In this issue, you will find updates on the scope of the diabetes Chief, Division of Diabetes, Endocrinology, and Metabolism …
C M E - C E RT I F I E D N E W S L E T T E R
DIABETES PULSE
Editors Note
Dear Colleagues:
Update on Insulin Therapy
H I G H L I G H TS F RO M T H E 6 6 t h S C I E N T I F I C S E S S I O N S O F T H E A DA
University of Medicine and Dentistry of New JerseyCenter for Continuing and Outreach Education
The 66th Scientific Sessions of the American Diabetes Association, held June 9-13, 2006, in Washington, DC, offered a rich array of scientific and educational presentations on the epidemiology, mechanisms, and management of diabetes mellitus and associated metabolic disorders This newsletter summarizes the highlights of the sessions, providing you, the practitioner, with information of greatest relevance to your clinical practice In this issue, you will find updates on the scope of the diabetes epidemic; new data on glycemic control, with a focus on insulin and physiologic regimens; and results of late-breaking clinical trials of new therapies, including GLP-1 and DPP-IV inhibitors There are also reports on two important symposia on current approaches to insulin therapy: Modern Diabetes Management: Effective Insulin Strategies–Integrating Art and Science, which I chaired, and
Inpatient Insulin Therapy: Benefits and Strategies for Achieving Glycemic Control I hope you find this issue of Diabetes Pulse educational and informative Sincerely, Stephen N Davis, MD Chief, Division of Diabetes, Endocrinology, and Metabolism Rudolph Kampmeier Professor of Medicine Professor of Molecular Physiology and Biophysics Vanderbilt University School of Medicine Nashville, Tennessee
Controlling Glycemia and CV Risk Factors in 80 of Patients Offers Potential for Reducing Serious Complications by 10 Million and Cost Savings of 150 Billion
In his address to the 66th Scientific Sessions of the American Diabetes Association ADA, Robert A Rizza, MD, President, Medicine Science, of the ADA, issued a call to action to US physicians to commit themselves to improving the care of their patients with diabetes Dr Rizzas address, Cure, Optimal Care, and Total Commitment–What If They Happened Tomorrow? urged increased funding to find a cure for diabetes Until a cure is found, the ideal, according to Dr Rizza, would be optimal care, or 100 of patients achieving the ADAs recommended goals, but as a more realistic approach, he urged physicians to adopt the goal of committed care,
wherein at least 80 of people would achieve the recommended goals Such committed care would reduce the number of serious diabetes complications by more than 10 million and save 150 billion over 30 years, according to results derived from Archimedes, a mathematical model of the health care system originally developed at Kaiser-Permanente Archimedes uses equations to simulate metabolic pathways and the processes that lead to complications1 It has accurately predicted results of major randomized trials and uses data from clinical trials to generate clones of individual patients to model the course of their disease over time The Archimedes projections used by Dr Rizza showed that without intervention, over the next 30 years, diabetes will result in 121 million serious adverse events related to diabetes, including 35 million heart attacks, 13 million strokes, 6 million episodes of renal failure, 8 million new cases of blindness or eye surgery, 2 million amputations, and 62 million deaths The model predicts that a cure for diabetes would reduce the overall number of these serious events by 14 million per year, a number that more than justifies spending far more than the current costs of
research to find a cure, said Dr Rizza Dr Rizza presented the Archimedes analysis of what the impact would be if all patients with diabetes received optimal care to meet recommended ADA goals: A1C of 7, blood pressure of 130/80 mm Hg, the use of statins to normalize cholesterol, a body mass index of 25 kg/m2, the use of a daily baby aspirin, and smoking cessation Optimal care would result in 18 million fewer serious diabetes-related events over the next 30 years Today, however, optimal care is not always achievable because of comorbidities, poor adherence to treatment, and/or current reimbursement policies, and Dr Rizza described what he called committed care as a more realistic goal With committed care, 80 of patients would achieve the ADA goals minus body mass index, which is omitted in this model Implementation of committed care could lead to an overall reduction in serious
Release Date: September 2006 Expiration Date: October 31, 2007 Jointly sponsored by the University of Medicine and Dentistry of New Jersey UMDNJ and UMDNJCenter for Continuing and Outreach Education and by QED Communications, Inc
This activity is supported by an educational grant from sanofi-aventis,
US
Copyright 2006 UMDNJCenter for Continuing and Outreach Education All rights reserved, including translation into other languages No part of this activity may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval systems, without permission in writing from UMDNJ Center for Continuing and Outreach Education
1
TARGET AUDIENCE
This activity is designed for primary care physicians and other health care professionals with an interest in the treatment of type 2 diabetes
LEARNING OBJECTIVES
Upon the completion of this activity, participants should be able to: Discuss the most recent developments related to glycemic control in patients with type 2 diabetes Understand how these new developments affect the use of insulin therapy in the overall treatment strategy Discuss how this emerging information should impact clinical decision making for patients with diabetes Discuss the treatment of glycemia in hospitalized patients
complications by more than 10 million over the next 30 years: a 30 reduction in heart attack risk 5 million fewer, 5 reduction in stroke risk 600,000 fewer,
7 reduction in risk of renal failure 12 million fewer episodes, 10 reduction in the risk of serious eye disease 18 million fewer cases of blindness or eye surgery, and 11 reduction in deaths 18 million fewer The cost savings would be an estimated 150 billion over the next 30 years
The Number of Americans With Diabetes Will Increase by Nearly 200Over the Next 45 Years
The number of Americans with diagnosed diabetes is expected to increase by 198 by the year 2050 according to new data presented by K M Venkat Narayan, MD, MPH, of the Division of Diabetes Translation of the Centers for Disease Control and Prevention CDC This exceeds a previous estimate of the projected burden of diabetes in 2050, based on US government statistics up to 1999, which had put the expected number of people with the disease at 39 million Dr Narayans new estimate is based on data from the US National Health Interview Survey, 1984-2004, combined with US Census Bureau data for the years 2000-2004, and predicts that the number will instead be 483 million, a jump of 93 million people over the earlier estimate2 What Dr Narayan and colleagues found has profound implications for the US population and health care
system The number of Americans with diabetes is expected to rise from 162 million in 2005 to 483 million in 2050, a prevalence of 12 compared with the CDC prevalence estimate of 56 in 20053 Dr Narayans research suggests that 87 of this increase is due to the increase in incidence rates of diagnosed diabetes between 2000 and 2004 The fastest-growing age group with diagnosed diabetes is expected to be those aged 75 years or older 470 in females and 423 in males, and the fastest-growing ethnic group is expected to be Hispanic females 495 and Hispanic males 465
