terms of the
psychological misery, but FDA is primarily interested in comparative safety
of products that have essentially equivalent efficacy and would use that as
a way of judging the overall merits of the therapy

Dr Tamborlane commented that this was very helpful, because there are
aspects of quality of life that have to
do with symptoms or adverse effects
of the therapy, but there also are aspects that are simply quality of life
that usually fall under the rubric of patient convenience, which is not
looked on favorably by insurance companies One could say that an aspect of
what is being called convenience is that life is more livable with the
disease when there is a better way of delivering a drug to a patient or
monitoring control of the drugs action

Dr Orloff remarked that it was his impression that currently there is a
change from the time when FDA would have said that greater convenience
would have had to translate to greater efficacy by showing that, for
example, people tended to adhere to the therapy better, compliance
improved, and thus some meaningful clinical outcome was improved Now FDA
is saying it is comfortable with validated, tested quality of life
instruments that are customized for the disease and the treatment being
studied

Dr Tamborlane replied that diabetes care is really all about making life
easier for persons with diabetes, but calling a therapy tool or measure a
convenience is not usually understood in this light He was very glad
that FDA was interested in this He also
suggested that tools for measuring
the quality of life of approaches and concepts were needed

Dr Orloff offered some observations he thought might be valuable in FDA
and NIH interactions Quality of life is an interesting rubric that has
come to take on a lot of meanings, but what they were talking about here
was quality of life specific to treatment In other words, quality of life
is a big area Quality of a persons treatment for diabetes is specific In
clinical trials for drugs, quality of life is specific to that trial In
asking about the impact of one form of therapy versus another form of
therapy, on how the patient perceives life as a person with or without, in
this case, diabetes, Dr Orloff said he would be cautious in trying to get
standardized instruments that would fit all possible scenarios, because
that would be difficult to do, given the different kinds of profiles that
drugs present in terms of how people react to them, how they incorporate
them, and the symptoms that go along with them

For Dr Marrero, an important point was that quality of life is a moving
target in relation to therapy While initially a patient may not like
something; later, with experience, the
person may like it a lot He cited
his own experience with the insulin pump as an example In the beginning,
he did not like the pump at all As mentioned by Dr Saudek, it was an
external device constantly attached to him With time and experience, it
became more agreeable His assessment of his quality of life thus varied,
based on his initial and then later experience Questioned in the initial
phase, his response would have been very negative Six months later, his
assessment would have been very different This is an important issue,
because a patients decisions about treatment are based on the quality of
treatment life-what it does to ones life and well-being in the long-term,
what it does in terms of convenience of management of the disease, what the
tradeoff is in terms of efficacy versus tolerability, and so forth Dr
Marrero strongly recommended that this quality of life issue be amplified
in the interface between FDA and NIH

The first days meeting was adjourned at 5:37 pm

Day 2: perspectives on the Future of Prevention and Therapy

Session VI: Prevention of Type 2 Diabetes
Moderator: Sanford Garfield, PhD, Senior Advisor for Biometry and
Behavioral Research Program, DDEM,
NIDDK

The Metabolic Syndrome
Robert H Eckel, MD, Professor of Medicine and Professor of Physiology and
Biophysics, University of Colorado Health Sciences Center UCHSC; Denver;
Program Director, NIH-sponsored Adult General Clinical Research Center,
UCHSC, Denver

In the absence of Dr Barbara Howard, who could not attend the meeting, Dr
Eckels task for the day was to cover both her and his portions of the
agenda First, he discussed definitions, demographics, and disease risks
related to the metabolic syndrome, particularly risks for cardiovascular
disease and diabetes Secondly, he spoke of the metabolic syndrome as a
therapeutic target for the prevention of type 2 diabetes

Overview of Metabolic Syndrome

Definitions Dr Eckel presented the following major definitions of the
metabolic syndrome as offered by 1 the National Cholesterol Education
Program NCEP and the Adult Treatment Panel III ATP IIII guidelines; 2
the World Health Organization WHO; and 3 for the American Association
for Clinical Endocrinologists AACE and the Association of Clinical
Endocrinologists, the insulin resistance IR syndrome:

NCEP/ATP WHO
3 or more
Hyperinsulinemia or fasting plasma
glucose 110mg/dl
Abdominal circumference AND at least 2 of
the following
men 40 in women 35 in Abdominal circumference:
Triglycerides 150 mg/dl Def 1: W/H 090 or BMI 30 kg/m2
HDL cholesterol Def 2: Waist 94 cm 37 in
men 40 mg/dl women 50 mg/dl Dyslipidemia
Blood pressure 130 diastolic or 85 systolic Triglycerides 150
mg/dl OR
Glycemia as fasting plasma glucose 110 mg/dl HDL cholesterol 35
mg/dl
Blood pressure 160/90 OR on medication
Microalbuminuria, AER 20 ?g/min

AACE/ACE
Cluster of abnormalities
Blood pressure and lipid criteria of NCEP/ATP III
Abnormal glucose tolerance ie, if type 2 diabetes
not present
Fasting glucose of 110-125 mg/dl OR
2-hour post-glucose 75g 140 mg/dl
BMI and waist circumference increased risk but
Not a criterion

Needs to be adjusted for ethnicity
Other factors increasing risk
Eg, family history of type 2 diabetes

Dr Eckel noted that the criteria for glycemia has been reduced to 100
mg/dl, which will change the prevalence of the metabolic syndrome but only
by a couple of percents, not 5 to 10 percent He added that the NCEP/ATP
definition is more CVD-driven whereas the WHO definition is more diabetes-
driven This difference is important when speaking of preventing diabetes
Hyperinsulinemia in the WHO definition is defined as the upper quartile of
the non-diabetic population AACE urged glucose tolerance testing if
diabetes itself were not already present AACE allowed for ethnic
differences in waist circumference For example, African Americans tend to
have a larger waist but the type of fat distribution varies decreased
visceral, increased subcutaneous

In Dr Eckels opinion, the metabolic syndrome is more than these criteria
If one thinks of the metabolic syndrome as the insulin resistance syndrome,
which is open to controversy, the following components that affect insulin
resistance would apply:

Cigarette smoking
Presence of
small dense LDL and HDL particles
Increases in the following:
apoB, which reflects atherogenic dyslipidemia
uric acid
fibrinogen, PAI-1, viscosity
inflammatory markers as reflected by increased hsCRP, IL-6
asymmetric dimethyllarginine decreased nitric acid
homocysteine
Decreases in adiponectin, reflecting insulin sensitivity

Demographics Dr Eckel stated that the current emphasis on the metabolic
syndrome is the result of the prevalence of obesity According to the 2001
Behavioral Risk Factor Surveillance System BRFSS, every State now has a
greater than 15 percent prevalence of obesity, in spite of the inaccuracies
of self-reporting body weight and BMI in a telephone survey Data from
National Health and Nutrition Examination Surveys NHANESs show that since
1999, there has been a 2 to 3-fold increase in the prevalence of obesity
as defined by a BMI 30 kg/m2In fact, data for obesity in the United
States projected by Dr Peter Kopelman in 2000 Kopelman, PG Nature
Insight 404:637, 2000 were superseded by the later NHANES data However,
if Dr Kopelmans slopes continue as projected, 42 percent of Americans
will have a BMI 30 kg/m2 by 2025 NHANES data also
show a dramatic
increase in obesity in children and adolescents over the last four decades
Dr Eckel noted this ensures we will have the metabolic syndrome with us
for some time

Etiology of Obesity Dr Eckel explained that the issue of obesity relates
to the balances between energy intake and energy expenditure The gene pool
has not changed, although today there is awareness of monogenic syndromes
and susceptibility genes The environment is where most of the problem has
arisen through increased food availability, especially energy-dense foods
and larger portion sizes, and reductions in physical activity

Dr Eckel described an experiment asking what the effects of being
sedentary for 24 hours had on substrate utilization and the energy
intake/expenditure balance in people randomized to either a high-
carbohydrate 60 percent of calories or a high-fat diet 40 percent of
calories, followed by a wash-out period, and then put on the opposite
diet The important part of this longitudinal study, supported by NIDDK,
was the impact of this type of energy balance assessment on changes in fat
mass and body weight over 4 years Subjects included normal weight,
overweight, and obese men and women
and remained on the diets for several
weeks and then had energy balance measured in the hold room calorimeter
chamber where they lived and were inactive for 24 hours These people were
weight-maintaining before they entered the chamber The calorimeter
assessed oxygen consumption and CO2 production, and because urinary
nitrogen was known and protein balance can be determined, fat balance and
carbohydrate balance could be calculated On the high-carbohydrate and high-
fat diets, subjects respectively had 800 and approximately 925 calories of
positive energy balance Those on the high-fat diet had 400 calories of fat
balance, whereas those on the high-carbohydrate diet were nearly zero for
fat balance Dr Eckel said that this last data indicates that those on the
high-carbohydrate diet, although overfed, did not convert the calories to
fat within the 24 hours of inactivity The CHO balance was understandably
higher on the high-carbohydrate diet than on the high-fat diet, but protein
balance was the same regardless of diet

Over the 4 years of the study, fat mass measured by kg/year changed by 031
015, a p value of 00477, and weight measured by kg/year changed by 029
015, a p value of
00592 Dr Eckel pointed out that this represents the
importance of power analyses in predicting outcomes because they had
powered a p value of 005 for weight gain over the 4 years Dr Eckel
stated that the overall results of this study, after 4 years of subsequent
analysis, showed that it was how people responded to carbohydrates that
determined their weight and fat mass In a 24-hour inactive state, if a
person is in positive carbohydrate balance, then the person is protected
from weight gain or fat mass gain

Dr Eckel said the overall prevalence of the metabolic syndrome is about 23-
24 percent; however, NHANES reports differences in populations African-
American men probably have a lower prevalence because their triglycerides
are lower and their HDL is higher Hispanic women have a greater
prevalence, probably due to a combination of waist circumference and
fasting glucose Of the components that lead to the prevalence of the
metabolic syndrome, waist circumference is more prominent in women than in
men; triglycerides are higher in white men, which probably drives the
higher prevalence of the syndrome in white men Men and women are about
equal in HDL cholesterol 40 men, 50 women
Hypertension and fasting
glycemia are higher in men than in women

Causes of Metabolic Syndrome Dr Eckel pointed to obesity as possibly the
foundation of the metabolic syndrome, but in discussing causes, there
remains the issue of whether the metabolic syndrome represents an insulin-
resistant state He noted that Dr Gerald Reaven had established the
principles of the metabolic syndrome a decade before its definition by
listing a number of covariants that are highly associated with each other
and reflect inadequacies in insulin sensitivity Free fatty acids FFAs
are central to the development of the metabolic syndrome or to insulin
resistance One of the most sensitive impacts of insulin action is anti-
lipolysis Once there is an increase of FFAs, then lipolysis tends to be
enhanced, which results in a vicious cycle of increased production of FFA
and insulin resistance The FFA burden then drives the prothrombotic state
and the production of atherogenic lipoproteins, which are modified in
density The increase in FFA flux also drives the defect in insulin-
mediated glucose disposal and the increased production of glucose by the
liver and kidney, and in susceptible individuals, this
leads to impaired
glucose tolerance and hyperinsulemia Dr Eckel stated that the link
between hypertension and insulin resistance is much more questionable and
has generated considerable controversy He cited an article by Dr Gerald
Reaven, Dr Earl Ford, and others in the May 2004 issue of Diabetes
Diabetes 2004 May;535:1195-1200,] that reported the results of steady
state plasma glucose SSPG tests in more than 400 persons that identified
the metabolic syndrome in about 20 percent The study investigators did not
find any relationship between SSPG and blood pressure Dr Eckel thinks
that, therefore, the metabolic syndrome in part reflects insulin
resistance, however if hypertension is to be included other factors must be
involved

Metabolic Syndrome and Risk of Atherosclerotic CVD Dr Eckel presented
data from the Kuopio study that investigated the impact of the metabolic
syndrome, using WHO criteria, for mortality, in 55-year-old men, from
coronary heart disease, CVD, including stroke, and all other causes of
mortality The study showed that when the data was adjusted for
cholesterol, smoking, and other known cardiovascular risk factors, there
was an impressive relative risk of the
metabolic syndrome impacting all
three causes of mortality in the study subjects Dr Earl Ford in NHANES
III presented a comparison of ATP III and WHO criteria and the prevalence
of self-reported myocardial infarction and stroke in persons over the age
of 20 who had or did not have the metabolic syndrome Dr Eckel pointed out
that Dr Fords data indicate that WHO and ATP III criteria are basically
equivalent in predicting CVD

Dr Charles Alexander and Dr Steven Haffner analyzed the impact on CVD of
the metabolic syndrome, with or without diabetes, from NHANES III data for
persons 50-years-old and older They reported Diabetes 2003;52:1213 that
without the metabolic syndrome or diabetes, the prevalence of CVD in this
group is 87 percent When persons have diabetes without the metabolic
syndrome, the prevalence of CVD is approximately the same 75 as for
those without either diabetes or the metabolic syndrome Dr Eckel stressed
that having diabetes certainly implies the presence of the metabolic
syndrome; however, if someone has diabetes and is not overweight and does
not have high blood pressure or lipidemia, then the risk of CVD is nearly
the same as that of someone without diabetes When
the metabolic syndrome
is present without diabetes, the prevalence of CVD doubles 139;
however, when the person has both the metabolic syndrome and diabetes, the
prevalence jumps to 192 percent, almost 3 times the risk for diabetes
alone

Metabolic Syndrome and Risk of Diabetes Dr Eckel emphasized that the
literature is weak in this area and, although it shows that the metabolic
syndrome is a predictor of new-onset diabetes, better evidence is needed
regarding how the metabolic syndrome predicts diabetes Based on literature
published in the last 4 to 5 years, the risk of diabetes in someone with
the metabolic syndrome is about 2- to 4-fold To estimate the risk, one
would have to apply the metabolic syndrome criteria to the study data on
the cohorts from various clinical trials

