Important data on diabetes presented at the. 65th Annual Scientific Sessions of the American present in those with Type 1 diabetes and a relative …
Diabetes2005
From the 65th Annual Scientific Sessions of the American Diabetes Association San Diego, CA
Sponsored by Ya l e U n i v e r s i t y S c h o o l o f M e d i c i n e , Department of Internal Medicine, Section of Endocrinology
2001 2002 2003 2004 2005 2006 2007
Vo l u m e 1 1
June 13, 2005
Issue 4
Important data on diabetes presented at the 65th Annual Scientific Sessions of the American Diabetes Association come to you in Diabetes 2005, a newsletter CME program that is being offered to you by Yale University School of Medicine with the support of Takeda Pharmaceuticals America, Inc and Eli Lilly and Company Fax or e-mail delivery to your office of Diabetes 2005 will be followed by a Diabetes 2005 booklet ACC and ADA newsletters in the mail After successfully completing the quiz and evaluation therein contained and remitting a 10 certificate fee to the Yale Office of Continuing Education, you will qualify for up to 55 Category 1 credits towards the Physicians Recognition Award of the American Medical Association to be issued by Yale University School of Medicine Diabetes 2005 is being offered to physicians practicing in the United States After successfully
completing this program, participants will be able to: Explain the pathogenesis of Type 2 diabetes, especially the coexisting roles of insulin resistance and insulin secretion Recognize the clinical manifestations of the macrovascular and microvascular complications of diabetes and describe appropriate therapeutic interventions Recognize the important association between insulin resistance/metabolic syndrome and atherosclerosis in patients with Type 2 diabetes Identify evolving and emerging management strategies for diabetes eg, combination antihyperglycemic therapy, new insulin delivery systems, new glucose monitoring techniques, novel drugs Describe the approach to managing dyslipidemia, hypertension, and cardiovascular risk factors in patients with diabetes Yale University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education to physicians Yale University School of Medicine designates this continuing medical education activity for a maximum of 55 Category 1 credits towards the AMA Physicians Recognition Award Each physician should claim only those hours of credit that he/she actually spent in
the educational activity
New Paths to Glycemic Control
The pathophysiology of Type 2 diabetes involves both insulin resistance as well as progressive -cell dysfunction Until recently, the treatment of Type 2 diabetes has focused predominately on improving insulin sensitivity metformin, thiazolidinediones and/or augmenting insulin availability secretagogues, insulin injections The closer researchers look, the more it becomes apparent that there are other fundamental hormonal derangements in this condition that may play a more central role in its development and progression than initially considered A good example is the growing appreciation of the adipocyte and its altered secretory function in the obese state Another exciting area involves glucoregulatory hormones of pancreatic and gut origin Glucagon, for instance, is a powerful islet cell product that increases hepatic glucose production, while also modulating insulin secretion Another islet peptide, amylin, has several effects, including reduction of glucagon secretion, delay of gastric emptying, and probably central effects to decrease caloric intake The incretins, peptide hormones secreted by enteroendocrine cells of the
gastrointestinal tract, augment insulin secretion in a glucose-dependent fashion, while simultaneously having many of the aforementioned effects attributed to amylin The development of analogs or agonists of these glucoregulatory hormones or agents that delay their degradation has been an area of active investigation for the past five years Numerous presentations at this weeks meeting discussed the use of these new medications alone or in combination with other orally administered antihyperglycemic agents or insulin trast, is normal in Type 2 diabetes, although some resistance to its effect may be present The use of GLP-1 agonists, analogues, or agents that slow GLP-1s inactivation by dipeptidyl peptidase IV DPP-IV may offer an effective alternative to insulin therapy in patients uncontrolled with traditional oral antihyperglycemic agents The former are injectables, whereas the latter have the advantage of being available in pill form Exenatide, a GLP-1 agonist initially discovered in the saliva of the gila monster, was found by Heine and colleagues 9-OR to provide similar glycemic control with weight loss, rather than gain, as compared to glargine in Type 2 diabetic patients