METHOD OF INSTRUCTION
Participants should read the learning objectives and review the activity in its entirety After reviewing the material, complete the post-test consisting of a series of multiple-choice questions The activity is complemented with references that contain the rationale for the correct answer to each post-test question, as well as a description identifying the section of the activity that contains the correct answer, allowing participants to review the material as needed, thus finalizing their educational participation Upon completing this activity as designed and achieving a passing score of 70 or more on the
post-test, participants will receive a letter of credit awarding AMA PRA Category 1 Credit TM and the test answer key four 4 weeks after receipt of the post-test, registration, and evaluation materials Estimated time to complete this activity as designed is 1 credit hour
ACCREDITATION
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education ACCME through the joint sponsorship of UMDNJCenter for Continuing and Outreach Education and QED Communications, Inc UMDNJCenter for Continuing and Outreach Education is accredited by the ACCME to provide continuing medical education for physicians UMDNJCenter for Continuing and Outreach Education designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit Physicians should only claim credit commensurate with the extent of their participation in the activity This activity was peer-reviewed for relevance, accuracy of content, and balance of presentation by Demian Elder, MD, and pilot-tested for time required for participation by Syed Hasan, MD, and Kinshasa Morton, MD
Early Initiation of Insulin Therapy Has Benefits for
Glucose Control
Initial treatment of glycemia in type 2 diabetes involves medical nutrition therapy and oral hypoglycemic agents OHAs However, a good argument can be made for starting insulin therapy earlier to maximize glucose control and prevent the development of disease-related complications During a debate at the ADAs 66th Scientific Sessions, Michael Alvarsson, MD, PhD, of the Karolinska Hospital in Stockholm, Sweden, argued against delaying insulin initiation by asserting that early treatment has been proven to rapidly normalize glucose levels, may improve beta-cell function by providing a rest for beta cells, and may temporarily improve endogenous insulin secretion The approximately 50 decrease in insulin secretion already present at the time of diagnosis, Dr Alvarsson said, has effects on cardiovascular CV function that can be eased by early insulin treatment Further, patients treated early with insulin have fewer episodes of uncontrolled hyperglycemia over time, require lower insulin doses, and appear to experience less weight gain In response to objections that insulin use affects patients quality
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DIABETES PULSE
FACULTY
Update on Insulin Therapy
Editor Stephen N
Davis, MD Chief, Division of Diabetes, Endocrinology, and Metabolism Rudolph Kampmeier Professor of Medicine Professor of Molecular Physiology and Biophysics Vanderbilt University School of Medicine Nashville, Tennessee CME Activity Academic Advisor Demian Elder, MD UMDNJRobert Wood Johnson Medical School Department of Medicine New Brunswick, New Jersey Reviewers Syed Hasan, MD University of Alabama at Birmingham Department of Family Medicine Huntsville, Alabama Kinshasa Morton, MD UMDNJRobert Wood Johnson Medical Center Department of Family Medicine New Brunswick, New Jersey
of life because of the need for injections, Dr Alvarsson said that the United Kingdom Prospective Diabetes Study showed that quality of life is affected more by complications of diabetes than by intensive efforts to control glucose Mayer B Davidson, MD, of Charles R Drew University of Medicine and Science in Los Angeles, on the other hand, argued for maximizing oral therapy before starting insulin, saying that insulin therapy presents a major lifestyle change for patients because of the necessity for injections and self-monitoring of blood glucose Dr Davidson said that a better approach is gradually
escalating intensification of treatment, starting with metformin to maximally tolerated dose, then adding other oral agents to maximally tolerated doses before initiating insulin He said that physicians dont intensify oral therapy enough Dr Davidson felt that more time is needed to properly educate patients about their disease Dr Alvarsson, however, noted that eventually all patients will require insulin and that there are potential benefits, still being investigated, to insulin therapy over oral agents In terms of overcoming barriers of logistics or patient resistance, he noted that physicians attitudes are all important in how their patients accept treatment Dr Alvarssons themes were reinforced by Stephen N Davis, MD, of Vanderbilt University School of Medicine in Nashville, Tennessee, who chaired the symposium Modern Diabetes Management: Effective Insulin Strategies–Integrating Art and Science Dr Davis presentation, Early Insulin Therapy: The Key to Glycemic Control, reviewed the rationale for early insulin therapy Normal biphasic insulin secretion is altered in the progression from impaired glucose tolerance IGT to frank diabetes, and initially, the first phase of insulin
secretion in response to a meal is reduced in patients with IGT4 When diabetes becomes overt, first-phase insulin secretion is abolished and the second phase of insulin secretion is reduced by 50 to 80 Figure 15 Early insulin use to replace the impaired secretion promotes Physiologic Insulin Secretion metabolic control and temporarily prolongs endogenous insulin 24-h profile secretion6 The question is which insulin regimen to use initially
50
DISCLOSURE
In accordance with the disclosure policies of UMDNJ and to conform with ACCME and Food and Drug Administration FDA guidelines, individuals in a position to control the content of this education activity are required to disclose to the activity participants: 1 the existence of any financial interest or other relationships with proprietary entities producing health care goods or services, with the exemption of nonprofit or government organizations and nonhealth-care-related companies, within the past 12 months; and 2 the identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved Faculty Disclosure Declarations Stephen N Davis, MD, has received grants/research
support from Bayer Corporation, Eli Lilly and Company, and sanofi-aventis Demian Elder, MD, reports no conflict or financial interest with any manufacturers of products or providers of services None of the reviewers had relationships to disclose Off-Label Usage Disclosure This activity contains information of commercial products/ devices that are unlabeled for use or investigational uses of products not yet approved Lilly/Alkermes human insulin inhalation powder, liraglutide, sitagliptin, and vildagliptin are investigational and not included in the labeling approved by the US FDA for the treatment of type 2 diabetes
Insulin U/mL
50 25 0
B
150 100 50 0
FIGURE 1 MIMICKING NATURE WITH INSULIN THERAPY: BASAL-BOLUS CONCEPT 5
Glucose mg/dL
78
Physiologic Insulin Secretion 24-h Profile
Insulin U/mL
50 25 0 Basal Insulin
DISCLAIMER