Metabolic Syndrome as a Potential Target for Prevention of Type 2 Diabetes

In considering the particular components of the metabolic syndrome that
would make the best therapeutic targets for prevention of type 2 diabetes,
Dr Eckel selected waist circumference, blood pressure, and glycemia
Physical activity for weight reduction seems to reduce waist circumference
more than diet alone, although this has not
been thoroughly substantiated
Based on this relationship to physical activity, he recommended keeping
waist circumference on the target list The rationale for blood pressure
lowering relates to the increasing number of clinical trials in which ACE
inhibitors or ARBs have proven to reduce the incidence of type 2 diabetes
Ways to reduce triglycerides relate to most of the elements of the
metabolic syndrome, but aside from weight reduction, he set triglycerides
aside as a target Nicotinic acid is the only reasonable pharmacological
target to raise HDL cholesterol, and this is not a promising intervention
to reduce the incidence of diabetes in individuals with impaired glucose
tolerance; in fact, it does the opposite Dr Eckel felt that there
basically was not enough evidence for intervening with dyslipidemia as a
target The effects of statins and fibrates on type 2 diabetes incidence
are modest at best and mostly absent In fact, niacin can increase
glycemia Blood pressure and insulin resistance as reflected in abdominal
obesity and impaired glucose tolerance were better targets

Treatment of Hypertension Dr Eckel listed four classes of drugs commonly
used to treat hypertension:
diuretics, beta blockers, ACE inhibitors, and
ARBs Diuretics and beta blockers tend to increase the incidence of
diabetes There are only modest effects on insulin secretion On the other
hand, clinical trials have shown that ACE inhibitors captopril,
lisinopril, ramipril and ARBs losartan, candesartan do reduce the
incidence of diabetes, as secondary outcomes of using these blood pressure-
lowering drugs The overall effects in lowering type 2 diabetes incidence
have been relatively modest but significant, with the exception of the
SCOPE trial with candesartan relative risk 081, p009 Dr Eckel felt
the effects were insufficient in impact to recommend these drugs as a
primary strategy, but there was a rationale for using an ACE inhibitor or
ARB as adjunctive therapy in the setting of the metabolic syndrome Dr
Eckel said to keep in mind that the trials supporting this rationale were
not conducted on the basis of the metabolic syndrome and prevention of type
2 diabetes

Treatment of Insulin Resistance A more fruitful area of intervention
within the metabolic syndrome is insulin resistance, particularly
obesity/abdominal obesity and impaired glycemia Dr Eckel recommended
converting
abdominal android fat distribution to lower body gynoid fat
distribution He remains unconvinced that obesity in women that puts most
of their fat below their waist leads to CVD and diabetes, but feels more
evidence is needed to show whether or not this is true

Weight reduction is the target to reduce waist circumference Dr Eckel
briefly reviewed some clinical trials on weight reduction and its effects
on diabetes In the Finnish Diabetes Prevention study, 522 men and women,
ages 557 years, with BMI of 31246 kg/m2 were randomized as a control
group and a lifestyle intervention diet and exercise group and had a mean
follow-up of 32 years with an oral glucose test to indicate diabetes The
lifestyle intervention diet included restricted fat, especially saturated
fat, and increased fiber The lifestyle intervention group had a 55-60
percent reduction in new-onset type 2 diabetes The DPP 27 centers in the
United States, 3, 234 men and women, ages 25-85, with an average BMI of 34
kg/m2 was a 32-year ramdomized trial with three arms-placebo, lifestyle
modification goal 7 percent weight loss, and metformin 850 mg bid A
fourth arm was discontinued earlier due to concern over potential
adverse
events from the use of troglitazone Lifestyle had the greatest effect on
preventing type 2 diabetes, followed by metformin Both of these strategies
favorably modified insulin sensitivity and thus are strategies to use to
target insulin resistance in the metabolic syndrome

Dr Eckel asked How long will the weight loss last? Even in the highly
constructed and controlled DPP, weight was regained He also asked, How
long will the prevention of type 2 diabetes last? Both are crucial
questions He added that before considering pharmacological interventions
to lose weight, it is important to remember that lifestyle changes do work
Dr Eckel said it was also interesting that the diets used in the Finnish
study and DPP were both diets that restricted fats, not carbohydrates

Moving on to weight-loss drugs, Dr Eckel noted that there are basically
two choices in anorectics Sibutramine is FDA-approved for weight loss;
phentermine is not listed but is commonly prescribed because it is much
less expensive Dr Eckel thought that in spite of the phen-phen issue,
phentermine remains a major anorectic being used by physicians The other
choice as a weight-loss drug is orlistat, a lipase inhibitor
There are no
clinical trials using these in the prevention of diabetes, but there is the
XENDOS study in which orlistat plus lifestyle change resulted in more
weight reduction than lifestyle change plus placebo Again, there was the
regaining of weight that always occurs Orlistat plus lifestyle reduced the
incidence of diabetes in subjects with IGT by 45 percent and in all
patients by 373 percent compared to the placebo plus lifestyle

Dr Eckel listed other hypoglycemic therapies that might favorably modify
insulin sensitivity: sulfonylureas, meglitinides, ?-glucosidase inhibitors,
metformin, and thiazolidinediones There are no such trials with
sulfonylureas or meglitinides As mentioned, metformin was used fairly
successfully in DPP In the STOP-NIDDM Studies to Treat or Prevent Type 2
Diabetes trial, there was a dramatic impact of acarbose an ?-glucosidase
inhibitor on patients with IGT in reducing all CVD events, and especially
myocardial infarction from 12 events in the placebo group to 1 event in
the acarbose group Dr Eckel added that there is some concern about the
validity of the results of STOPP-NIDDM involving selection bias, inadequate
blinding, bias in data analysis, and
potential sponsoring bias

Dr Eckel cited Dr Ronald Evans review of work on PPAR compounds in
Nature Medicine Nat Med 2004 Apr;104:355-61 Thiazolidinediones do not
cause weight reduction, but they change where body fat is deposited For
example, in a study by Dr Miyazaki and colleagues Miyazaki Y et al JCEM
2992;87:2787 after 16 weeks of pioglitazone, there was dramatic
redistribution of abdominal fat from the visceral depot to the subcutaneous
depot Data from that study also showed that changes in visceral fat
contribute to improvements in insulin sensitivity, since the visceral fat
area predicts the metabolic clearance rate of insulin and thus reflects
insulin sensitivity Likewise, Dr Tom Buchanans study of troglitazone
Buchanan, TA et al Diabetes 2002;51:2798 showed a long-lasting benefit
in the prevention of type 2 diabetes in high-risk Hispanic women with
gestational diabetes, even subsequent to discontinuation of the drug in the
study Dr Eckel concluded that the PPAR class of compounds looks promising
in the prevention of type 2 diabetes in patients with the metabolic
syndrome

The PPARs that are available, at least those targeted for reduction of
insulin sensitivity, are
largely the PPAR? class Many pharmaceutical
companies have bi-agonist drugs that combine PPAR?/? properties The
properties reflect mostly changes in fatty acid metabolism and the relate
to both carbohydrate and lipid metabolism Dr Eckel added that recently
the PPAR? compounds or, theoretically, ligands that impact the PPAR?
system, seem promising, as described by Dr Ronald Evans group Yong-Xu et
al, Cell 2003; 113:159-170 This study showed that by modification of the
PPAR? system, fat metabolism could be altered in a way that enhanced fatty
acid oxidation and prevented obesity and, ultimately downstream, in Dr
Eckels opinion, type 2 diabetes and the metabolic syndrome that precedes
it This is an area in human biology, physiology, and pharmacology that
there is not much information on yet, but a promising area of this PPAR
class of drugs

Dr Eckel also listed other non-FDA-approved drugs that affect the
metabolic syndrome by modifying weight first and then incidentally type 2
diabetes These include anti-epileptics topiramate, zonisamide, MCH-1
inhibitors, cannabinoid antagonists, GLP-1 and DPP-IV inhibitors, and other
new players in the field At this time, there are limited data
on these
drugs in terms of their application to patients with the metabolic syndrome
and much less data on their application to the prevention of type 2
diabetes Zonisamide has shown an impressive weight reduction in obese
persons compared to placebo Gadde, KM et al JAMA 2003;289:1823 as has
topiramate in a randomized trial Bray, GA et al Obes Res 2003;11:727
Dr Eckel recommended that these compounds and their side effects be
intensely studied

In summary, Dr Eckel said The metabolic syndrome is upon us and is going
to increase its prevalence, and likely predict a much higher incidence of
type 2 diabetes, as well as coronary heart disease and stroke Lifestyle
interventions should be the initial and sustained therapeutic approach
Some drug therapies already seem to work such as metformin, TZDs, ACE
inhibitors, and ARBs A variety of other therapeutic options appear to be
forthcoming As illustration of what can be done, Dr Eckel showed a
before slide of a patient who had all the components of metabolic
syndrome plus type 2 diabetes and an after slide of this attractive
patient after successful weight reduction

Discussion Dr Garfield asked Dr Eckel if he would be more
optimistic
regarding intervening to reduce triglycerides if future therapies such as
use of adiponectin to promote fatty acid oxidation existed today Dr Eckel
responded that he understood that adiponectin is being considered as part
of the pharmacological toolbox to treat type 2 diabetes and IGT The idea
of modifying triglycerides as a target reflects opportunities to modify
triglyceride production rates and/or lowering triglycerides by increasing
removal of triglycerides from the system The evidence is that increasing
lipoprotein lipase modifying clearance is probably not the way to reduce
triglycerides, but modifying production rates reflects that fatty acids are
being partitioned into different pools So if triglycerides are not going
into triglyceride biosynthesis, because of this effect on AMP kinase they
are going to oxidative metabolism, then here the PPAR?s become particularly
attractive There is not much evidence that metformin, also an activator of
AMP kinase, does much to serum triglycerides Dr Eckel said he thus thinks
that targeting triglycerides will be an indirect method of altering fatty
acids He also suspected that insulin sensitivity would improve
with
triglycerides just being an innocent passenger

The comment was made that metformin has not been studied enough yet to know
how far up the dose response curve would go in terms of activating AMP
kinase, and also what the effect of these and other tissues would be
Metformin per se may not do what is needed; we do not know for sure what
the possibilities are of that mechanism, depending on how much and where it
can be activated

The Diabetes Prevention Program and New Perspectives on the Metabolic
Syndrome
Harry Shamoon, MD, Professor of Medicine and Associate Dean for Clinical
Research, Albert Einstein College of Medicine, Bronx, New York

Dr Shamoon stated that he would present a brief overview of the DPP data
and some new analyses from the study that might shed light on the metabolic
syndrome and the issue of should it be treated, and if so, how should it be
treated Dr Shamoon acknowledged the contributions of the many DPP
investigators, many of whom are now involved in the DPPOS He noted that
DPP was sponsored by several NIH institutes and offices in addition to
NIDDK ie, National Center on Minority Health and Health Disparities;
National Center for Research Resources, GCRC
Program; National Institute of
Child Health and Human Development, National Institute on Aging, and Office
of Research on Womens Health, other Federal agencies ie, Indian Health
Service, Centers for Disease Control and Prevention, the American Diabetes
Association, and private industry ie, Bristol-Myers Squibb, Warner-
Lambert, LifeScan, Inc, Merck Co, Health OMeter, Nike Sports Marketing,
Hoechst Marion Roussel, Inc, Slim Fast Foods Co, Merck-Medico Managed
Care, Inc, and Quaker Oats Co

Primary Goal and Results Dr Shamoon said the primary goal of DPP was to
prevent or delay the development of type 2 diabetes in persons with
impaired glucose tolerance The study design included a randomized three-
group clinical trial at 27 sites with a common protocol across all sites,
staff training, and a data quality control program The criteria to define
a high-risk IGT population was a 2-hour post OGTT plasma glucose of 140-199
mg/dl and a fasting glucose in the non-American Indian population of 95-125
mg/dl, thus persons from the upper end of the glucose range Other
eligibility criteria were being 25 years of age or older and having a BMI
24 kg/m2 Persons from all ethnic groups were
recruited with a goal of up
to 50 percent from high-risk ethnic populations The study interventions,
following randomization and the giving of standard lifestyle
recommendations to all the subjects, were intensive lifestyle, metformin,
and placebo NEJM 346:393-403, 2002

The DPP was very successful in recruiting ethnic minorities plagued with
the problems of diabetes The DPP population was 20 percent African
American, 16 percent Hispanic, 5 percent American Indian, 4 percent Asian
or Pacific Islander, and 55 percent Caucasian There was a two-thirds
women to one-third men gender distribution Besides the 45-59 age group
49, there were young people ages 25-44 31 and older people over 60
years of age 20

Dr Shamoon said the primary outcome of the DPP was glucose: 1 annual
fasting plasma glucose FPG and a 75 gm OGTT with the following criteria
for a diagnosis of diabetes: FPG 126 mg/dl or 2-hour 200 mg/dl with
either of these confirmed by a repeat test and 2 a semi-annual FPG of
126 mg/dl, confirmed

The lifestyle intervention was a multi-component effort involving
behavioral and medical components to achieve a minimum weight loss of 7
percent of body weight and maintenance of
weight loss with a dietary fat
goal of 25 percent of calories from fat and a calorie intake goal of 1200-
1800 kcal/day In addition, sustained physical activity of a minimum of 150
minutes per week was encouraged and documented Medication interventions
were 850 mg per day of metformin escalating after 4 weeks to 850 mg twice a
day compared to placebo

Dr Shamoon confirmed that the DPP subjects were an obese group The
average BMI was 340 67 kg/m2 Weight loss was a predominant effect of
both lifestyle and metformin and was dramatically different initially in
the lifestyle group, although some weight was regained after almost 4
years At study end, there still was about a 4 kilo reduction in weight
from baseline in the lifestyle group Leisure physical activity was by self-
report; it increased and was maintained by the lifestyle group in
comparison to the placebo and metformin groups In terms of adherence to
medication regimen, Dr Shamoon reported that approximately 80 percent of
participants took at least 80 percent of their prescribed placebo or
metformin dose over the course of the study, with just slightly better
adherence in the placebo group