uncontrolled on metformin plus sulfonylurea therapy In a 26-week study, investigators randomized 551 patients to exenatide 5 g twice daily for four weeks, then 10 g twice daily or insulin glargine once daily At study conclusion, similar reductions in HbA1c levels were observed in both treatment groups 10 from baseline levels of 82, as were the percentages of patients with HbA1c levels 7 48 exenatide, 46 glargine A significant difference was observed in weight change: those treated with exenatide lost 23 kg while those given insulin gained 18 kg Nocturnal hypoglycemia was significantly less frequent with exenatide compared with glargine 09 vs 24 mean events/patient year, p 0001 The effects of exenatide in combination with metformin, or a sulfonylurea, or both on HbA1c and weight loss were found to be durable in an 82-week study by Blonde et al 477-P In the trial, 393 patients who completed one of three 30-week treatment arms placebo, exenatide 5 g, or exenatide 10 g administered subcutaneously twice-daily were entered into an open-label extension and given exenatide 5 g twice daily for four weeks followed by 10 g twice daily for 48 weeks At week 30, patients treated with exenatide
exhibited a dose-dependent reduction of HbA1c and weight, with these reductions sustained at week 82 Figure 1 Mild to moderate nausea was the most frequent adverse event Exenatide was recently made available on the US market as Byetta
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Incretins: Insulinotropic Peptides
Incretins modulate pancreatic islet secretion as part of the enteroinsular axis Two incretins have been discovered to affect glucose metabolism: glucagon-like peptide-1 GLP-1 and glucose-dependent insulinotropic polypeptide GIP Of the two, GLP-1 has garnered the majority of investigative interest as it is clearly deficient in persons with Type 2 diabetes and therefore may be a more significant target GIP, in con-
Supported through an unrestricted educational grant from Takeda Pharmaceuticals America, Inc and Eli Lilly and Company
Diabetes2005
American Diabetes Association
San Diego, CA
Volume 11
Issue 4
June 13, 2005
New Paths to Glycemic Control Continued from page 1
In a placebo-controlled study, an investigational long-acting half-life of 10 days GLP-1 analogue, CJC-1131, significantly reduced HbA1c, without increasing the risk for hypoglycemia, in patients previously
inadequately controlled by metformin alone or metformin plus a sulfonylurea 10-OR The effects of CJC-1131 on HbA1c were dose dependent -06 with low-dose [21 106 g/kg] and -11 with high-dose [26 097 g/kg] Gastrointestinal intolerance, primarily during the first four weeks of treatment, and moderate nausea were the most frequent adverse events Brazg and American collaborators 11-OR assessed the effect of MK-0431, an orally active selective DPP-IV inhibitor, in a group of patients with inadequate control of their Type 2 diabetes despite a stable dose of metformin In the twoperiod crossover trial, 28 patients baseline HbA1c 65 - 96 receiving metformin were randomized to the DPP-IV inhibitor followed by placebo, each administered for four weeks, or vice versa As compared to metformin plus placebo, treatment with metformin plus the DPP-IV inhibitor produced significantly greater reductions in fasting plasma glucose -203 mg/dl, p 0001, mean daily glucose -280 mg/dl, p 0046, and fructosamine levels -337 mmol/l, p 0003, a marker of blood glucose control over a two- to threeweek period Treatment with the DPP-IV inhibitor produced no weight gain and no increased incidence of
gastrointestinal or hypoglycemic events In a 12-week dose-ranging efficacy study that enrolled 743 patients baseline HbA1c 63 - 110 by Scott and colleagues of New Zealand 41-OR, MK-0431 at doses ranging from 5 to 50 mg twice daily produced placebo-subtracted differences in HbA1c that ranged from -04 to -08 in a dose-dependent manner Treatment with the DPP-IV inhibitor produced no significant weight change and was well tolerated with few reported episodes of hypoglycemia
Figure 2 Effects of 26 Weeks of Pramlintide on HbA1c, Body Weight, and Short-Acting Insulin Dose
ShortActing Mean Body Insulin HbAlc Weight Dose kg ShortActing Mean Body Insulin HbAlc Weight Dose kg
0– -5 — -10 — -15 — -20 — -25 –
Guthrie et al Type 1 DM n265 Karl et al Type 2 DM n166