The views expressed in this activity are those of the faculty It should not be inferred or assumed that they are expressing the views of sanofi-aventis, US, any other manufacturer of pharmaceuticals, UMDNJ, or QED Communications, Inc It should be noted that the recommendations made herein with regard to the use of therapeutic agents, varying disease
states, and assessments of risk are based upon a combination of clinical trials, current guidelines, and the clinical practice experience of the participating presenters The drug selection and dosage information presented in this activity are believed to be accurate However, participants are urged to consult the full prescribing information on any agents presented in this activity for recommended dosage, indications, contraindications, warnings, precautions, and adverse effects before prescribing any medication
Suppresses glucose production between meals and overnight
D
B
150
L
Nearly constant levels 50 of daily needs
Glucose mg/dL
100 50 0 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
AM PM
Basal Glucose
Time of Day
Adapted with permission from Bergenstal RM, et al In: DeGroot LJ, Jameson JL, eds Endocrinology 4th ed Philadelphia, PA: WB Saunders; 2001:821
3
Dr Davis reviewed a study where premixed insulins were used in combination with metformin: approximately one third of patients achieved A1C 7 after 24 weeks, but two thirds of patients experienced hypoglycemia7 Basal insulins have been suggested because their steady pharmacokinetics provides effective 24-hour insulin
replacement Insulin detemir is a new analog that has a long duration of action; however, the pharmacokinetics shows that it does not provide full 24-hour coverage except at high doses, which are associated with a peak after injection8 Insulin glargine has been shown to be a truly peakless insulin that lasts 24 hours, has lower intersubject variability than NPH and ultralente, and closely mimics continuous subcutaneous insulin infusion, the gold standard of basal insulin replacement9 Another presentation on basal insulins was part of the main ADA program In insulin-resistant patients with type 2 diabetes who required 16 U/day of insulin, insulin glargine injected at bedtime maintained blood glucose closer to targets than daily injections of insulin detemir10 Blood glucose in basal supplement tests averaged 127 5 mg/dL with insulin glargine, compared with 143 4 mg/dL with insulin detemir P005, leading Eckart Jungmann, MD, of St-Vinzenz-Hospital in Rheda-Wiedenbrück, Germany, to conclude that insulin detemir should be injected twice daily in patients needing intensified insulin therapy, while insulin glargine could meet basal insulin requirements effectively when injected once
daily10 The rationale for physiologic insulin therapy to provide tight glycemic control and prevent diabetes complications was outlined at the same symposium in the presentation Mimicking Physiology: Appropriate Bolus Therapy by Vivian A Fonseca, MD, of the Tulane University Health Sciences Center in New Orleans, Louisiana Dr Fonseca reviewed data from the Diabetes Control and Complications Trial DCCT showing that the intensive therapy arm had less microvascular disease even at similar levels of A1C In another recent publication from the DCCT/Epidemiology of Diabetes Interventions and Complications EDIC Study Research Group, intensive therapy was shown to be associated with reduced CV events11 Dr Fonseca suggested that the benefit of intensive therapy is a result of minimizing glucose excursions Data published in JAMA in April 2006 showed that postprandial glucose excursions are associated with increased urinary secretion of markers of free radical production and oxidative stress, suggesting that blood glucose variability is an important target of diabetes treatments12 Dr Fonseca suggested that optimal glucose management should attempt to duplicate the natural pattern of insulin
secretion; the combination of a fast-acting prandial insulin and long-acting basal insulin provides good physiologic coverage, closely mimicking the bodys natural insulin cycle In addition to its effects on reducing free radical production, Dr Fonseca reviewed other postulated benefits of insulin on vascular disease In vitro studies suggest that insulin has antiinflammatory effects by suppressing activation of transcription factor NF kappa B, which regulates transcription of genes for inflammatory mediators In addition, insulin has been shown to suppress production of adhesion molecules and monocyte chemoattractant proteins
Transitioning to Basal Insulin in Combination With OHAs Provides Effective Glycemic Control
Several studies were presented on the use of the basal insulin glargine in combination with OHAs for patients who had failed OHA therapy Results from the APOLLO study, a 44-week, parallel, open-label trial in patients with type 2 diabetes who had failed OHA therapy, presented by Reinhard G Bretzel, MD, PhD, of Justus-Liebis-University Hospital in Giessen, Germany, showed that basal insulin glargine and prandial insulin lispro, added to existing OHA regimens, were
similarly effective in improving glucose control in patients who could not meet target A1C levels on OHA alone13 Insulin glargine provided better fasting and nocturnal glucose control Table 1, and insulin lispro, better postprandial glucose control The mean number of hypoglycemic events was significantly lower among patients receiving insulin glargine versus lispro 54 vs 244 events/patient-year Patients who received basal insulin glargine had fewer insulin injections and required less self-monitoring of blood glucose BG Insulin doses were similar glargine 421 IU/day and lispro 451 IU/day at the end of the study13 TABLE 1 APOLLO RESULTS 13
Insulin Glargine OHA n 174 Mean SD A1C FBG mg/dL Nocturnal BG mg/dL
FBG fasting blood glucose
Insulin Lispro OHA n 174 Baseline 864 095 179 41 177 53 End Point 677 083 145 34 129 33
Baseline 871 095 186 36 177 44
End Point 696 067 111 27 118 39
Nonsignificant difference that met the study end point of noninferiority for insulin glargine vs insulin lispro; P00001 vs insulin lispro; P 00017 vs insulin lispro
Insulin glargine added to OHA is safe and provides improved glycemic control in older patients with type 2
diabetes, according to results from the Glycemic Optimization with Algorithms and Labs at Point of Care GOAL A1C study14 This conclusion comes from a 24-week study conducted in 2164 primary care practices in the United States that included 4251 patients aged 65 years or younger, 1086 patients aged 65 to 74 years, and 384 patients aged 75 years or older The researchers found that compared with the younger group, older patients 65 years achieved lower fasting plasma glucose FPG levels and similar A1C levels despite lower doses of insulin glargine Rates of hypoglycemia tended to be higher in the two older groups, but overall were quite low severe hypoglycemia was 021/year in the oldest group 14 Dosing with insulin glargine to achieve a target FPG of 110 mg/dL provides the best balance of A1C improvement and risk of severe hypoglycemia, according to results from the Glycemia Optimization Treatment GOT trial, reported by Robert A Tanenberg, MD, of the Brody School of Medicine at
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DIABETES PULSE
Update on Insulin Therapy
East Carolina University in Greenville, North Carolina, and colleagues The randomized, open-label trial compared 5 dosing algorithms of insulin glargine FBG targets