As has been reported often, Dr
Shamoon repeated that for the DPP
participants as a group, the risk of diabetes was reduced 31 percent by
metformin and 58 percent by the lifestyle intervention versus placebo
Secondary analyses show that lifestyle, followed by metformin, was similar
for both men and women in lowering the risk for diabetes By age, there
were some differences In the 25-44 age group, metformin and lifestyle were
almost equally effective in reducing the incidence of diabetes In the 45-
59 years of age, metformin was intermediate In the 60 years and older
group, lifestyle was the most effective, with metformin and placebo being
about equally effective

Dr Shamoon continued with the analyses by showing that in the least obese
group BMI 24-29, metformin was much less effective than lifestyle In the
most obese group BMI 35, metformin was basically equivalent to
lifestyle in reducing the incidence of diabetes Dr Shamoon said fasting
glucose obviously plays a big role in the conversion to diabetes His data
showed that in subjects with the lowest range of fasting plasma glucose
concentrations 95-109, the diabetes incidence rates were much lower than
in the group with the higher glucose concentrations
110-125 Again, there
was a stepwise effect, with metformin having an intermediate effect on the
prevention of diabetes compared to lifestyle Across all ethnic groups, the
effects of lifestyle in reducing risk of diabetes was the most effective
intervention, with metformin again being the second most effective

Regarding adverse events, based on 100 person years, Dr Shamoon reported
that metformin was well tolerated There were no differences in major
adverse events Gastrointestinal symptoms, not unexpectedly, were greater
in the metformin group compared to the placebo or lifestyle intervention,
and musculoskeletal symptoms were slightly higher in the intensive
lifestyle intervention

Following the reduction of incidence of diabetes, there was still a trend
in the DPP cohort toward a rising fasting plasma glucose even with the two
successful therapies Dr Shamoon said whether there is an inexorable
change to developing diabetes, a possible question is Is the effect of the
drug, for example, transient? The DPP tried to address this question with
a 1-week withdrawal of metformin, followed by a re-challenge with an OGTT
Diabetes Care 26:977-980, 2003 The test showed that the rate
of
prevalent diabetes declined a little, but the summary conclusion of the
analysis was that approximately one-quarter of the effect of metformin to
prevent development of new diabetes can be attributed to an acute
pharmacologic effect; after washout, metformin still reduced the incidence
of diabetes by 25 percent compared to the placebo Dr Shamoon interpreted
this data to indicate that lowering plasma glucose with metformin has its
own effect beyond prevention of diabetes by mechanisms unknown

Dr Shamoon explained that the DPP was originally designed as a four-group
study Between 1996 and 1998, subjects were randomized to troglitazone 585
of the total of 2,345 subjects, as well as the other three arms Due to
emerging data on the hepatoxicity of troglitazone, and the death of one
subject, the drug was discontinued in 1998 and ultimately withdrawn from
the US market 2 years later Analysis of the data on diabetes incidence
rates per 100 person years for the four groups up to discontinuance of
troglitazone was not different than the final results The lowest projected
incidence was with the troglitazone; however, the safety of the drug
precludes its use Although troglitazone was
highly effective, there was
not a significant difference between it and intensive lifestyle as an
intervention Unlike Dr Buchanans Tripod Study, Dr Shamoon said that DPP
did not find a persistent effect of troglitazone on prevention of diabetes
Data on incidence of diabetes after troglitazone was discontinued in 1998
showed that, while there was no catch-up increase in incidence, the
cumulative incidence basically followed the same trend as placebo,
suggesting there was no persistent effect of that brief 9-month exposure to
troglitazone

Conclusions and implications drawn by Dr Shamoon regarding the two drugs
used in DPP to prevent diabetes included the following:

Metformin was safe and effective, particularly in younger and more obese
persons; its effect did not wash out after 1 week, suggesting it did not
simply mask hyperglycemia

Troglitazone markedly reduced diabetes incidence during its brief use,
but the action did not persist after it was discontinued

The effect of troglitazone was due in part to improved insulin
sensitivity with maintenance of insulin secretion This same mechanistic
effect was true for intensive lifestyle on the prevention of
diabetes

DPP Secondary Goals and Results The secondary goals of the DPP as listed
by Dr Shamoon were to reduce CVD events, reduce CVD risk factors, and
reduce atherosclerosis The DPPOS will look at the data for these outcomes;
Dr Shamoon therefore said he would not directly address this data in the
current meeting in discussing the metabolic syndrome He posed the
interesting question of whether the metabolic syndrome is related to CVD
directly, not just to CVD as a complication of the diabetes developed
following IGT

Metabolic Syndrome and DPP Many of the subjects in DPP had at baseline a
family history of type 2 diabetes, a history of high cholesterol and
hypertension, in addition to obesity and IGT, and, in women, a history of
gestational diabetes Dr Shamoon pointed out that thus some members of
this cohort were likely to have metabolic syndrome Objectives of the new
analysis were to determine the prevalence of the metabolic syndrome in this
multiethnic DPP population with IGT and to evaluate the effect of the two
interventions-intensive lifestyle changes and metformin-on the incidence of
the metabolic syndrome in those subjects without the syndrome at baseline
Data were also
analyzed on those who did have the syndrome at baseline The
definition selected to make the diagnosis of metabolic syndrome was that of
the NCEP ATP III, 2001

Only fifty-three percent 1,711 of the 3,234 persons had the metabolic
syndrome at time of randomization Prevalence did not vary by gender or age
group, but did vary by ethnicity, being highest in Caucasians 57 and
lowest in Asians 41 Dr Shamoon explained that one of the reasons for
this difference might be that the NCEP criteria were developed for
Caucasians, or there may be other reasons for this Prevalence of the
components of the metabolic syndrome did vary by age group The most
frequent combination of components was high waist circumference elevated
triglycerides low HDL The least frequent combination of components was
elevated fasting plasma glucose elevated blood pressure low HDL In
those with the metabolic syndrome, a waist circumference 102 cm 40 in
in men or 88 cm 35 in in women was true for all age groups Low HDL
cholesterol was clearly less important in the older age group and more
important in the younger persons Conversely, hypertension was more
prevalent in the older age group and less so in the younger
group
Triglycerides were about the same across all the age groups

Looking at those without the metabolic syndrome at baseline, the DPP study
group asked What did the interventions achieve? There were 1,523 subjects
without the metabolic syndrome 490 in the placebo group, 503 in the
metformin group, and 530 in the lifestyle group In the 3 years of the
study, there was a risk reduction of about 17 percent in the metformin
group versus the placebo group, 41 percent in the lifestyle group versus
placebo, and 29 percent in the lifestyle intervention group versus the
metformin group The lifestyle reduction rate was therefore similar to that
for prevention of diabetes, but not quite as potent

Data presented by Dr Shamoon for the 3-year incidence of the components of
the metabolic syndrome for those without the syndrome at baseline showed
that those in the placebo group had a 33-percent incidence of reaching the
criteria for waist circumference, compared to a significantly reduced 15
percent and 8 percent, respectively, in the metformin and intensive
lifestyle groups Low HDL cholesterol was not affected by these
interventions compared to placebo, and triglycerides were reduced in
the
intensive lifestyle group As expected, occurrence of high fasting plasma
glucose was prevented by intensive lifestyle and metformin Hypertension
was reduced only in the intensive lifestyle group

In the subjects with the metabolic syndrome at baseline, the 3-year
incidence data for the various components was very high in the placebo
group as shown in Dr Shamoons slide of this data Waist circumference was
modestly but significantly reduced by both the metformin and lifestyle
intervention HDL cholesterol, interestingly, was about equally increased
in both the metformin and lifestyle groups, and lifestyle also had an
effect on triglycerides and blood pressure Lifestyle also reduced fasting
plasma glucose about 5 percent more than metformin, but both were
significantly better than placebo, of course

Conclusions and Implications from Dr Shamoon for this DPP volunteer cohort
selected for the high end of IGT and treated for 32 years included the
following:

Over 50 percent of the cohort had metabolic syndrome at baseline in
contrast to NHANES III data for persons over 20-years-old 22 percent in
the United States Ford ES, Giles WH, Dietz WH Prevalence of the
Metabolic
Syndrome Among US Adults: Findings From the Third National
Health and Nutrition Examination Survey JAMA 2002; 2873:356-359
Among people age 50 years and older with IGT, a recent analysis of the
NHANES III data set suggests 33 percent have the syndrome Alexander CM,
Landsman PB, Teutsch SM, Haffner SM NCEP-Defined Metabolic Syndrome,
Diabetes, and Prevalence of Coronary Heart Diseases Among NHANES III
Participants Age 50 Years and Older Diabetes 2003; 525:1210-1214
Components of the metabolic syndrome varied by age, gender, and race
Waist circumference and low HDL criteria were more prevalent in the
younger group; blood pressure was more prevalent in the older group;
triglycerides were equivalent across all groups
Waist circumference and low HDL criteria were more prevalent in women;
fasting plasma glucose and blood pressure criteria were more prevalent
in men
In order of prevalence, the metabolic syndrome was more prevalent in
Caucasians, then in African Americans, Hispanics, American Indians,
and Asians
Metformin was not effective in preventing the metabolic syndrome in women
and was less effective in
persons with the higher fasting glucose; it was
most effective in obese and younger men
Intensive lifestyle intervention prevented the metabolic syndrome by
decreasing waist circumference and blood pressure, not by correcting
dyslipidemia, surprisingly

In summary, Dr Shamoon emphasized that the DPP has provided a valuable
reservoir of stored samples and biomarkers and information to help design
new studies and chart the course in this complicated area of obesity and
its effect on the metabolic syndrome and the risk for diabetes and/or CVD

Discussion

In response to a question from Dr Garfield regarding the possibility of
there being a single target for drug action within the metabolic syndrome,
Dr Eckel said that, with the exception of hypertension, he thought the
other components could be targeted by a single intervention, particularly
if insulin resistance is considered the working paradigm For example, C-
reactive protein can be influenced by fibrins Other inflammatory markers
can be favorably modified Prothrombotic components as risk factors for CVD
can be improved by agents that improve insulin sensitivity

Dr Shamoon added that,
independent of the data about preventing diabetes
with metformin in DPP, enough data exists showing the effect of metformin
on preventing and treating the metabolic syndrome components The challenge
to the community, including ADA, is to define a treatable subgroup of
individuals who are most likely to respond to metformin Dr Shamoon
answered Dr Garfields question about what research support would be
needed from NIH and FDA to determine if the metabolic syndrome is an actual
syndrome or a coincidental aggregate of several syndromes, by suggesting
that NIDDK apply resources and mine new information from trials with
children One of the problems in studying the metabolic syndrome in adults
is that aging and obesity complicate the analysis For larger kinds of
analyses of the pathophysiology of the syndrome, he believed that children
or adolescents would be the best starting point

Dr Amy Rosenberg, FDA, noted that everybody recognizes there is a growing
epidemic of obesity and type 2 diabetes in children She pointed out that
children are a captive audience Most are in school until nearly 18 where
there is a real opportunity to focus on lifestyle issues, such as exercise
Currently, the
amount of time for recess and for physical education has
been cut back Dr Rosenberg recommended that there be a major public
health effort to evaluate the benefits of physical education programs in
schools and perhaps to expand them so that children will be inculcated with
the importance of diet and physical activity She stressed the enormous
benefit to be gained by preventing obesity in children, and therefore type
2 diabetes

Dr Shamoon agreed His researchers had published some papers in
collaboration with a Columbia University group analyzing 2- and 3-year-old
Hispanic children, from upper Manhattan, in whom the biomarkers of insulin
and C-reactive protein were already present and related to BMI

Dr Tamborlane referred to a paper being published in June 2004 by Dr
Caprio from Yale reporting that the incidence of metabolic syndrome is more
than 40 percent for obese teenagers and obese pre-adolescent children, a
real problem that supports the need for studies in children, not only for
prevention, but also to look at management and interventions Dr
Tamborlane suggested a MetNet, a network approach to not only do a very
large study that would take years but also smaller studies
focused on
interventions such as proof-of-concept studies of therapies for children
DPP showed that in 20- to 49-year-olds, metformin is as effective as
lifestyle Similar studies are needed for children Dr Tamborlane stressed
that researchers and physicians are focusing in pediatrics on the rising
incidence of type 2 diabetes, but they believe it is only the tip of the
iceberg-a warning signal for the future What they will be seeing as these
young people approach their 20s is an 18-year-old with a heart attack

Dr Garfield commented that shortly after publication of the DPP results,
ADA presented a position paper in Diabetes Care on recommendations based on
the DPP as well as other studies within a similar timeframe The paper
encouraged the lifestyle changes, but urged caution in prescribing drugs
for those at risk Dr Garfield asked if the speakers thought we were now
at a point when drugs could be recommended as part of NDEPs outreach
efforts

Dr Shamoon noted DHHS Secretary Tommy Thompsons prescription to Americans
has had at least a limited impact in encouraging the lifestyle
intervention As a national mandate or public health task, this is
important, but difficult to carry out
Dr Shamoon questioned, though, why
2 years after the publication of the DPP results, there is not an
indication for the use of metformin In New York at least, physicians are
eager to treat patients at an earlier level of their glycemic history, and
metformins safety record is remarkable

Dr Eckel stressed that the public health issue before the American public
and most of the civilized world is that the metabolic syndrome is set by
obesity with CVD as the primary outcome, either directly or by way of
diabetes Educating the public about lifestyle changes is important for
modifying obesity and for good health in general, but this cannot be
accomplished readily Therefore, Dr Eckel thought the pharmaceutical
industry would actually be the one to accomplish this task better than
healthcare professionals, researchers, or government agencies
Nevertheless, the message about eating better and being more active needs
to continue to be promoted A related issue to some extent is that even if
a patient fails weight reduction, the person still can become more active
and eat well The quality of the diet also can potentially impact hard
outcomes that relate to the consequences of obesity and the
metabolic
syndrome or diabetes Dr Eckel emphasized that these are messages that
need to be forthcoming, but there also is a need to take a more aggressive
approach through a pharmacological intervention in those patients who
cannot modify the components of metabolic syndrome by lifestyle alone