80 mg/dL, 90 mg/dL, 100 mg/dL, 110 mg/dL, 120 mg/dL for the rate per year of severe hypoglycemic events and percent of patients with final A1C 7 The study population was 4823 patients with type 2 diabetes and A1C 7, who were not currently on insulin therapy After 24 weeks of treatment, between 315 and 438 of patients achieved target A1C at mean glargine doses ranging from 594 to 782 IU/day Rates of severe hypoglycemia, though low overall, increased with increasing dose Dr Tanenberg and colleagues found that the mean dose of glargine used to achieve an FBG of 110 mg/dL 622 375 IU/day provided the best overall benefit-to-risk ratio, with mean A1C of 752 322 of patients at 7 and a very low risk of severe hypoglycemia 003 0008/year15 Results from clinical trials, however, do not always provide the full picture Stephan A Schreiber, MD, a diabetes specialist from Quickborn, Germany, summarized 32 months of experience using insulin glargine in clinical practice in Germany16 The data confirm that initial improvements in A1C over 9 months reduction from baseline of 16 and FBG reduction from baseline of 77 mg/dL are maintained over the long term with the use of basal insulin glargine plus
OHA in patients with type 2 diabetes Patients had no change in body mass index during the time period, and only 2 hypoglycemic episodes were reported This clinical experience supports the use of basal insulin glargine in daily practice, with no loss of glycemic control and no changes in weight over 32 months of treatment
The researchers found that the patients of physicians who ranked positive feedback from patients or fewer hypoglycemic events more highly than improving blood sugar control or flexibility of use had higher average A1C levels over the study period In addition, physicians who gave higher estimates of the number of patients who would achieve target A1C levels at week 12 of the 24-week study, suggesting confidence in the therapy, had lower average patient A1C levels, perhaps illustrating their willingness to pursue intensive therapy18
Clinical Inertia Leads to Delays in Intensifying Diabetes Therapy and to Poor Glycemic Control
Two population studies presented at the 66th Scientific Sessions provide evidence that health care professionals are not moving quickly enough to intensify diabetes treatment and improve glycemic control A review of medical records from
primary care practices in the United Kingdom showed that initiation of insulin therapy was delayed in 50 of patients despite A1C levels of 8 or higher19 For patients with A1C of 7 or 9, the average time to starting insulin was 63 years and 42 years, respectively Delay in insulin initiation was not mediated by the presence of complications, such as retinopathy 46 years or neuropathy 46 years19 Patients already on insulin could benefit from more intensive regimens Among patients receiving insulin monotherapy, a review of A1C levels in adult patients with type 2 diabetes in Germany and the United Kingdom found that A1C levels were greater than 7 in 756 of patients, 9 in 323 , and 10 in 18220 These results suggest that patients on insulin therapy could benefit from more intensive physiologic regimens
Patient and Physician Attitudes Influence Successful Initiation and Intensification of Insulin Therapy
Group education is commonly used in the diabetes community Hannele Yki-Järvinen, MD, of the University of Helsinki in Helsinki, Finland, presented data from 120 patients that showed initiation of insulin in small groups of 4 to 8 patients, rather than individually, provided equally
effective glycemic control and patient satisfaction with treatment but reduced the time spent by medical personnel by 4917 William Herman, MD, MPH, of the University of Michigan in Ann Arbor, and colleagues reported data from the GOAL A1C trial showing that physician beliefs about the efficacy of insulin glargine use are associated with better A1C control18 TABLE 2 CHANGES IN PATIENTS UNCONTROLLED ON PREMIXED INSULIN SWITCHED TO INSULIN GLARGINE 22
A1C, n 4965 Baseline 3 months Change
Different Regimens for Intensifying Diabetes Therapy Are Compared
Options for intensifying diabetes therapy include the addition of basal insulin to an OHA or switching to a premix injected twice daily Several studies compared basal insulin glargine with a premix Once-daily insulin glargine plus OHA was shown to be as effective at achieving target A1C and FBG levels as a twice-daily injection of 30 insulin aspart premixed formulation over 6 months21 Mean A1C levels were reduced from 851 to 75 in the glargine group and from 915 to 79 in the premix group Target A1C was achieved by 294 and 25 in the glargine and premix groups, respectively, and target FBG, by 353 and 25 Mean insulin doses at 6 months
were 118 IU in the insulin glargine group and 261 IU in the insulin aspart premix group21 Additional studies showed that insulin glargine improved glycemic control in patients with type 2 diabetes whose glycemia was not controlled on premixed insulins22,23 In one study, 5045 patients poorly controlled on premixed insulin most were on an oral antidiabetic drug were switched to insulin glargine plus an oral antidiabetic drug At 3 months, patients saw a mean 11 decrease in A1C, a decrease of 55 mg/dL in FBG, and a weight loss of 16 kg, all significant changes from baseline P0001Table 222
FBG, mg/dL n 4815 178 48 124 26
Body Weight,kg n 4958 852 144 836 141
16 32
83 12 71 08
11 10
55 45
P0001 Wilcoxon signed rank test
5
In a second study, by Melanie Davies, MD, of the University of Leicester in Leicester, England, and colleagues, patients switched to a regimen of insulin glargine with or without OHA and with or without a prandial insulin once daily, twice daily, or more than twice daily experienced significant additional decreases in A1C levels over baseline values achieved on twice-daily premixed insulin23 These 2 studies suggest that patients can be safely
transitioned from premix to insulin glargine and achieve greater glycemic control As shown by Dr Davies and colleagues, optimal control was achieved by combining basal insulin glargine with a prandial insulin, such as lispro, aspart, or glulisine Transitioning to basal-bolus regimens, however, may be challenging, because it requires patients to count carbohydrates to adjust their mealtime doses However, Richard Bergenstal, MD, of the International Diabetes Center in Minneapolis, Minnesota, and colleagues proposed a simple algorithm for adjusting mealtime glulisine doses This algorithm, based on preprandial glucose patterns, was found to be effective and less complex than using a carbohydratecounting plan24 Bolus doses of glulisine were adjusted weekly in accordance with the algorithm, which added 1, 2, or 3 U based on premeal glucose patterns This strategy was compared with dose adjustment by carbohydrate counting in adjusting the insulin-to-carbohydrate ratio At 24 weeks, patients in both groups achieved target A1C Use of this simple algorithm titration improved safety, with fewer hypoglycemic events Figure 224 Dr Bergenstal and colleagues concluded that use of this algorithm
could help patients transition more smoothly to basal-bolus regimens when required, and hoped this would encourage physicians to initiate such regimens earlier in treatment of type 2 diabetes FIGURE 2 SIMPLE ALGORITHM TO ADJUST MEALTIME GLULISINE VS CARBOHYDRATE COUNTING 24
Intensive Diabetes Treatment Not Associated With Cognitive Effects