Dr Bob Silverman, Merck and Co, Inc, asked if it would be useful to the
therapeutic community if there were drugs available and indicated for the
treatment or the prevention of metabolic syndrome Dr Shamoon answered
that if there were agreement on the criteria for the metabolic syndrome and
the definition of the syndrome as a treatable entity, there already is an
effective drug to prevent metabolic syndrome in some groups such as younger
more obese men The results suggest that if one targets the glucose
component roughly described by the DPP cohort, metformin might be effective
in reducing other components of the metabolic syndrome

Dr Eckel stated the pharmaceutical industry should think about targeting
the metabolic syndrome as an intervention that could have long lasting and
favorable consequences, not only for diabetes but particularly for CVD

Dr Richard Bradley inquired, What does it
mean to prevent diabetes with a
drug that lowers glucose levels? Why not just treat patients who develop
diabetes? What benefit is actually being accrued? He also asked what would
be the endpoint to prove that a drug impacted the metabolic syndrome

Dr Shamoon explained that in treating diabetes, one actually treated
hyperglycemia, the salient feature of the disease There are different
components of hyperglycemia along the continuum of increased hepatic
glucose production, postprandial hyperglycemia, plasma glucose per se, and
other defects A drug that prevents the rise in hepatic glucose production,
which is metformins major effect, prevents the occurrence of fasting
hyperglycemia, which is the definition of diabetes So it is somewhat
circular in that sense

Two outcomes suggested by Dr Eckel would be either reduction in incidence
of diabetes or, since the definition for the metabolic syndrome in the
United States is based on atherosclerotic cardiovascular disease not
diabetes, reduction in CVD events He added that determining the
appropriate outcome for a drug to be approved was an important question for
discussion

Dr Harold Lebovitz, State University of New York, stated that
the
practicing physician requires more specific guidance They are being told
all about the metabolic syndrome and about CVD They are being told about
the severe consequences of diabetes However, when it comes to an
intervention, they are uncertain about what they can really do They have
known since 1960 that losing weight and exercising helps their patients
prevent diabetes, but in the real world this has not been effective Now
two drugs are known to be effective-metformin and acarbose They have been
used for years and have excellent safety records Dr Lebovitz strongly
recommended that these drugs be approved for use in treating patients with
the metabolic syndrome

Dr Orloff said that the group would probably spend some time at the panel
discussion on the issue of indication In a discussion about indications,
it will be important to look at who in fact is the target population, for a
broad prevention kind of indication First, insulin resistance seems to be
a unifying mechanistic starting point for the CVD risk-related
abnormalities that comprise the syndrome For diabetes, not everybody with
metabolic syndrome develops diabetes and not everybody with diabetes has
metabolic syndrome
Dr Orloff asked how to reconcile what appear to be
somewhat disparate results from the DPP with regard to prevention of
diabetes with metformin and prevention of metabolic syndrome with
metformin, given that the two are not 100-percent correlated in the current
observational database

Dr Eckel said that over half of the DPP subjects already had the metabolic
syndrome at baseline It is therefore difficult to look at the database and
the impact on diabetes versus the metabolic syndrome, when the majority
already had the outcome

Dr Shamoon added that such secondary analyses are difficult The question
seemed to be based on the metformin and lifestyle interventions being less
effective in preventing transition to the metabolic syndrome than they were
in preventing diabetes, thus raising the issue of choice of a target Dr
Shamoon said that is why he recommended targeting subgroups, since the DPP
subjects were specifically selected on the basis of having high glucose
resistance and therefore there may have been a group with the metabolic
syndrome with no degree of fasting hyperglycemia

Dr Eckel commented that interventions that modify glycemia may in fact
work through different
mechanisms, so the metformin effect on insulin
resistance, although it does improve insulin sensitivity, is mostly a
hepatic effect, whereas the TZD class of drugs has a plethora of effects
that involve potentially multiple tissues such as adipose tissue, muscle,
and liver The idea of modifying insulin resistance with drugs that have
multiple mechanisms of action is very different than thinking about an
intervention that is more glycemia targeted It is necessary to understand
drug action related to the indications for insulin resistance and glycemia,
both separately and together

Asked what would be appropriate endpoints for FDA to approve a drug for an
indication of insulin resistance or metabolic syndrome, Dr Eckel replied
that perhaps the criteria would be that the drug favorably modifies at
least two of the three out of five components of the metabolic syndrome He
added that this was a matter for discussion Dr Shamoon said that from a
gluco-centric point of view, in a high-risk population like the DPP
subjects, the lowering of triglycerides has to be done independently from
treatment of hyperglycemia Dr Eckel added that only 15 percent of the
subjects with the metabolic
syndrome also had hyperglycemia, using the 110
cutpoint

Session VII: Industry and Advocacy Perspectives
Moderator, Robert Meyer, Director, Division of Metabolic and Endocrine
Drugs, FDA

Drugs
Simeon Taylor, MD, PhD, Vice President, Discovery Biology, Pharmaceutical
Research Institute, Bristol-Myers Squibb, Hopewell, New Jersey

Dr Taylor listed the following objectives for pharmaceutical research and
development RD: production of safe and effective drugs, addressing unmet
medical needs, and, ultimately, extending and enhancing human life Dr
Taylor stressed these objectives are not trivial undertakings faced with
the challenges the industry faces such as the need for cost-effective drug
development and for increased success rates, especially in the very
expensive late stages of the RD process Learning which drugs fail fast
in earlier stages is critical as well as being able to predict go-no go
business decisions early on

To illustrate the RD process, Dr Taylor presented a schematic depicting
the two major phases: drug discovery and clinical development Together,
these phases tend to span nearly a decade The drug discovery phase
includes the following steps:

Target
identification
Target validation
Lead generation
Lead optimization
Pre-clinical safety

Dr Taylor stated that, during the basic research phase of drug discovery,
novel target identification and validation depend on efficacy and the
potential for mechanism-based toxicity, as with the PPAR? compounds and
their tendency to cause edema With the mapping of the human genome, the
industry now has more potential targets for disease Biomarkers provide
evidence for inhibiting targets and are useful to predict dose-response in
these In addition, through DNA and blood tests, biomarkers identify the
exceptional patients who may be at risk for toxic reactions to a drug The
practicing physician does not want to titrate the dose for each patient, as
is necessary for the patient with diabetes Of course, this principle of
one dose fits all has to be different in prevention trials

The second RD clinical development phase is comprised of the following
trials and elements familiar to those present:

Phase 1: Safety
Phase II: Efficacy
Phase III: Registration
Phase IV: Post-marketing

Dr Taylor pointed out that during the translational research period of
RD, surrogate markers not only
predict clinically relevant outcomes but
are key to acceptance of the drug for regulatory approval He stressed that
the Phase I and II trials conducted by the Government and by academia are
of great importance to the pharmaceutical industry in identifying
surrogates and in establishing safety and efficacy of drugs He
particularly noted the large, longitudinal trials such as the DCCT, UKPDS,
and the epidemiology of diabetes studies with the Pima Indians Dr Taylor
suggested that such trials offer excellent opportunities for public-private
partnerships in basic scientific research, translational research, and
developing regulatory policy

As an example of the benefit to the pharmaceutical industry of such
studies, Dr Taylor referred to the landmark DCCT study that demonstrated
that HbA1c could serve FDA as a surrogate marker in predicting the efficacy
of intensive glycemic control interventions to prevent the development and
progression of complications in type 1 diabetes Likewise, the DPP showed
that metformin was very effective in preventing type 2 diabetes in high-
risk persons with impaired glucose tolerance, especially in young obese
men Dr Taylor asked how much benefit would
need to be shown for FDA to
approve the use of metformin in this subgroup

To meet the objective of targeting unmet medical needs through development
of new drugs, Dr Taylor said he would select prevention of diabetes, the
metabolic syndrome, and prevention of the chronic complications of
diabetes, which are not being prevented as well as could be done with the
knowledge we have gained He emphasized that the pharmaceutical industry
would be facilitated by the establishment of clear criteria for approval of
drugs to address these unmet needs Such criteria exist in other areas, but
not for obesity and prevention of type 2 diabetes

In summary, Dr Taylor stressed that success could be achieved by the
partnering of Government, academia, and the private sector in sharing the
objectives to identify and develop safe and effective drugs that address
unmet medical needs and enhance and extend human life

Biologics
Alain Baron, MD, Senior Vice President, Clinical Research, Amylin
Pharmaceuticals, San Diego

Dr Baron defined biologics as those products that are often first-in-class
drugs and/or novel therapies for which RD research and development
largely takes place in settings other than
those of the large
pharmaceuticals Biologics include peptides, proteins, cytokines,
monoclonal antibodies, and cell- or gene-based therapies They tend to
employ non-oral routes and target important unmet medical needs The
scientific community and technology are often advanced in the area of
biologics far ahead of the regulatory guidelines for their use in the
practicing healthcare community Dr Baron stressed that, therefore,
regulatory risk and other uncertainties impede companies from investing in
RD programs in novel therapies

Dr Baron emphasized that industry takes decided financial, scientific,
clinical, and developmental risks in translating basic research advances
and bringing novel therapies to the marketplace There is a clear value
chain Following the RD stage, with its inherent risks, there is also the
risk involved in the regulatory review stage Finally, industry assumes a
high degree of responsibility for the long-term safety and for the
acceptability of such therapies following their introduction into the
marketplace Industry recognizes that innovation does not come without
risk, but it must carefully define and implement risk controls at various
levels of the
process

The previous day, Dr Baron had asked where in the list of serious diseases
one should place type 1 diabetes on a scale of 1 to 10, if cancer is an 8
He explained that the importance of the answer to this question is that the
seriousness of a disease is a paramount factor in determining the amount of
risk one is willing to take to develop a therapy and to use the therapy
His answer would be that type 1 diabetes and insulin-requiring diabetes are
incredibly serious and require very serious therapies Given the choice
between type 1 diabetes at the age of 16 and stage 1 lymphoma with a 95-
percent cure rate, Dr Baron would opt for the lymphoma He urged that
diabetes be taken as seriously and with the same sense of urgency as cancer
and AIDS, diseases for which patients undergo an incredible degree of
therapy risk, as do patients who undergo pancreatic transplantation, islet
transplantation, immunomodulation, and immunosuppression Today, in spite
of important advances in insulin therapy, glycemic control for the type 1
and insulin-requiring patients is not optimal They do not achieve their
glycemic goals Dr Baron said he would therefore place the emphasis in his
presentation on
the issue of risk and the need for a better glucose-
lowering therapy

Dr Baron offered the hope that in time there will be a cure for type 1
diabetes through immodulation, stem cell, islet transplantation, islet
growth, and gene transplantation therapies Meanwhile, over the past 20
years, intensive insulin therapy with glucose monitoring has enabled
patients to lower their glucose, but with increasing insulin dose the risk
of hypoglycemia also increases Dr Baron noted that every new insulin
coming on the market is associated with an increase in hypoglycemia or loss
of control or both The sweet spot for each person is highly
individualized, which is why an insulin vial does not have a label
specifying how to use it The patient learns how to use it over time With
hypoglycemia, the patient backs off the insulin With hyperglycemia, the
patient adjusts the insulin dose This can take place on a moment-by-moment
basis Clinics are staffed with nurses and diabetes educators to help
patients with this Adjusting the dosage takes time Dr Baron pointed out
that, thus, patients have accepted this incredibly high risk of insulin
therapy, which is actually a dangerous therapy

In his opinion,
while waiting for an actual cure, the greatest unmet need
in type 1 diabetes and insulin-requiring type 2 diabetes is the need for a
novel therapy to provide another control variable beyond the single-control
variable we have today, insulin While insulin is clearly necessary for
life, it is not necessarily sufficient to achieve optimal glycemic control
Risk and regulatory guidelines continue to be daunting problems to
development of such a system, not just technical- and patient-related
barriers

Dr Baron stated that the critical question then is What is an acceptable
risk-benefit ratio for novel therapies? Also, if a second control variable
is added to intensive insulin therapy, how can it be studied? This is a
real challenge If there is a partial cure, for instance with a cell-based
therapy in which a little bit of insulin is coming out of the cell but not
enough to make the patient insulin independent, how can the therapy be
studied and the risk-benefit ratio be evaluated? Are blinded studies with a
novel therapy appropriate-and safe-when the sweet spot is individualized
for each patient and takes so much time to determine? Dr Baron concluded
that the insulin experience in a
blinded study-all that had been learned
about diet, exercise, insulin dose, monitoring, and insulin adjustment for
each subject-would actually be lost in a blinded study testing a second
control variable, making such studies impossible to do

Another question raised by Dr Baron was Is superiority of HbA1c always
necessary for approval? Dr Taylor had made the same point with regard to
implantable insulin therapies IITs Variables other than HbA1c matter in
patients with IIT, such as postprandial glycemic excursions Although
HbA1cs of 7 and 75 are achieved in patients treated with insulin, they
have incredible excursions and anxiety over those excursions So the HbA1c
level really does not help in that regard Patients want glycemic control
that is more predictable, with fewer fluctuations and less hypoglycemia
Weight control matters to patients Quality of life matters to them
Complications are a major concern Dr Baron recommended that the
scientific community and industry listen to patients rather than being
concerned only with validated instruments that might be had 20 years from
now

In discussing risk and a cure or partial cure, Dr Baron raised questions
about the value of insulin
independence or partial independence at any
cost He asked who would determine the level of acceptable risk-patients,
industry, FDA? Dr Baron noted these are very difficult questions but ones
that must be answered if innovation is to take place

On the path to novel drugs and consideration of the value chain, Dr Baron
stressed that each partner has a large area of responsibility FDA has to
be basically dispassionate yet passionate They have to be careful and also
innovative This is a very tight, tight balance Dr Baron said the
solution requires risk management Clearly, all the answers cannot be in
place before going to the marketplace The marketplace teaches us about a
lot of things, as has been seen with insulin Years of experience have made
insulin acceptable in the marketplace He continued that all innovation has
risk, and there is a learning curve Reducing regulatory uncertainties are
essential to spur innovation Ultimately, however, if these therapies are
not brought to the marketplace, there will not be an incentive for any more
research translation, and all will suffer; most of all the patients will
suffer

Devices
David Horwitz, MD, PhD, Vice President, Medical and Clinical
Affairs,
LifeScan, Inc, Milpitas, California

Dr Horwitz explained that he was representing the device industry and, in
particular, the Advance Medical Technology Association and the Blood
Glucose Working Group He planned to speak primarily about in vitro
diagnostics and innovations in blood glucose monitoring, including home
glucose monitoring and, with a liberal definition of in vitro, continuous
glucose monitoring

Dr Horwitz pointed out that innovations in glucose monitoring systems have
improved accuracy, speed of testing, sample size, the ability to sample
from alternative anatomic sites, and the ability to gain more information
from meters data summaries, trend analysis, and so forth Monitors are
easier to use, are more convenient, have safety features such as 24-hour
patient hotlines, and have special features, including data analysis
through interfaces with computers

For the future, Dr Horwitz foresees continuous monitoring, open-loop
control of insulin pumps, the artificial pancreas, ie, mechanical
pancreas, and the ability to optimize and individualize diabetes
management with actionable health information Achieving these goals will
require exploring and facilitating a
number of research, regulatory, and
reimbursement areas Relevant questions include:

How can we advance and enhance the regulation of in vitro diagnostics?
How can we address the reimbursement challenge?
How can we fund the research to move the field forward?

Regulation Dr Horwitz commended the FDAs progressive efforts to aid the
device industry The availability of published guidance documents make the
regulatory path clear and facilitate the ability to get products to market
more quickly and cost-effectively The new 510k paradigms enable industry
to take a shorter loop for a less risky product or for measures that are
not likely to affect product performance For example, the regulatory path
has been simplified by the ability to classify open-loop infusion pump
controllers as Class II devices, even though they do not have a true
predicate device Another important regulatory advance cited by Dr Horwitz
has been the ability for de novo classification of a device as Class II
when there is not a predicate device, instead of going the Pre-Market
Approval PMA route, which has facilitated getting devices on the market

The FDA Modernization Act FDAMA has enhanced communication with
FDA
through the ability to meet with FDA and solve problems ahead of time,
instead of conducting a study, submitting the data, and then finding out
that the wrong study was conducted from the FDAs regulatory point-of-view
This has also helped to get products to the marketplace more quickly Dr
Horwitz remarked that the FDA Office of Combination Products is becoming
more and more important as products become a combination of devices and
biologics, devices and drugs, biologics and drugs, and so forth In the
area of in vitro diagnostics, the Office of In Vitro Diagnostics, which
looks at products throughout their lifecycle, has eased the process of
working with FDA

In considering how FDA can prepare for new technologies, Dr Horwitz said
that one obvious area that FDA is currently engaged in is global
harmonization of premarket reviews He noted that industry must deal with
differing requirements, types of studies, and device standards in different
parts of the world, which increases costs and time for developing products
and bringing them to market Achieving global harmonization is a
particularly important area for the industry Another helpful area would be
to develop criteria for
device down-classification, such as reclassifying
Class III devices without a predicate device down to Class II where the
regulatory path is clearer and products can be on the market sooner This
is critical in the device area, particularly for in vitro diagnostics,
where product lifecycles are often only 2 or 3 years long before the next
generation comes out, unlike pharmaceuticals that often have a 10-year or
longer lifecycle

Dr Horwitz noted that screening for diabetes has been getting a lot of
attention While there is some controversy over who should be screened,
when screening is indicated, glucose test strips are not an approved
indication for screening Nevertheless, the device firms are constantly
being asked for glucose test strips for screening Dr Horwitz said that
resolving this issue depends on establishment of a public health policy for
diabetes screening that considers and balances the tradeoffs between
diagnostic accuracy standards and the accuracy of the test strips and
establishes appropriate criteria The clinical studies needed to establish
this indication involve large populations that are beyond the scope of the
industry to study and may benefit from
NIH-sponsored studies

The review of genetic diabetes testing was another area in which Dr
Horwitz felt FDA needed to develop criteria to regulate in vitro
diagnostics test systems, test reagents, test kits, and related
pharmacogenetic products that look at various genetic aspects related to
diabetes As more and more drugs and different mechanisms for the treatment
of diabetes are considered, there is a need to choose what drug might be
the most important and which genetic factors are most important Dr
Horwitz suggested that some of the regulations today, such as those related
to analyte-specific reagents, are perhaps no longer completely relevant
given the new directions being taken in genetic research He added this is
an area that needs some advanced thinking to speed the regulatory processes
as these diagnostics begin to reach the market

Reimbursement Dr Horwitz pointed out that blood glucose monitoring
equipment seems to be continually targeted for Medicare payment reductions,
creating a major reimbursement challenge for the industry As the incidence
of diabetes grows, the cost of monitoring will obviously grow The problem
is being specifically called out now in Medicare
legislation Reimbursement
limitations directly impact patient access to what, for many, is the most
appropriate technology in managing their diabetes Dr Horwitz added that
lack of reimbursement for this equipment has the potential to affect blood
glucose monitoring compliance by patients, and the impact of non-compliance
on blood glucose control has clearly been shown Reimbursement issues also
limit the availability of new technologies, because they are not
reimbursable and thus not immediately billable Obviously, from a business
standpoint, reimbursement affects the willingness of companies to invest in
additional RD to provide new products and new services for the market and
can inhibit development of new molecular tests and pharmacogenomic
solutions, as well as new devices As an example of the reality of the
issue, Dr Horwitz cited data showing that Medicare costs from 1982 to 2001
grew by 382 percent, while spending for in vitro diagnostics was
essentially flat, which, as a proportion of overall Medicare expenses,
indicates a significant decrease in spending for in vitro diagnostics

Dr Horwitz noted that there has been an increasing public health policy
emphasis on the
importance of diabetes as a public health measure and, as a
result, an increase in awareness of diabetes He stressed that todays
meeting is evidence of the concern as are DHHS Secretary Tommy Thompsons
frequent statements about preventing diabetes and its complications At the
same time, the Centers for Medicare Medicaid Services CMS have had to
enact policies that discourage diabetes testing and monitoring More cuts
are planned for the future In noting this discrepancy in public policy,
Dr Horwitz said this is currently a major issue for the industry, and one
that needs to be addressed through proper research on what really is cost-
effective therapy

In closing his remarks, Dr Horwitz listed the following areas of needed
research according to the device industry:

Effectiveness of screening using blood glucose monitors, which is going
to have more and more impact as the potentially diabetic population
grows
Medical and economic benefits of tight glycemic control in type 2
diabetes In type 1, this is clearly established In type 2 diabetes,
there is an important need to translate research findings into clinical
practice, especially in the primary care community,
where therapy targets
are not being reached and where educational efforts are needed to provide
the data that glycemic control is important
Optimization of ways to achieve the desired glycemic control, an area
where research is significantly lacking

Dr Horwitz suggested the following research questions regarding optimizing
ways to use self monitoring of blood glucose to achieve glycemic control:
When should it be done? How should it be done? By whom should it be done?
How should it be used to guide therapy? Is postprandial testing important?
Is control of postprandial glucose important? Advances being made include
advances in biomarkers and surrogate endpoints, which can certainly help in
studies Questions remain about non-glycemic or non-HbA1c endpoints There
are also the quality of life issues that have been discussed at this
meeting and frequency of hypoglycemia issues as indications for therapy,

Recommendations for fostering innovation in diabetes care, presented by Dr
Horwitz for the industry, included regulations that facilitate the
introduction of innovative products; payment systems that place emphasis on
early detection and optimization of treatment to prevent
complications; and
increased research dollars to find ways to make living with diabetes easier
by discovering solutions for better screening, better management, and
better cellular, genetic, and pharmacogenomic therapies

American Diabetes Association
Nathaniel Clark, MD, RD, National Vice President of Clinical Affairs,
American Diabetes Association, Alexandria, Virginia

Dr Clark acknowledged the collaborative relationship ADA has had with NIH,
particularly NIDDK, and with FDA over a number of years He noted that an
important role of ADA, as the representative of the 18 million persons with
diabetes and the increasing numbers of those who are at risk, is to be the
translator of the research being funded The ADA call center receives 20
thousand calls per month from persons asking questions about diabetes,
questions about this drug or that, about treatment options, and so forth
ADA also receives 300 thousand visits per month through its website and
requests for the books, magazines, and journals the association publishes
Dr Clark stressed that this connection with the diabetic and pre-diabetic
populations and their families and friends provides ADA with a tremendous
opportunity to
get the word out The overall question for him as he sits
in meetings like this one is, What is the word? What is the word that we
should be getting out?

The mission of the American Diabetes Association is to prevent and cure
diabetes and to improve the lives of all of those affected by it
Prevention has obviously been in the press of late, and ADA has been very
active in this critically important and highly challenging area Dr Clark
cited CDC data that predicts that a child born this day has a one-in-three
chance of developing diabetes in his/her lifetime New numbers based on the
redefinition of pre-diabetes are that perhaps 40 million Americans have pre-
diabetes When researchers and clinicians came together and discussed
defining a normal blood glucose level in the fasting state as less than100
mg/dl, not the previous 110, Dr Clark wondered if the full significance of
that decision was clear to everyone This simple change doubled the number
of people with pre-diabetes The public health impact of doubling the group
was not a major topic in the scientific discussions about whether the data
warranted this redefinition How to treat 40 million persons with pre-
diabetes is now a
primary issue for research translation and thus an issue
of major concern for ADA

As mentioned earlier, ADA saw the impressive DPP as a proof-of-concept
study and put out a position paper addressing the DPP results Dr Clark
said the main message from the DPP was that lifestyle change is very
effective in preventing or delaying progression to diabetes in those at
high-risk, roughly twice as effective as using a medication such as
metformin The main issue for ADA was how to translate that result, what
should be done to operationalize it The National Diabetes Education
Programs Small Steps, Big Rewards and other programs that Secretary
Thompson has supported have helped advance the cause of diabetes
prevention ADA has supported these

As a Registered Dietitian, in addition to being a physician, Dr Clark
wondered if the prevention of diabetes through lifestyle change concept was
still being undersold It is very difficult to receive reimbursement for
dietitian services or for increasing a patients physical activity level
On the other hand, there is a drug that works, and so the question is
raised, Why not approve this drug for prevention and use it? As a
physician, Dr Clark admitted it
is much easier to write a prescription
than it is to get patients to undergo lifestyle changes On the other hand,
the benefits of losing moderate amounts of weight and increasing physical
activity are so enormous globally-across a persons complete health
spectrum-compared to the relatively small gains of simply improving blood
glucose levels with a medication He added that these obviously are
controversial areas

Dr Clark explained that the reason ADA interpreted the DPP the way they
did emphasizing lifestyle change over medication was because of their
deep concern that once that study was published and people saw that
metformin worked, practitioners would immediately move to the drug option
and ignore the lifestyle option This concern continues and a recent
example of their reason for it was an interesting article in the Washington
Post about pre-disease The article spoke of an endocrinologist in
Washington, DC, who prescribed metformin for a 15-year-old girl, even
though her laboratory results of blood glucose levels did not qualify for
pre-diabetes by any criteria, new or old He put her on the drug because he
felt that her insulin level was somewhat elevated Dr Clark stressed
that
responses such as this to research results clearly raise questions about
indications for use of a drug, about endpoints, and about the goals of
treatment

Referring to Dr Nathans earlier concern about not appropriately using the
drugs we have now for treating diagnosed diabetes, Dr Clark raised the
issue of diverting attention from this valid concern by talking about drugs
for pre-diabetes In the field of diabetes, there also are already many
drugs to treat hyperglycemia, hypertension, and dyslipidemia to prevent
complications in diabetes, yet these are not being used optimally to treat
these problems While it is important to support approval of new therapies
by FDA, there is also a need to promote better use of existing, proven
therapies

Dr Clark introduced the problem that ADA and the public face in trying to
interpret research studies that are done in very different ways The DPP
was an excellent, randomized, long-term, controlled trial that produced
excellent data Dr Clark though is repeatedly asked by the media to
comment on other studies being published by colleagues He is presented
with such questions as Is it true that Oolong tea prevents diabetes? That
drinking five
to six cups of coffee a day prevents diabetes? That eating
peanut butter prevents diabetes? That having your blood tested for an
increased iron level predicts diabetes? The public is being challenged to
compare a study done by correlating numerous variables using a computer to
show that five to six cups of coffee prevents diabetes with the DPP that
showed that lifestyle change and metformin prevent diabetes The publics
attempt to compare and interpret results from such disparate study designs
is a challenge for the ADA, the FDA, and NIH in terms of their prevention
translation efforts

The second part of ADAs mission is seeking a cure for diabetes Dr Clark
said this begins with supporting good research Along with NIHs expansive
efforts, ADA provides seed grants to encourage young researchers and to
enable them to collect the data to apply for an NIH grant Islet cell
research is an area about which ADA receives many questions

The largest area that Dr Clark is personally involved in has to do with
improving the lives of those with diabetes, including the development of
ADAs evidence-based clinical practice guidelines Dr Clark emphasized
that defining the cutpoint for HbA1c or LDL or
any of the diabetes-related
factors has to be based on good research ADA largely relies on NIH for
this basic and clinical research

In the area of medication, ADA obviously relies on the FDA in terms of what
gets approved ADA and FDA have collaborated well to date and plan to
continue doing so in the future in looking at how drugs are used and what
problems might occur For example, a working group assessed the effect of
glitazones in terms of edema and congestive heart failure As the
manufacturers came through and presented their data, a member of the FDA
staff was present to comment on the validity of the data and assist the
working group in preparing their paper At a recent meeting on
antipsychotic use and the development of diabetes, an FDA representative
was invited to present the agencys experience in this area Lastly, Dr
Clark said that, at the request of FDA, a future working group would be
looking at hypoglycemia, including to what extent hypoglycemia should be
used as an endpoint in new drug approvals and equipment approvals and if
there is there is special relevance of night-time hypoglycemia

Dr Clark noted that there has been an explosion over the last 10 years in
the
number of drugs to treat diabetes, specifically new insulins, new oral
medications, a number of drugs for dyslipidemia, and also a number of ACE-
inhibitors and ARBs for treating blood pressure This plethora of new
drugs, along with what we know about diabetes and risk factors, has led to
the issue of whether simply having diabetes is a sufficient indication to
be on all these pills Also, is there a need to develop what has been
called the polypill-a single pill that contains, for example, aspirin, an
ACE inhibitor, and a statin and is prescribed upon diagnosis of diabetes?
Dr Clark added that then the question would become if for those with pre-
diabetes or the metabolic syndrome, who are also at risk, should these
drugs be introduced earlier and earlier into peoples lives, even though
all these drugs have potential side effects?