Data presented at the 66th Scientific Sessions provided reassurance about the long-term safety of intensive insulin therapy by dispelling concerns about detrimental cognitive side effects due to hypoglycemic events Alan M Jacobson, MD, of the Joslin Diabetes Center in Boston, Massachusetts, reported data from 1059 patients with type 1 diabetes from the DCCT that showed no change in a battery of neuropsychological tests that were administered during the DCCT and at a 65-year follow-up25 This finding was true for patients in the intensive insuli 
n therapy and conventional glucose-control groups The researchers discovered that higher A1C levels were associated with small declines in motor speed and psychomotor efficiency in the conventional treatment group The differences were significant and favored the intensive glucose-control group Data for
patients with type 2 diabetes are needed to confirm this positive finding
Inhaled Insulin Offers Alternatives for Patients
Presentations on inhaled insulin, a route of administration recently approved by the FDA,26 suggest that this new approach may be an effective alternative for patients who require insulin therapy Julio Rosenstock, MD, of the Dallas Diabetes and Endocrine Center and The University of Texas Southwestern Medical Center in Dallas, presented data for inhaled human insulin Exubera in patients with type 2 diabetes showing sustained glycemic control over the 2-year study period27 These data were from an open-label, parallel group, multicenter, randomized trial comparing inhaled insulin n 319 with subcutaneous insulin n 316 using highly standardized pulmonary function testing All patients were also treated with basal insulin Rosenstock and colleagues found small 15 of mean baseline treatment-group differences in changes from baseline in the primary end point of pulmonary function forced expiratory volume in 1 second and CO diffusing capacity; these changes occurred early and remained stable throughout the 2 years Cough was increased in the inhaled insulin group, but
it was mild in most instances and occurred within minutes of dosing Glycemic control was similar in both groups, with greater reductions in FPG and less weight gain in the inhaled insulin group Inhaled human insulin Exubera has an onset of action similar to that of rapid-acting insulin analogs and has a duration of glucose-lowering activity comparable to subcutaneously administered regular human insulin26 Another study, presented by Klaus Rave, MD, of the Profil Institute for Metabolic Research in Neuss, Germany, compared the use of the Lilly/Alkermes human insulin inhalation powder HIIP system with subcutaneous insulin lispro in 15 nonsmoking healthy individuals and 30 nonsmoking subjects with moderate chronic obstructive pulmonary disease–15 with bronchitis and 15 with emphysema28 Compared with the healthy subjects, the 15 patients with chronic bronchitis and 15 patients with emphysema
Mean A1C Across Study Weeks
85 82 80 81 79 75 70 65 0 2 6 73 73 69 67 68 12 67 18 66 66 24 Carb Counting Algorithm
A1C
80
Week
6
Mean A1C Acr
DIABETES PULSE
Update on Insulin Therapy
had reductions in total insulin exposure [44 P0001 and 22 P 013, respectively] and in metabolic effect
[40 P001 and 33 P001, respectively]
Agents Targeting the GLP-1 Pathway Promise Increased Glucose Control as Adjuncts to Current Therapy
Two new classes of diabetes drugs that leverage the effect of incretins, hormones produced by the gut in response to a meal, were the subject of several sessions and late-breaking trial presentations Carol H Wysham, MD, of the Rockwood Clinic in Spokane, Washington, at a symposium titled Clinical Use of Incretin Mimetics–Our Experience With Exenatide explained how researchers suspected that hormones in the gut were influencing insulin secretion and identified the so-called incretin effect and related hormones, mainly 2 intestinal insulin-stimulating hormones, glucagon-like peptide-1 GLP-1 and gastric inhibitory polypeptide GIP In patients with type 2 diabetes, the secretion of GIP is generally normal However, GLP-1, which stimulates insulin secretion, suppresses glucagon secretion, normalizes gastric emptying, is rapidly metabolized, and is deficient in patients with type 2 diabetes, thus presenting an attractive target for intervention Figure 3 At present, 2 types of drugs targeted at influencing GLP-1 levels in type 2 diabetes are in use or
under investigation: GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase IV DPP-IV The GLP-1 receptor agonists, such as exenatide and liraglutide, increase circulating GLP-1 by their resistance to degradation, whereas DPP-IV inhibitors, such as, vildagliptin and sitagliptin, increase circulating GLP-1 by blocking the action of the peptide that inactivates GLP-1 FIGURE 3 HOW INCRETINS INFLUENCE INSULIN SECRETION
a sulfonylurea, or both, had mean decreases in A1C of about 11 from baseline, beginning at 12 weeks and remaining stable throughout, and reductions from baseline in FPG of 252 mg/dL, according to Robert Henry, MD, of the Veterans Medical Research Foundation in Hyattsville, Maryland, and colleagues30 Notably, patients also experienced progressive weight loss, with an average loss at 2 years of 47 kg from baseline30 Bernard Zinman, MD, of Mount Sinai Hospital in Toronto, Ontario, presented a study of exenatide in combination with a thiazolidinedione TZD with or without metformin in 233 subjects with type 2 diabetes not controlled by TZD with or without metformin Dr Zinman and colleagues found that after 16 weeks, patients who had received exenatide achieved
additional improvements in A1C, fasting serum glucose, and postprandial glucose compared with those who received placebo31 The exenatide patients had average decreases in A1C of 08 from baseline, and 62 achieved A1C 7, compared with 16 in the placebo group The fasting serum glucose was 27 mg/dL lower in the exenatide group than in the placebo group Patients receiving exenatide experienced an average weight loss of 15 kg compared with 02 kg in the placebo group, and the rate of mild and moderate hypoglycemia did not differ between groups31 Not all patients respond to exenatide, however Dr Wysham said that among her patients, 12 had no response, 22 had no weight loss, and about 15 had worsening glycemic control after 1 to 2 years of therapy The most common adverse event was nausea 50, which usually resolved after 3 to 7 days and could be minimized if the exenatide was taken after a meal Dr Wysham cautioned that exenatide is not a substitute for insulin and added that it is not indicated for type 1 diabetes or recommended for patients with renal impairment creatinine clearance 30 mL/min Another GLP-1 receptor agonist, liraglutide, is currently in phase 2 trials as a once-daily therapy
Tina Vilsbøll, MD, of Novo Nordisk in Bagsværd, Denmark, presented the results32 Liraglutide, administered as a once-daily injection given in the morning, has been shown to lower glucose for 24 hours In a study of 165 patients with type 2 diabetes, change from baseline A1C after treatment with 19 mg/day liraglutide was -17 Patients lost about 3 kg of weight at the highest dose and slightly less with the 125-mg dose Bo Ahrén, MD, of Lund University in Lund, Sweden, described the rationale for, and clinical results with, DPP-IV inhibitors He noted that DPP-IV inhibitors are orally available and all studies have shown these compounds to be remarkably safe33 Adverse events usually do not differ from placebo, and unlike the GLP-1 receptor agonists, these compounds are weight-neutral Studies also suggest DPP-IV inhibitors may increase beta-cell function The DPP-IV inhibitor sitagliptin was shown, in a late-breaking presentation by Peter Stein, MD, of Merck Co, Inc, Rahway, New Jersey, to be noninferior to glipizide at reducing A1C in a head-to-head comparison among patients with type 2 diabetes Patients with inadequate glycemic control on metformin monotherapy were randomly assigned to