According to Dr Clark, there also are current questions applicable to
laboratory tests ADA is very proud of the HbA1c standardization program
using a reference range, which was largely based on data from the DCCT The
Association is interested in trying to standardize the insulin assay, so
that this assay can be used more effectively They are also looking
at the
same issues with regard to C-peptide Dr Clark explained that a very
important question that comes up now is in regard to home testing of HbA1c
and of lipids Once a laboratory test is moved out of the clinical arena
where there is a physician or other experienced healthcare provider to
determine when to get the test and to interpret the test, costs may
increase while benefits may not change or decrease For example, to what
extent is it a good idea for patients to check their HbA1c once a day, once
a week, or once a month as current guidelines suggest checking 2-4 times
per year? Will such home testing provide the patient with any truly useful
information?

In summary, from the American Diabetes Associations perspective, Dr Clark
said they take very seriously the responsibility to dispense reliable
information, to help those with diabetes whom ADA serves, and to work
closely with NIH and FDA Certainly, together the three organizations can
accomplish more than any one group can separately

Juvenile Diabetes Foundation International
Robert Goldstein, MD, PhD, Chief Scientific Officer, Research Department,
Juvenile Diabetes Research Foundation International, New York

Dr
Goldstein said he was really a pinch-hitter for either an articulate
child with diabetes or a mother JDRF is run by dedicated volunteers who
would be very interested in everything that was discussed at this meeting
He stressed that, in addition to NIH, FDA, academia, and the pharmaceutical
industry, the future also depends on foundations and advocacy groups

The mission of JDRF is to find a cure for type 1 diabetes and its
complications through supporting research Cure is defined as restoring
blood sugar to normal, preventing complications, and preventing diabetes
Dr Goldstein explained that over the past 6 or 7 years, JDRF has been
becoming increasingly focused, as opposed to becoming increasingly
broadened, in its research agenda for a cure He listed the following
significant outcomes on a 5-year path toward a cure:

Generate permanent euglycemia by islet transplantation without chronic
immunosuppression
Generate a replenishable, stable, universal source of glucose-responsive
beta cells and insulin-secreting cells that resist immune attack for
human transplantation and begin Phase 1 trials
Restore euglycemia and insulin independence by activating endogenous beta

cell regeneration and inducing immune tolerance to beta cells in animal
models of autoimmune diabetes Dr Goldstein remarked that regeneration
with a capital R is becoming a topic for a variety of disorders
Create permanent euglycemia and prevent complications with a closed
mechanical loop artificial pancreas
Encourage novel approaches to predict and novel therapeutics to prevent
and treat complications
Accurately predict the risk of type 1 diabetes and develop novel
therapeutics to prevent diabetes, including a vaccine to prevent this
disease JDRF is working with a variety of NIH institutes, as well as
governments outside the United States, to accomplish this

Dr Goldstein explained that although it is not a typical cure item, the
closed loop artificial pancreas is a goal that responds to children and
parents wanting their lives to be better in terms of their ability to
manage and control their disease and, thus, they would settle for a device
to help them do that while waiting for the promised cure JDRF has stopped
funding this area of research and secured funding of approximately 4
million from the Department of Defense specifically to promote
innovative
work to accomplish this goal

After 9/11, JDRFs funding leveled off somewhat In FY 2003, the
associations 81 million research budget was divided up approximately into
57 percent for achieving euglycemia, 27 percent for prevention of
complications, and 16 percent on prevention of type 1 diabetes
Dr Goldstein said that this year, JDRF will spend approximately 93
million on research

Presenting a pie chart depicting where JDRF research funds are spent, Dr
Goldstein noted that 38 percent of the 2003 money was allocated outside the
United States JDRF has partnerships with medical research councils in 10
to 15 countries that advocate for type 1 patients and promoted enhanced
activity on their research and public health agendas in their respective
countries He pointed out that both Finland and Sweden, where there is a
tremendous amount of type 1 diabetes, have wonderful healthcare systems
that permit JDRF to do clinical trials that probably would be more
difficult to do in the United States They collect enormous amounts of
phenotypically well-characterized patient specimens that JDRF is trying to
bring together so that other researchers will have access to them When
clinical
trials are conducted outside the United States, the study groups
look to FDA for ultimate guidance This is also true for the EU regulatory
system, and so forth Dr Goldstein assured those present that JDRFs
funding of research outside the United States has not been in order to work
where the rules were less difficult, but to go where there are excellent
patient resources and dedicated physicians

Dr Goldstein stated that JDRF is sponsoring clinical trials in islet
transplantation-a cooperative clinical trial with NIDDK and another one
with CMS and NIH in Medicare recipients, which will provide a post-kidney
transplant opportunity JDRF also is organizing its five largest European
groups to complement this US activity Dr Goldstein said that over the
past couple of years since the Edmonton protocol publication, the focus of
attention has been on freeing patients from having to take insulin shots
He stressed that, unfortunately, many of the publications have emphasized
insulin-independence and have under-emphasized the ultimate therapeutic
benefit of islet transplantation itself Over time, insulin-independence
drops off; however, the therapeutic benefit remains Dr Goldstein
recommended
that more attention be paid to documenting and observing this
ultimate benefit Taking some insulin would not be a terrible imposition on
the patient population currently receiving transplants

New onset type 1 diabetes immune intervention represents a frustrating
paradigm for JDRF, according to Dr Goldstein JDRF has a study group
working with CD3 The group is based in Brussels, but the Principal
Investigator overseeing the trial is in France The research reagent was
not permitted to cross the border from England to France, but was allowed
to go from England to Brussels The government of Belgium supports a
diabetes registry and tracks the patients This is an example of the kind
of opportunities that exist overseas In the United States, JDRF is
sponsoring anti-CD3 trials in new onset type 1 diabetes Anti-CD3 has shown
a potentially reasonable effect, but given over a period of time, it also
has some toxicity issues To date, Dr Goldstein feels the issue of issue
of trials in children, particularly prevention trials in at-risk children
who are quite healthy, has not been adequately addressed This partially
explains why most type 1 prevention studies are being done with insulin,
because
a lot is known about insulin and about its safety Dr Goldstein
emphasized that working with the next generation of therapeutic agents is a
huge challenge in efforts to move forward Many, if not most, of the
current approaches to immune modulation involve toxicities that the
scientific community is not used to and thus do not know whether these
toxicities are theoretical or real Dr Goldstein stressed that a way must
be found to deal with this issue if the field is to advance

Other clinical trials supported by JDRF include advanced glycation
endproduct AGE inhibition for which the group has seeded a grant that is
blocking RAGE receptors and trying to work on complications An issue in
this clinical trial is the difficulty of obtaining high quality material
Dr Goldstein explained that there is not a lot of venture capital
available for these very early novel therapies The FDA in particular does
not like the use of research grant-level material; the agency wants higher
quality material Dr Goldstein commented that this was another area for
future discussion

Dr Goldstein also raised the issue of collecting ell-characterized patient
populations in order to begin to stratify and find
subgroups, particularly
for genetic studies or therapeutic trials in molecular medicine, genomics,
and proteomics He stressed that this is a resource that all groups
currently need NIDDK has made a commitment to accept the challenge of
assembling these critical patient populations in a manner suitable for
researchers to gain access This often requires re-consenting people from
international studies to have modern and up-to-date consent to do new
studies Once this resource is freed up, Dr Goldstein is optimistic that
the work will go forward more quickly in type 1 than in some other disease
areas where such resources do not exist

Regarding stem cell research, Dr Goldstein stated that JDRF took the
position, politically and scientifically, after August 2001, that more work
was needed than could be done in the United States at NIH Therefore, JDRF
has partnered with half a dozen countries in an effort to derive new stem
cell lines, characterize existing lines to study beta cell development,
promote information exchange and research according to the highest ethical
standards, and make the stem cells freely available to researchers by
removing the constraints that currently exist with
the NIH lines The
effort is being carried out by the International Stem Cell Forum, which was
organized in the United Kingdom by the Medical Research Council and is made
up of groups from numerous countries, including NIH from the United States
Additional information about the Forum and its objectives is available at
http://wwwmrcacuk Dr Goldstein announced that within the next 6 to 9
months, the Forum will be characterizing about 50 new cell lines, including
ones with human fetuses He acknowledged that for FDA and for anyone
wanting to do therapeutics based on embryonic stem cells, the challenge
will be how to bring potential therapeutics from outside the United States
into the United States; however, it is JDRFs hope that this will occur,
ultimately, but not next week, of course

Dr Goldstein concluded by saying JDRF also has a program for supporting
small companies, usually headed by academics who have come up with a novel
idea It is sort of a pre-SBIR Small Business Innovation Research type
program

Discussion

To lead off the discussion, Dr Meyer noted that the industry speakers had
presented a litany of challenges and areas of therapy
requiring research
He asked Drs Clark and Goldstein if they saw the gaps or failures to
achieve optimal therapy in clinical practice being driven by lack of
adequate therapies and/or devices or by inadequate use of the therapies
currently available

Dr Clark responded that, in general, his feeling and that of ADA was that
there are an enormous number of tools that are not being used effectively
at this time There clearly are gaps, and ADA supports and looks forward
eagerly to new drug and device development Meanwhile, his and ADAs wish
would be for better utilization of what already exists rather than waiting
for the creation of something new

Dr Goldstein declined to give an answer for JDRF, but personally, he
agreed with Dr Clark that the United States is not doing all that it could
do In Scotland, for example, all persons with diabetes are registered in a
database, along with every laboratory test, x-ray, prescription, and so
forth Of course, Scotlands population is around 5 million people Anyway,
4 or 5 years ago, the database showed that insulin-dependent diabetics were
not getting eye exams, so they instituted a mandatory eye check and
achieved a 95-percent compliance This
did not increase their costs because
they had a basic infrastructure in place Dr Goldstein said one had to be
amazed at a functioning healthcare delivery system that could accomplish
this type of thing In other countries, particularly ones interested in
islet transplants, their quality control and their ability to achieve tight
control is exceptional In Finland, for instance, it does not matter who
the patient is, access to all the specialty information is available for
anyone with type 1 diabetes That is not true in the United States

Dr Taylor agreed that delivery of the healthcare technology that exists is
imperfect, but was unsure if that presented an either/or choice regarding
development of new therapies versus application of current ones Type 1
patients who receive the absolutely very best care available in the world
with the best utilization of the technology still do not achieve normal
HbA1c They still have diabetic complications, which is why JDRF is looking
for a cure Similarly, with metabolic syndrome, cardiovascular risk, and
type 2 diabetes, people who receive the very best available medical care
still have problems controlling their weight Dr Taylor suggested that
the
issue may be that therapies need to be more user-friendly in order to do a
better job of getting people to use the available therapeutic modalities
An implantable closed-loop pump, for example, or an artificial beta cell,
would make patient compliance much easier Dr Taylor said there would
still be economic issues to address, but outcomes would be better

Dr Clark commented that there might be more success in diabetes clinics if
there were fewer meters or monitors available, which were selected based on
patient and provider characteristics Today, for example, some children
have three or four different types of meters, and there is therefore no
easy ability to download results effectively because every instrument
requires its own software program When the different manufacturers are
asked about standardization, the answer is that there is no possibility at
this time of standardizing the technology

Dr Tamborlane brought up the reimbursement challenge in attempting to run
a large-scale treatment program for youth with Type 1 diabetes He said the
fee-for-service model to pay for intensive diabetes care for 1,000 children
is just not a doable operation As a result, his group must
subsidize the
care with money from whatever source they can Dr Tamborlane stressed that
other reimbursement models were needed, such as global fee models or
disease management models He suggested that this was a target for the
advocacy groups to pursue He mentioned that JDRF has a committee and a
grant to look at how to pay for the personnel required to implement
advanced technologies

Dr Goldstein responded that JDRF had not solved the problem yet but were
continuing to work toward a solution The associations focus has been on
research so it has been difficult to shift to paying attention to fixing
the healthcare system

Dr Clark added that even though we have good meters and good insulins,
there is not a willingness to reimburse the time of healthcare
professionals that is needed to help patients make maximum use of these
existing technologies For example, physicians and their staff members
spend a lot of time going over glucose levels with patients, particularly
over the telephone, and there is no reimbursement for this The
reimbursement issue is an important point in physicians better applying
what is known about diabetes care

A member of the audience asked what processes were
available to help
investigators and evaluators make conscious, deliberate use of the unique
expertise of patients More to the point, in order to provide patients with
access to therapies that have ambiguous results in terms of being safe and
effective for average patients in a static protocol, what can be done to
enable patients to conduct their own personal clinical trials to determine
what is safe and effective for them As background to the question, the
inquirer said that when her daughter was diagnosed with type 1 diabetes 15
years ago, the Chief of Pediatrics at Joslin Diabetes Center told her that
once she learned to care for her daughter under his tutelage, she would
know more about her care than he would know This statement was confirmed
by many other professionals over the years until now, at 19, the patient
knows better how to care for herself than any physician does In looking at
the development of new therapies and in designing clinical trials, how are
procedures decided for evaluating whether the new therapy is right for an
average patient and whether the therapy will have the proper effect on
average levels of blood glucose, granting that there is no such person as
an
average patient? New trials and evaluations are based on fixed
protocols Her daughters protocol changes every day, sometimes every hour
Use of HbA1c was a huge advance for research, but it is wrong to call it a
gold standard because there is never an average blood glucose

Dr Baron responded that on the device side, glucose meters, in particular,
are largely a consumer-driven market Market research begins at the user
level Different users clearly have different desires, different wants, and
different preferences That is one reason why there are so many multiple
products Dr Baron suggested that large databases are obviously needed to
obtain the statistics for the average patient A challenge that must be
dealt with is how to deal with small numbers of persons in special
situations Should this be part of the practice of medicine or part of the
regulatory process?

Dr Horwitz commented that patients make choices all the time For some
investigators, pumps are the ultimate form of delivery of insulin
Currently there are approximately 120,000 to 150,000 patients on pumps
Clearly, most patients with diabetes have opted not to use pumps Others
have opted to discontinue the pump and to go on
to Lantus therapy Others
have discontinued regular insulin and gone to newer insulin analogs Dr
Horwitz agreed that all patients are different and all of them have their
own paradigm of what is best for them Mean values do not respect the
individual With respect to type 1 diabetes, Dr Horwitz believes it is
such a devastating disease, that patients do need to be listened to more
carefully

Dr Taylor remarked that industry and regulatory agencies do work together
to ensure that compounds meet minimal standards of safety and efficacy
before they are made available for patients in clinical trials Once a drug
is approved, there is in effect a post-marketing clinical trial to further
monitor the drugs safety In exceptional cases, where early data are
especially encouraging, the FDA and the industry partner work to make a
product available on a compassionate use basis if it is believed that there
is value in making it available to people who would otherwise be harmed by
preventing early access to the product, even if the product has not met the
normal regulatory standards for approval There are many controls involved
in this early availability, but the practice does recognize the issue
that
for some patients, this is an appropriate course of action

Dr Taylor went on to say that it is sadly true that, for the most part,
patients with either type 1 or type 2 diabetes must be viewed as a more or
less homogenous group, Physicians are taught to treat the average patient
However, Dr Taylor said that over the next 10 or 20 years, genetic ways,
for example, will be found to identify patients who vary from the average
and who have special characteristics These patients will then be treated,
not necessarily as absolutely individualized patients, but as members of a
definable group of patients for whom particular treatment regimens have
been identified as being safe and especially effective He added that this
is one of the important areas for contributions from Government and private-
sponsored research

Dr Horwitz added that gene identification of subtypes of type 1 and type 2
diabetes is needed There are patients with type 1 diabetes who can achieve
reasonable glycemic control and not gain a massive amount of weight Others
cannot This needs to be recognized, rather than simply telling the weight-
gaining patients they are not doing the treatment correctly Residual
C-
peptide secretion in a patient enables that patient to get better control
Not everybody has the same degree of residual C-peptide secretions Dr
Horwitz recommended identifying patients who have particular needs He said
it is wrong to ignore the fact that there are highly motivated people who
cannot achieve the results from a therapy for which other people are
successful

Dr Alex Szidon, DARA BioSciences, asked the panel to identify elements or
hallmarks to keep in mind that would foster preclinical and early clinical
development of new diabetes and obesity drugs further down the road This
would be a valuable benefit to take away from the symposium, along with the
discussions about clinical outcomes and endpoints

Dr Horwitz responded that it is difficult to ask that investments be made
in targets that are uncertain with regard to the risks and the regulatory
process In the drug development industry currently, it is better to be
number two in coming up with a novel class of medications because you can
piggyback on number ones risks and experience This happened with statins
Dr Horwitz thinks this will also be true with ACE inhibitors The ability
to take a novel chemical entity or
a biological therapy all the way to the
marketplace is so daunting today because of the uncertainties that, in
order for choices to be made early on, there needs to be a better sense of
the risk-benefit ratios in terms of what patients want and what the FDA
thinks is in the best interest of patients, rather than what is the easiest
regulatory door to get through Dr Horwitz recommended that the FDA
continue to aggressively initiate conversations with industry about better
risk management methods Otherwise, he believes it will be very difficult
for people to invest in true innovation early on

Dr Taylor disagreed slightly It is partially true that to get a drug
approved that is the nth in its class is appealing because of the lower
risk On the other hand, to get a drug that is say 5th in its class but
that truly adds value, that really distinguishes itself, that is going to
make a real difference for patients, is extremely challenging For the most
part, people in the industry try to balance the risks If there is a class
of drugs that are seen as having benefit but there is a problem with the
drug, people will try to improve it There needs to be room for improvement
with any drug to
make a difference with patients and have a commercial
success It does make life easier if some of the risks are known, if a
company knows what kind of data will be needed to have a new class of drug
approved This allows the company to make a fair and reasonable assessment
of its risks It is the unknown and unmeasurable risks that are
particularly discouraging

Dr Horwitz said that Dr Taylors statements were correct In a big
company with a portfolio of risk, there can be four or five versions of a
drug that is known to work and that people have accepted The difficulty is
when people look for go-no-go decisions and the regulatory path is unclear
This makes for a very risky situation in the minds of the business people
Dr Horwitz stressed that for true innovation to occur, and it is
happening, industry does have to be bold They are very capable when the
science is there to be harnessed Industry has to be convinced that the
need is serious, for instance for better type1 treatments They are aware
of this seriousness for AIDS and for cancer, where in a sense the risk is
minimal because death is the other outcome To deal with the epidemic of
diabetes in children, where the level of
incidence of children with type 2
diabetes is replacing the level of those with type 1 diabetes, is going to
require bold thinking on the part of research and industry It is a
daunting task There are many tough decisions that all parties must make-
the Government, industry, academia, advocacy groups, patients, healthcare
professionals, third-party payers, policymakers and decisionmakers, and the
general public who ultimately pay the bills

Session VIII: Targeting Safe and Effective Prevention and Treatment: Steps
Forward by FDA and NIH
Moderators: David Orloff, MD, FDA, and Judith Fradkin, MD, NIDDK

Panel Members: Drs Robert Eckel, Christopher Saudek, Harry Shamoon, Robert
Sherwin, William Tamborlane, and Simeon Taylor

Dr Orloff convened the panel and expressed his appreciation to Dr
Garfield and to Dr Fradkin for their assistance in organizing this
meeting He particularly wanted those present to be aware of Dr Fradkins
clarity of insight about this area and her knowledge of the people at the
forefront of the issues

Dr Fradkin responded that the partnership with Dr Orloff had been
excellent and expressed her appreciation for those who had come together to
share their knowledge,
perspectives, recommendations, and commitment to the
goals of the meeting She noted that the speakers had presented eloquent
descriptions of both the public and the private burden of diabetes As
stakeholders, they had offered a wide range of perspectives Dr Fradkin
acknowledged that selecting targets and moving forward was a challenging
task for all and, in particular, for NIH and FDA

Dr Fradkin asked the panel to comment on two issues:

What might NIH and FDA do to further enhance the research climate and to
enable industry to translate the discoveries coming from academia into
new therapies?
What is a meaningful outcome for prevention and treatment studies in
diabetes?

With regard to the second question, Dr Fradkin listed insulin independence
or increased beta cell function or C-peptide preservation as choices for
outcomes for islet transplantation She added that a meaningful outcome for
treatment or prevention of the metabolic syndrome is also important, since
the syndrome is becoming a large, emerging problem as a collection of risk
factors for CVD and diabetes

Dr Shamoon responded that the workforce issue is one that NIH could be
addressing Referring to NIHs
Roadmap Initiative, he remarked on the
enormous number of targets, possibilities, and opportunities that
fundamental science has created in the last 20 years The gap now is the
lack of trained clinical investigators to carry the science forward He
emphasized that an important task of the next generation of clinical
investigators is to take the up these problems in a way that addresses
public health Dr Fradkin commented that NIH recognizes this need and
continues to be active in encouraging medical students to pursue research
careers

Dr Tamborlane stated that for youth with type 1 diabetes, he would
encourage industry to move forward in the technological development of
artificial pancreases as a key area New sensors are overcoming obstacles
that stood in the way for the past 20, 30, or 40 years Dr Tamborlane
thought it likely that the artificial pancreas will be a successful mode of
treatment well before the problems and risks from islet transplants and
immuno-suppression are resolved in children

Regarding meaningful outcomes for type 1 diabetes, Dr Tamborlane listed
HbA1c, reduced risk of hypoglycemia, improved quality of life, and reduced
treatment burden He said that the 900
type 1 diabetes patients at the Yale
clinic are doing so well with an HbA1c of 75 that he tells them that, for
the most part, they have beaten diabetes This control of their
hyperglycemia will have a tremendous impact on late complications The
problem is that they must beat diabetes every day That is the burden, and
that is what exposes them to risk Dr Tamborlane stressed that this daily
struggle is the top problem that needs to be solved

Dr Sherwin said that an important area for NIH support would be
development of drugs, particularly a vaccine for type 1 diabetes This is
not area that is on the radar screen of the large pharmaceutical companies
because of the size of the market In clinical trials, NIH could help
determine the risk-benefit ratio for islet transplantation once the
procedures move ahead sufficiently for it to be potentially more readily
available; identifying the risk-benefit ratio would help with reimbursement
and product development issues In reducing the risk of CVD, trials are
needed to answer what extent lowering glucose in people with the metabolic
syndrome contributes to the equation of treating dyslipidemia and lowering
blood pressure to optimal levels,
along with aspirin treatment Dr
Sherwins bias is that hyperglycemia does have an impact, but FDA would
need evidence of this as an endpoint for the metabolic syndrome Meaningful
endpoints for type 2 diabetes are first, prevention of CVD; second,
prevention of complications of diabetes; and third, achieving a sense of
well-being, which is hard to define but is relevant

Dr Sherwin continued that the daunting task is identifying surrogate
endpoints There are valid endpoints for cholesterol, blood pressure, and
glucose He asked if there was a valid endpoint yet for treating insulin
resistance, as this would be a major problem for FDA in relationship to the
metabolic syndrome Dr Sherwin stressed this was an area that needed
further discussion and debate in a larger forum to resolve Other issues to
be discussed further include endpoints for treatment of persons with pre-
diabetes and pre-CVD Something other than CVD itself is needed Dr
Sherwin recommended that preparing a position paper for FDA on these
subjects was in order

Dr Taylor stated that preventive medicine is a huge challenge If someone
has pneumonia, the person is given penicillin and gets better-a very short-
term endpoint
Whereas preventive medicine has much longer time spans DCCT
required about a decade He explained that it is difficult for a
pharmaceutical company that has a patent clock ticking to consider trials
in which the patient may well expire by the time the outcome study is done
Dr Taylor said it would therefore by very helpful if there were validated
surrogate markers, like HbA1c, viewed as an outcome rather than as a kind
of risk factor He suggested that Phase II studies could identify
biomarkers that could help industry assess risk and make decisions early
on, even if they were not FDA-approved biomarkers For example, once HbA1c
and LDL were validated as mechanisms for insulin and statins, respectively,
then industry knew that any mechanism that changed these biomarkers was
going to predict a good outcome This is not known for HDL If it was known
that HDL is truly the good cholesterol and that raising it would be
beneficial, then HDL as a surrogate marker would stimulate industry to seek
ways to raise it

Dr Eckel pointed out that raising HDL per se could not be the endpoint
because of other factors equally important to an outcome For example, one
of the ways to raise HDL cholesterol
the most is eating the Atkins diet On
the other hand, a diet of high intake of saturated fats and cholesterol
will likely not provide a satisfactory outcome for CVD

A panel member commented that NIH needs to continue to investigate the
genetic, molecular, cellular, and pathophysiologic causes of disease It is
not NIHs job to develop drugs but the institutes can assist the process
through clinical trials like those suggested by Dr Sherwin It was noted
that NIH sponsors workshops for medical students to teach them clinical
research skills and introduce them to clinical research as a potential
opportunity for their future Also, through its K-series awards, NIH has
several mechanisms to develop clinical support for the transitional
scientist What was needed was support for R01 investigators who must
compete with cellular and molecular biologists The speaker suggested that
in investing in clinical research, which is the pathophysiological basis of
drug development to some extent through helping to understand the
mechanisms by which drugs work, NIH is assisting the industry Another role
NIH plays is in training those who have the tools and capability of
understanding the mechanisms of
disease operation

A panel member spoke about the major issue of long-term weight maintenance
after weight loss He said he was not actually convinced that there was a
health benefit to weight reduction if the weight loss is not maintained,
although all the biomarkers say there is Current clinical trials have
demonstrated the transient nature of weight loss Once a person is obese,
that person tends to maintain that body weight against most odds The
speaker stressed that the public message of prevention of weight gain is
what should be heeded NIHs LookAHEAD is an important clinical trial to
show whether or not people at high risk of CVD can, under the best of
circumstances, not only lose weight, but maintain the weight loss over
years and gain a long-term benefit with respect to cardiovascular outcomes

In reference to raising HDL by different mechanisms, a panel member
referred to a recent article in the New England Journal of Medicine about
cholesteryl ester transfer protein CETP inhibitors that showed that CETP
inhibitors raise HDL and lower LDL and triglycerides Broussau, ME et al
NEJM 350:1505-1515; April 2004 He raised the concern that the mechanisms
by which HDL changes and
how the changes relate to the atherosclerotic
process are unknown For instance, if HDL is raised by modifying its
clearance, then the HDL is being raised in a mechanism that does not relate
to its ability to reverse cholesterol transport It is the lipid-poor HDL
that binds membranes in reverse cholesterol transport It is not modified
clearance

Dr Taylor stressed that his earlier comments about the need for support
for research in biomarkers for atherosclerotic disease or the metabolic
syndrome was not specifically about HDL but about how critically important
these problems facing the Nation are with respect to the growing numbers of
obese youngsters If the country must wait for a decade-long clinical
trial, the epidemic of heart disease in 20- and 30-year-olds will already
be taking place

Dr Saudek commented that as FDA moves forward in the management of
diabetes, the agency will have to increasingly think of the burden of the
disease Established biomarkers can show that something is effective in
managing HbA1c or managing biomarkers for CVD and so forth He stressed
that the burden of treatment is a major factor today While there are
patients who are excellent at managing their
treatment regimens, there are
many more who are not and are not capable of doing so Type 1 diabetes
involves dozens of interventions every day Anything that eases that burden
of treatment is going to pick up another small percentage of people who
will be successful in managing their disease