sitagliptin 100 mg or glipizide up to 20 mg added to existing therapy In the 52-week results, both treatments significantly P0001 decreased A1C
SMALL INTESTINE
Absorbed glucose in circulation stimulates insulin secretion by pancreatic ß cells
PANCREAS
ß Cell Incretins enhance glucose-dependent insulin secretion INSULIN
Glucose in lumen of intestine stimulates secretion of incretins
Exenatide is currently available in the United States as a subcutaneous injection recommended for twice-daily administration prior to the morning and evening meals29 In an open-label extension trial, patients treated for at least 2 years N 283 with exenatide in addition to metformin,
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levels 067 compared with baseline, with similar numbers of patients achieving the target A1C of 7 63 of patients on sitagliptin and 59 of patients on glipizide Patients who received sitagliptin had a mean weight loss of 15 kg over the 52-week period, while those who received glipizide had a weight gain of 11 kg from baseline Sitagliptin was generally well tolerated, with few reports of hypoglycemia of any severity 49 compared with 32 in the glipizide treatment group; P000134 Another study reported that
sitagliptin improved glycemic control with a neutral effect on weight when added to pioglitazone in patients with type 2 diabetes35 In 2 other trials, another DPP-IV inhibitor, vildagliptin, provided additional reductions in A1C when added to pioglitazone compared with pioglitazone alone and similar reductions in A1C as those achieved with rosiglitazone monotherapy In the first study, 592 treatment-naïve patients with type 2 diabetes were randomly assigned to treatment with vildagliptin alone, pioglitazone alone, or a combination at 2 different doses In the overall patient population, the combination of vildagliptin 100 mg plus pioglitazone 30 mg produced a significant reduction in A1C compared with pioglitazone 30 mg alone 19 vs 14; P0001 Patients who received the combination experienced no additional weight gain and less edema than those taking pioglitazone alone, according to Dr Rosenstock, who presented the data36 In the second trial, 697 treatment-naïve patients with type 2 diabetes were randomly assigned to 24 weeks of treatment with vildagliptin 50 mg twice daily or rosiglitazone 8 mg once daily37 Vildagliptin decreased A1C levels by 11 from baseline, which was noninferior
to rosiglitazone Vildagliptin did not affect body weight, but patients treated with rosiglitazone gained an average 16 kg P000137 The evidence from these studies suggests that DPP-IV inhibitors may be useful additions to the oral treatment of type 2 diabetes, either alone or in combination with other oral agents
hyperglycemia was 16 to 5 times higher in patients after a heart attack, 17 to 62 times higher in patients with unstable angina, and 34 to 151 times higher in patients after a stroke Hyperglycemia had a lesser effect on mortality in patients with sepsis, pneumonia, and pulmonary embolism, and no apparent increased risk for those with chronic obstructive pulmonary disease or hepatic failure These differential effects may explain the inconsistencies seen in the results of intervention trials to control inpatient hyperglycemia, Dr Falciglia said, adding, it may be a wise use of resources in future trials to consider disease type and focus on those populations that appear to be at greatest risk Another interesting finding was that the effect was greatest in patients without diagnosed diabetes It is not clear why hyperglycemia occurs in hospitalized patients who do not have
diagnosed diabetes, nor why they may have worse outcomes in some cases than people with diagnosed diabetes, said Dr Falciglia, All patients should have their blood glucose levels monitored when they are admitted to an intensive care unit, because hyperglycemia occurs in one third of ICU patients
Benefits and Strategies for Inpatient Insulin Therapy
New findings underscore the urgency of controlling hyperglycemia in hospitalized patients During the symposium titled Inpatient Insulin Therapy: Benefits and Strategies for Achieving Glycemic Control, Bruce W Bode, MD, of Atlanta Diabetes Associates in Atlanta, Georgia, stated that causes of hyperglycemia in hospitalized patients include both diagnosed and undiagnosed diabetes, as well as hospital-associated diabetes of iatrogenic or stress-related origin Hyperglycemia has been estimated to occur in 38 of hospitalized patients, of whom only 26 had a history of diabetes Newly discovered hyperglycemia is associated with longer hospital stays, higher ICU admission rates, and a higher chance of being discharged to transitional or nursing home care rather than to home39 Anthony Furnary, MD, of the Starr-Wood Cardiac Group and Providence St
Vincent Medical Center in Portland, Oregon, reported data from the Portland Diabetic Project, an ongoing prospective nonrandomized, interventional study of 5534 cardiac surgery patients with diabetes that examined the effects on morbidity and mortality of hyperglycemia and its reduction using continuous intravenous infusion of insulin In his presentation, Impact of Hyperglycemia on Cardiac Outcomes, Dr Furnary stated that the study showed that hyperglycemia was associated with increased mortality, deep sternal wound infections, and longer hospital stays and that the use of continuous insulin infusion to control hyperglycemia in cardiac surgery patients independently reduced the risks of death and deep sternal wound infection by 65 and 63 both were significant at P0001 The study found that target glucose levels of 150 mg/dL and a 3-day postoperative course of continuous insulin infusion are important variables that affect improved outcomes Dr Furnary stressed that hyperglycemia in diabetics, not the diagnosis of diabetes itself, is the causal factor for infection
Late-Breaking Clinical Study Shows Hyperglycemia in 216,000 Hospital ICU Patients Contributes to Increased Mortality
A
landmark study of 216,000 patients admitted to intensive care units ICUs at VA hospitals showed that elevated BG is associated with increased deaths, as presented in the Late-Breaking Clinical Studies session at the ADAs 66th Scientific Sessions Hyperglycemia was found to be an independent predictor of mortality beginning at just 1 mg/dL above defined normal ranges 70 mg/dL to 110 mg/dL of blood glucose, according to Mercedes Falciglia, MD, of the University of Cincinnati College of Medicine in Cincinnati, Ohio38 Hyperglycemia independently predicted mortality in medical, surgical, and cardiac ICUs The mortality risk associated with hyperglycemia was highest among those without diagnosed diabetes and in those hospitalized for CV disorders, such as heart attacks, unstable angina, and strokes Compared with expected mortality rates from patients with similar diagnoses and comorbidities, the mortality risk associated with
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Update on Insulin Therapy