Dr Saudek continued by saying that for type 2 diabetes, losing weight is
critical Losing weight and getting active is a major need for a large
portion of the population of the United States; however, this fact has not
penetrated very far Given this situation, Dr Saudek asked what criteria
are being set up for approval of, for example, obesity drugs He said that
he sat in on a discussion for a company a few years ago and learned that
FDA had a criterion for effectiveness in managing diabetes that was
independent of blood glucose lowering In his practice, the first thing he
did for overweight diabetics was institute a weight management program
Thus, would not an effective weight reduction medication be valid as a
treatment for diabetes regardless of whether it had been shown in animals
or in people that it had an independent effect on blood glucose? Other
items that have been on the back burner,
such as insulin antibodies, also
should be continuously addressed

Dr Taylor suggested that major opportunities existed to help in
understanding new targets and to identify what would be good targets,
including genetic markers or other kinds of biomarkers to define
subpopulations that are particularly likely to benefit in terms of efficacy
or safety from a particular mechanism In the areas of drug development and
a regulatory path for drug approval, he said that important questions for
prevention of type 2 diabetes have followed the excellent work of the DPP
The DPP showed that there is a statistically significant impact of
lifestyle and/or metformin This statistic is important from the viewpoint
of science-based evidence, but it does not clarify the question of whether
or not a person should be treated prior to developing diabetes to delay the
onset for a year or a little longer Is that year delay really important?
Does something irreversible happen during that year? Other questions are
Should glucose be lowered even earlier? Are beta cells irreversibly
destroyed during that time period? Dr Taylor stressed that if FDA had
data showing there was a particular window of opportunity
for lowering the
glucose before there was irreversible damage, then people would take
notice In other words, there are policy implications for therapy beyond
showing a statistically significant difference in an endpoint

Dr Shamoon reminded those present that the design of clinical trials
frequently creates an artificial situation The assumption often is that
what happens in the clinical trial can be extrapolated to the broader
population, such as translating the interventions from DPP to other persons
with IGT, without conducting further trials Dr Shamoon said that some of
the frustration about having scientific-based evidence that is not being
put into practice is caused by setting the bar too high It is very
difficult to cost-effectively transition into everyday clinical practice
the results of a carefully designed clinical trial The subjects in the DPP
cohort who had all the CVD risk markers and transitioned to diabetes were
already close to becoming diabetic However, in this high-risk IGT cohort,
40 percent of those in the intensive lifestyle group and 30 percent of
those on metformin had normalized their 2-hour and fasting glucoses after 1
year After 4 years, 30 percent of
the intensive lifestyle group had normal
glucose tolerance In those who went back to normal, all surrogate markers
improved in a favorable direction

Dr Taylor said that he was not questioning the validity or importance of
the DPP results in suggesting learning more about the window for
irreversible harm to the beta cell His question was based on the burden
the regulatory and public health agencies face before spending the money
needed to try to prevent type 2 diabetes in all those considered at risk or
subjecting them to even the small risk of taking a medication His
intention was to suggest that further information would be helpful to them
in making their decisions

Dr Orloff agreed that additional information would be helpful He said
that the discussion so far clearly indicated that, regardless of what part
of the process a group is involved in, the concept of prevention is very
complicated FDAs responsibility in this area is as complex or more
complex, perhaps, than in any other area of the agencys work He presented
some of the principles under which FDA works and described how they come
into play in some of the practical aspects of FDAs job FDA is charged
through the Food,
Drug, and Cosmetic Act with labeling of drugs for safe
and effective use The mandate involves generating and translating into
labeling an enumeration of the expected benefits and risks for an
intervention He reiterated that this is extremely complicated in the
context of prevention Some of the issues in the prevention of type 2
diabetes involve determining which endpoints truly assess benefit Another
key issue is identifying the target population for the drug-who will
definitely benefit, who may possibly benefit, and who will not benefit

Dr Orloff stressed that in prevention versus treatment, the bar actually
has to be raised with regard to requirements for safety Even though a drug
may have been shown to be exceedingly safe for other indications, there are
always risks associated with drug treatment and their relative importance
obviously increases with decreasing risk of development of the target
condition, as exists in disease prevention

Dr Tamborlane commented that when he has participated as a consultant on
Phase III trials with children and questioned why the pharmaceutical
company was doing things a particular way when he thought it should be done
a very different way, the
feedback was This is what FDA wants When asked
if the study group had had an opportunity to discuss this issue with FDA,
the response was usually No Dr Tamborlane asked Dr Orloff what was the
best way to deal with such a situation, where a company calls in a
consultant with particular expertise in design and conduct of these types
of trials and runs into this kind of obstacle

Dr Orloff answered that one of the things that has come out of the new
legislation has been an easier and more enforceable process for formal
interactions between FDA and industry In addition, there are also many
informal interactions FDA gives guidance on the agencys current best
thinking on an issue Dr Orloff explained that his position and attitude
is that current is a keyword meaning that everything is always open to
change as more information is brought to bear on an issue He assured those
present that he would certainly listen if a drug company came to him and
said they thought there was a better way to do something based on expertise
gained from other similar trials by using a different method than the FDA-
specified one that would not only answer the questions FDA considered
important but answer other
questions that may be even more important Dr
Orloff added that bringing effective, safe products to market is an
enterprise where reasonable people have to come to agreement Sometimes
reasonable people will disagree, and that is life, but there is always a
way to come back and say, Tell me where you think I am wrong and tell me
why, and then we will continue the conversation

Regarding FDAs policy of calling together a panel of experts-very reliable
experts- to review the final product of studies and advise FDA, Dr
Tamborlane suggested that perhaps there could be a mechanism for meeting
earlier on with an impartial panel, perhaps from NIH or academia, to
provide advice to both sides on evaluation of products and study designs
and so forth

Dr Orloff responded that part of the process of guidance development
involves, or can involve, open public hearings That is what has been done
in the past and what is intended for future guidance development in
obesity, osteoporosis, and diabetes In addition, there is a Notice and
Comment process, whereby notice of the existence or issuance of a draft
guidance document is made in the Federal Register and comments are
requested To the greatest
extent possible, the FDA guidance system is an
open process

Dr Orloff next addressed the advisory process that Dr Tamborlane had
referred to that reviews individual products This process is to some
extent constrained due to the availability of limited information and
limited expertise not only on the subject matter, but in making the bridge
to regulatory decisions, which is complicated Advisors are not expected to
have regulatory experience Referring back to the separateness of the
guidance process for establishing the required criteria, Dr Orloff
stressed that no one wants to get to the point of an advisory committee to
discuss a particular product unless some ground rules have been laid
previously so those present understand the basic rules for approval of this
type of product

Dr Saudek raised the issue that in these 2-day advisory meetings, a great
deal of information is shared Could not that process become integrated,
not as a formal regulatory-related process, but as a way to get ongoing
conferencing with staff at FDA by objective, outside people who are not
linked to the company submitting the product? This could make the guidance
development process less passive People
have to initiate contact when
something is put in the Federal Register Dr Saudek suggested that a
special panel be brought together to discuss important study design issues
related to prominent subjects in public health, as for instance, the
studies to evaluate drugs for type 2 diabetes in adolescents Input from
the academic community might have improved those study designs

Dr Richard McFarland, Center for Biologics, FDA, agreed with Dr Orloffs
remarks about FDA having an open door In the Center for Biologics that
deals with many novel products that stretch the regulatory paradigm, there
is an advisory committee that meets to discuss issues in the realm of
translation between science or clinical trials and regulation This
committee, which does not review products for licensure, meets two, three,
or four times a year Public forums on held on various topics that have
generated substantial disagreement The committee is composed of standing
members and supplemented with members of other FDA advisory committees and
other people in the particular field under discussion FDA members also
participate Transcripts of the meetings are on the FDA website These
meetings contribute to the
development of FDAs current way of thinking
that Dr Orloff mentioned

Dr Taylor added that industry frequently discusses their relations with
FDA and he had never heard anybody say that FDA people were not willing to
meet with them There may be times when industry thinks it knows what FDA
has said and does not think another meeting would be productive, or there
may be delays in scheduling a meeting that interfere with a timeline and
make the meeting unnecessary later However, Dr Taylor said he would agree
that the door has always been open

A symposium participant commented that a lot is known about the risks for
heart disease, and preventing a myocardial infarction MI is common
practice When talking about pre-diabetes, people are really referring to
pre-myocardial infarction When someone is in the pre-myocardial infarction
state or has had a prior myocardial infarction, the person is treated with
a statin to lower high cholesterol The Scandinavian Simvastatin Survival
Study Lancet 344:1383, 1994 studies and data from other studies on
cholesterol lowering clearly show that when cholesterol was lowered in
patients with IGT, the risk of MI was lowered and mortality was lowered
In
spite of all the data that has been accumulated, the current recommendation
for treating IGT is basically to watch it, unless the person has elevated
blood pressure or elevated glucose, then the patient is treated for each of
those problems Much of the discussions about preventing diabetes are
largely about preventing microvascular disease, while these patients are
currently at risk for macrovascular disease The speaker thus recommended
that if cholesterol were treated in the IGT patient, even if the patient
had a normal LDL of 130, then the patient would be treated the same as a
patient with a prior myocardial infarction or a patient with diabetes In
response to a comment from Dr Tamborlane that there is no current evidence-
based data showing that lowering glucose is going to prevent cardiovascular
disease in the IGT group at high-risk for diabetes, the speaker said he was
referring to giving the IGT patient a statin not a glucose-lowering
medication

The symposium participant continued that not everybody with IGT develops
diabetes Although patients with diabetes tend to have macrovascular
disease and most will die of macrovascular disease, diabetes is a
microvascular disease
He noted that many patients are so elderly that they
never will suffer from microvascular disease, even when they develop
diabetes Meanwhile, there is a large body of data showing a huge impact is
possible on CVD in these patients, and it is not being done The
participants point also was that a clinical trial is not needed to answer
every question that comes up, when there already exists good data from
other trials that can be analyzed and applied He urged the group to mine
the data that they had, stressing that the approaching epidemic is serious
enough to call for such measures

Dr Sherwin said that in the consensus data, he believed there was a
recommendation to treat this high-risk population for cholesterol

Dr Fradkin stated that studying the metabolic syndrome from the viewpoint
of treating glycemia in persons with pre-diabetes or the metabolic syndrome
did not seem to be the practical direction to take Therapies studied in
relationship to the metabolic syndrome would likely affect multiple
components of the syndrome, rather than a specific component such as
glycemia On the other hand, the DPP interventions clearly did not exert
their effects solely on glycemia

Another
member of the audience followed up on the issue of the amount of
accumulated data that exists Researchers in CVD are conducting large
outcome trials and pooling the data in very large registries to find out
more about the natural history of cardiovascular disease The speaker
recommended that academia, NIH, and FDA do the same in diabetes This could
enable the sub-phenotyping of patients and increase understanding of how
these sub-groups respond to different drugs There are not a lot of
incentives for individual pharmaceutical companies to partner with one
other to do this, and this is not likely to happen; however these companies
do have quantities of data that are left behind as they move on to other
therapies Dr Fradkin noted that this was a good suggestion

Dr Tamborlane said that if IGT is defined as a disease, the outcome for
prevention would be a normal fasting glucose In DPP, the lifestyle
intervention was the most effective, but metformin was also highly
effective in restoring glucose to normalcy In the metabolic syndrome,
lowering blood pressure to normal would apply

A participant stated that defining a disease requires that there are
specific problems related to that
disease Other than by testing for IGT
itself, there are no symptoms of IGT in a patient It is unknown what
complications, if any, are associated with IGT In discussing biomarkers,
the speaker noted that they had not discussed the question of what
biomarkers are pathogenic and what markers are not In IGT, there is a
glucose abnormality that associates with cardiovascular disease The
question is whether or not IGT is the cause of early cardiovascular disease
or just a marker for it It was suggested this was the type of question
that an NIH study could address To call IGT a disease, it would have to be
shown that in itself IGT causes morbidity, not that it is just associated
with another disease Biomarkers have to be identified as to whether they
are a cause of a disease or whether they are an association of the disease
Which raises the question about obesity Is obesity a disease? Or is it
only associated with disease

Dr Shamoon responded that he had no doubt that obesity is a disease

On the other hand, Dr Eckel said he would call obesity a disorder, a
physiology of an expanded fat mass, the consequences of which are diseases
such as hypertension, dyslipidemia, glucose intolerance,
diabetes,
obstructive sleep apnea, pulmonary hypertension, and so forth There is
reasonably good evidence that in the early 20th century, through World War
I and World War II, being fatter allowed for greater survival when famine
ensued As a survival advantage, obesity has gone astray today because
people live so much longer

Dr Orloff remarked that the overall goal for all those present-industry,
academia, advocacy groups, and the government-was to extend life and to
improve health for type 1 and type 2 diabetes patients Based on the
recurrent message heard at todays meeting that tools currently available
were not being used optimally, he asked those present if they felt an NIH
consensus conference on prevention would now be appropriate to address the
issues raised in this meeting Dr Orloff commented that unconflicted, NIH
consensus conferences had historically been successful in moving fields
forward at a practical level in instructing physicians in how to manage
their patients and use the tools that they had available

Dr Saudek agreed that consensus was particularly needed regarding what to
do about the metabolic syndrome and about IGT He added that it would take
a good deal of
work to arrive at such a consensus

Dr Fradkin explained that, in general, consensus conferences are held when
the data is at a point to ensure a consensus can be reached She said she
believed that many of the important questions raised in todays meeting
needed to be addressed and answered before there would be sufficient clear
data for a consensus conference on, for example, longer-term transplants
The joint ADA-NIH group that looked at interpreting the DPP essentially was
a consensus conference that assessed the current state of the data There
really has not been much additional data beyond the DPP at this point that
would justify holding a consensus conference

Dr Taylor agreed that there are many questions left to be answered about
current and potential future therapies and suggested that there would be
some value in reaching consensus on what are the most important questions
to ask This would help in developing a plan for obtaining answers Dr
Fradkin agreed that clarifying the questions and the steps needed to answer
them would be a good approach before trying to arrive at consensus on
therapies based on current answers

Dr Orloff and Dr Fradkin thanked the speakers,
panelists, organizers, and
participants for their contributions to an excellent and successful
meeting

The meeting was adjourned at 12:40 pm

Source:lchd.com