after surgery and that the cardiac glycometabolic state influences mortality, both of which underscore the need to maintain normoglycemia in these patients Specifically, he argued that 3-day BG levels day of surgery
through postoperative day 2 are the true risk factors for morbidity and mortality Though several protocols have been tried, continuous insulin infusions are the standard of care for glycometabolic control in cardiac surgery patients The duration of continuous insulin infusions is as important as glucose control Infusions that completely control BG over 3 days normalize the postcardiac surgery risk for patients with diabetes to be comparable to that for patients without diabetes Dr Bode, in his presentation Achieving Intensive Glycemc Control: Inpatient Protocols and Outcomes, said that the importance of developing and instituting protocols for intensive glycemic control cannot be overstated and that an important part of such protocols is early and aggressive use of insulin, because insulin is the most powerful agent we have to control glucose The key elements of these protocols are adherence to current ADA and American Association of Clinical Endocrinologists AACE guidelines, simplicity and ease of use, identification of patients who require insulin or modification of current therapy, consideration of insulin infusion requirements and unique nutritional needs, and improvement of
patient education Figure 440,41 FIGURE 4 HOSPITAL TARGETS FOR GLUCOSE: ADA AND AACE GUIDELINES 40,41
signature only, get patients to goal quickly, have a minimal risk of hypoglycemia, be easily implemented, and, most important, be used throughout the hospital, not just in the ICU or postanesthesia care unit Nurse participation is crucial
Opportunities for Hospital Insulin Protocols Reviewed
Several presentations reviewed opportunities for improving the use of insulin in hospitalized patients Converting patients from IV insulin to subcutaneous insulin presents a challenge in some settings According to a study by Anita S Richard, APRN, and colleagues at the Ochsner Clinic in New Orleans, Louisiana, a method has been developed that effectively predicts an appropriate first dose of basal glargine insulin for critical care patients who are being converted from IV insulin42 Bedtime glargine dose is based on 75 of the most recent hourly infusion rate times 24 hours IV insulin is discontinued 1 hour after glargine administration Results from 25 cardiothoracic surgery patients treated with this step-down protocol were presented Few patients had FPG 140 mg/dL or 130 mg/dL 1 and 3,
respectively following transition to insulin glargine, and more than 40 had FPG 110 mg/dL Mean IV insulin dose prior to glargine administration was 19 12 range, 08-55 IU/hour, and the mean starting glargine dose was 328 221 range, 10-90 IU/hour42 A retrospective cross-sectional study of patients N 1718 who were admitted to academic medical centers for a variety of diagnoses, including pneumonia, renal failure, and CV disorders, and who had either insulin treatment or 2 consecutive BG 180 mg/dL found that hyperglycemia was still common, though hypoglycemia was rare43 In this study by David Baldwin, MD, and colleagues of the University HealthSystem Consortium in Chicago, Illinois, over the 72-hour study window, only 6 of patients had BG levels of 80 to 139 mg/dL on day 2, while 11 had median levels 200 mg/dL on all days and 21 had levels of 300 mg/dL or 70 mg/dL on 2 occasions on the same day Across all academic medical centers, median use of IV insulin or long-acting subcutaneous insulin was 45; 36 of patients with BG levels 180 mg/dL received only subcutaneous short-acting insulin According to Dr Baldwin, academic medical centers are having limited success meeting current ADA
guidelines, resulting in suboptimal glucose control
ADA FPG 90-130 mg/dL Peak postprandial glucose 180 mg/dL
AACE FPG 110 mg/dL Maximal glucose 180 mg/dL
ADA and AACE Critically ill patients 110mg/dL
Modify if Cardiac disease unstable Hypoglycemic unawareness Recurrent hypoglycemia
For the management of diabetes in hospitalized patients, Dr Bode said a basal-bolus regimen is preferred for patients who are eating, and a continuous variable rate IV insulin drip for those who are not, or are critically ill Patients on IV insulin will need to convert to subcutaneous insulin to maintain glycemic control, and here again, according to Dr Bode, a basal-bolus regimen is preferred because of its ability to mimic the normal physiologic profile of insulin The final component is discharge planning, so the patient can continue to maintain glucose control outside the hospital This step includes patient education and arrangements for early follow-up with the patients primary care physician Dr Bode emphasized that ideal insulin protocols should require
Large Clinical Trial Is Examining Effect of Insulin Regimens on CV Risk
Hyperglycemia is a known risk factor for CV disease, and
patients with diabetes are at increased risk for CV events The purpose of the ORIGIN study is to determine whether achieving and maintaining normoglycemia using basal insulin can reduce CV events in high-risk patients44 An additional factorial randomization will examine the effect of omega-3 fatty acids on CV events This randomized, multicenter trial has enrolled 12,612 patients with impaired fasting glucose IFG, IGT, or diabetes in 40 countries and will follow them for at least 4 years Subjects will receive either evening glargine or standard care consistent with clinical trial evidence; concurrently they will be randomized
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to receive either omega-3 fatty acids containing 465 mg eicosapentaenoic acid and 375 mg docosahexaenoic acid or placebo, allowing comparison of standard care alone, standard care plus omega-3 fatty acids, glargine alone, or glargine plus omega-3 fatty acids44 Glargine doses will be increased by 1 U/week until FPG levels are consistently maintained at 53 mmol/L 95 mg/dL44 Investigators have set primary outcome measures for the comparison of glargine and standard care as incident CV death, nonfatal myocardial infarction, or nonfatal stroke; and these 3
events plus revascularization, or hospitalization for heart failure The primary outcome measure for the comparison of omega-3 fatty acids and placebo is CV death Other outcomes include total deaths, microvascular events, and new-onset diabetes At baseline, the mean age of the subjects was 66 years; 65 were men Most subjects have diabetes 81, with the remainder having IFG or IGT Mean A1C is 65 and mean body mass index was 296 kg/m2 Almost half of subjects have a history of myocardial infarction or stroke 46, and more than half use CV drugs44
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2006 4 Davis S, Johns D, Maggs D, Northrup J, Xu H, Brodows R Substituting exenatide for insulin in patients with type 2 diabetes: an exploratory study Diabetes 2006;55suppl 1:A109 Abstract 456-P 5 Bergenstal RM, Kendall DM, Franz MJ, Rubenstein AH Management of type 2 diabetes: a systematic approach to meeting the standards of care II: Oral agents, insulin, and management of complications In: Degroot LJ, Jameson JL, eds Endocrinology 4th ed Philadelphia, PA: WB Saunders; 2001:821 6 Alvarsson M, Sundkvist G, Lager I, et al Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients Diabetes Care 2003;26:2231-2237 , 7 Schwartz S, Sievers R, Strange P, Lyness WH, Hollander P for the INS-2061 Study Team Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs Diabetes Care 2003;26:2238-2243 8 Plank J, Bodenlenz M, Sinner F, et al A double-blind, randomized dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir Diabetes Care 2005;28:1107-1112 9 Lepore M, Pampanelli
S, Fanelli C, et al Pharmacokinetics and pharmacodyamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro Diabetes 2000;49:2142-2148 10 Jungmann E Intensified insulin therapy of type 2 diabetes mellitus: insulin glargine vs insulin detemir as basal insulin Diabetes 2006;55:A118 Abstract 496-P 11 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications DCCT/EDIC Study Research Group Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes N Engl J Med 2005;353: 2643-2653 12 Monnier L, Mas E, Ginet C, et al Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes JAMA 2006;295:1681-1687 13 Bretzel RG, Linn T, for the APOLLO Study Group Equivalence of basal insulin glargine vs prandial insulin lispro for glucose control in type 2 diabetes patients on oral agents: results of the APOLLO study Diabetes 2006;55suppl 1:A76 Abstract 326-OR 14 Halter JB, Kennedy L, Herman WH, Miller MF Glycemic control and safety of
insulin glargine in elderly patients with type 2 diabetes mellitus: the GOAL A1C study Diabetes 2006;55suppl 1:A114 Abstract 480-P 15 Tanenberg RJ, Zisman A, Stewart J Glycemia Optimization Treatment GOT: glycemic control and rate of severe hypoglycemia for five different dosing algorithms of insulin glargine in patients with type 2 diabetes mellitus Diabetes 2006;55suppl 1:A135 Abstract 567-P 16 Schreiber SA The efficacy of long-term insulin glargine and oral antidiabetic therapy in patients with type 2 diabetes in clinical practice Diabetes 2006;55suppl 1: A134 Abstract 562-P 17 Yki-Järvinen H, Alvarsson M, Bystedt T, et al A randomized trial comparing initiation of basal insulin individually and in groups in type 2 diabetes Diabetes 2006;55suppl 1:A30 Abstract 125-OR 18 Herman WH, Kennedy L, Zhang Q Are physician beliefs associated with glucose control in type 2 diabetic patients treated with insulin glargine? Diabetes 2006;55suppl 1:A116 Abstract 486-P 19 Rubino A, McQuay L, Kvasz M, Tennis M Population-based study of time to insulin after failure of oral antidiabetic therapy in type 2 diabetes in the UK Diabetes 2006;55suppl 1:A76 Abstract 324-OR 20 Gough S, Frandsen KB, Toft
AD Failure of insulin monotherapy in patients with type 2 diabetes: a population-based study Diabetes 2006;55:477-P 21 Tamemoto H, Ikoma A, Saitoh T, Ishikawa S, Kawakami M Comparison of blood glucose control between insulin glargine plus oral hypoglycemic agents versus premix 30R formulation Diabetes 2006;55suppl 1:A474 Abstract 2049-PO 22 Hammer H Patients with type 2 diabetes inadequately controlled on premixed insulin: effect of initiating insulin glargine plus oral agents on glycemic control in daily practice Diabetes 2006;55suppl 1:A115 Abstract 481-P
23 Davies M, Storms F, Gomis R, for the ATLANTUS Study Group Insulin glarginebased therapy improves glycemic control in patients with type 2 diabetes suboptimally controlled on premixed insulin therapies Diabetes 2006; 55suppl 1:A108 Abstract 455-P 24 Bergenstal RM, Johnson ML, Powers MA, Wynne AG, Vlajnic A, Hollander PA Using a simple algorithm to adjust mealtime glulisine based on preprandial glucose patterns is a safe and effective alternative to carbohydrate counting Diabetes 2006;55suppl 1:A105 Abstract 441-P 25 Jacobson AM Effects of intensive and conventional treatment on cognitive function twelve years after the
completion of the Diabetes Control and Complications Trial DCCT Late-breaking clinical studies presentation at 66th Scientific Sessions of the American Diabetes Association, June 12, 2006; Washington, DC 26 Exubera insulin human [rDNA] inhalation powder Prescribing information New York, NY: Pfizer Inc; May 2006 27 Rosenstock J, Foyt H, Klioze S, Ogawa M, St Aubin L, Duggan W Inhaled human insulin Exubera therapy shows sustained efficacy and is well tolerated over a 2-year period in patients with type 2 diabetes Diabetes 2006;55suppl 1: A26 109-OR 28 Rave K, Hausmann M, de la Peña A, et al Pharmacokinetics and glucodynamics of human insulin inhalation powder in subjects with chronic obstructive pulmonary disease Diabetes 2006;55suppl 1:A26 Abstract 111-OR 29 Byetta exenatide injection Prescribing information San Diego, CA: Amylin Pharmaceuticals, Inc; April 2006 30 Henry RR, Ratner RE, Stonehouse AH, et al Exenatide maintained glycemic control with associated weight reduction over 2 years in patients with type 2 diabetes Diabetes 2006;55suppl 1:A116 Abstract 485-P 31 Zinman B, Hoogwerf B, Duran Garcia S, et al Safety and efficacy of exenatide in patients with type 2 diabetes
mellitus using thiazolidinediones with or without metformin Diabetes 2006;55suppl 1:A28 Abstract 117-OR 32 Vilsbøll T, Zdravkovic M, Le-Thi T, et al Liraglutide significantly improves glycemic control, and lowers body weight without risk of either major or minor hypoglycemic episodes in subjects with type 2 diabetes Diabetes 2006;55suppl 1:A27 Abstract 115-OR 33 Ahrén B DPP IV inhibitors–how do they work and what can they do? Presented at 66th Scientific Sessions of the American Diabetes Association, June 10, 2006; Washington, DC 34 Stein P Sitagliptin, a novel dipeptidyl peptidase-4 inhibitor, improves glycemic control in patients with type 2 diabetes Late-breaking clinical studies presentation at 66th Annual Scientific Sessions of the American Diabetes Association, June 13, 2006; Washington, DC 35 Rosenstock J, Brazg R, Andryuk PJ, Sisk CM, Lu K, Stein P Addition of sitagliptin to pioglitazone improved glycemic control with neutral weight effect over 24 weeks in inadequately controlled type 2 diabetes Diabetes 2006;55suppl 1:A132 Abstract 556-P 36 Rosenstock J The use of vildagliptin for treatment of patients with type 2 diabetes Late-breaking clinical studies presentation at
66th Scientific Sessions of the American Diabetes Association, June 13, 2006; Washington, DC 37 Rosenstock J, Baron MA, Schweizer A, Mills D, Dejager S Vildagliptin is as effective as rosiglitazone in lowering HbA1c but without weight gain in drug-naïve patients with type 2 diabetes Diabetes 2006;55suppl 1:A133 Abstract 557-P 38 Falciglia M Hyperglycemia and mortality in 252,000 critically ill patients Latebreaking clinical studies presentation at 66th Scientific Sessions of the American Diabetes Association, June 12, 2006; Washington, DC 39 Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes J Clin Endocrinol Metab 2002;87:978-982 40 American Diabetes Association Standards of Medical Care–2006 Diabetes Care 2006;29suppl 1:S4-S42 41 American College of Endocrinology Task Force on Inpatient Diabetes and Metabolic Control American College of Endocrinology Position Statement on Inpatient Diabetes and Metabolic Control Endocr Pract 2004;10:77-82 42 Richard AS, Bolton PM, Blonde L, Burshell AL Predicting basal insulin requirements for transition from intravenous to
subcutaneous insulin in hyperglycemic critical care unit patients Diabetes 2006;55suppl 1:A131 Abstract 551-P 43 Baldwin D, Boord J, Braithwaite S, et al The University HealthSystem Consortium benchmarking project: evaluation of hospital glycemic control at academic medical centers Diabetes 2006;55suppl 1:A104 Abstract 437-P 44 ORIGIN Trial Investigators Design and key features of the ORIGIN trial: outcome reduction with an initial glargine Diabetes 2006;55suppl 1:A523 Abstract 2264-PO
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