Pramlintide: A Synthetic Amylin Analog
Amylin, like insulin, is secreted by the pancreatic cells with absolute amylin deficiency present in those with Type 1 diabetes and a relative deficiency occurring in those with Type 2 disease The synthetic amylin analog, pramlintide, restrains hepatic glucose production by suppressing postprandial glucagon secretion in both Type 1 and Type 2 patients It has also been recently
released in the US as Symylin In an open-label study, Guthrie and associates 478-P evaluated the safety and efficacy of pramlintide on HbA1c, body weight, and short-acting
insulin use in 265 patients with Type 1 diabetes mean age 43 years, BMI 29 kg/m2, HbA1c 80, diabetes duration 21 years Pramlintide dose was escalated from 15 to 60 g as tolerated, with patients titrating their insulin to achieve glycemic targets At week 26, significant reductions in mean HbA1c, body weight, and short-acting insulin dose were observed Figure 2 Mean postprandial glucose trended lower 12 - 21 mg/dl across meals Similar effects on HbA1c, body weight, and shortacting insulin dose were observed in a study of 166 patients with Type 2 diabetes mean age 54 years, BMI 39 kg/m2, HbA1c 83, enrolled in a 26-week open-label study by Karl and US colleagues 48-OR Figure 2 In these patients, the mean postprandial glucose trended lower 40 - 49 mg/dl across meals In both studies, mild to moderate nausea and vomiting were the most frequently reported adverse events Although performed using a non-validated questionnaire, many patients reported better control over their blood sugar levels, weight, and ability to cope
with their disease As reported in previous editions of this newsletter, we continue to feel that these novel agents will have an important place in the management of diabetes They have multiple complementary effects to improve glucose metabolism without the weight gain often associated with other agents Table 1 Obviously the availability of pramlintide
Table 1 Summary of Agents
GLP-1 Agonists
Action Metabolic effects Activate GLP-1 receptors - insulin secretion glucose-dependent - glucagon secretion - Slow gastric emptying - food intake - ? -cell preservation - FPG, PPG, HbA1c - Weight loss Nausea SQ injections 2/day
DPP-IV Inhibitors
metabolism of endogenous GLP-1 - insulin secretion - glucagon secretion - Slow gastric emptying - ? -cell preservation
Pramlintide
Synthetic analogue of amylin - glucagon secretion -Slow gastric emptying - food intake - PPG, HbA1c -Weight loss Nausea SQ injections 3/day Type 1 and Type 2 diabetes inadequately controlled by multidose insulin
Figure 1 Effects of Exenatide
Week 30 Week 82 HbAlc Body Weight kg
Benefits in clinical trials Side effects Formulation
- FPG, PPG, HbA1c -Weight neutral Nausea Oral
Change from Baseline
1 0 -1
-2 -3 -4 -5
HbAlc
Body Weight kg
Availability/ Indications
Placebo Exenatide 5 g Exenatide 10 g
Exenatide, in Type 2 diabetes inadequately controlled on metformin and/or sulfonylureas
Investigational only
FPG fasting plasma glucose, PPGpostprandial glucose, SQsubcutaneous
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Diabetes2005
American Diabetes Association
San Diego, CA
Volume 11
Issue 4
June 13, 2005
New Paths to Glycemic Control Continued from page 2
and GLP-1 agonists only by injection will limit their use, as will concerns about side effects, such as nausea Of note, long-acting GLP-1 agonists are currently in development, which might require only
weekly or even monthly injections The DPP IV inhibitors are particularly attractive since they are now oral, although their effects on body weight and HbA1c appear to be less than the GLP-1 agonists Both GLP-1 agonists and the DPP IV inhibitors may eventually be particularly useful in early diabetes or even pre-diabetes, since both
appear to enhance -cell function and there is some data to suggest that they may also lead to -cell preservation Their precise role, however, in patient care will depend on a number of factors,
including our clinical experience with them over the next several years
MOMMY and ME-tformin
Pregnancy is a well recognized insulinresistant state, with increased levels of estrogens, human placental lactogen and cortisol, as well as a variety of other placenta-derived peptides impeding insulin action Gestational diabetes mellitus GDM is characterized by insulin-resistance and relative ß-cell decompensation Metformin easily crosses the placenta, is secreted into breast milk, and is considered a highly controversial therapeutic agent in insulin-resistant pregnant women In oral and poster presentations, the physiologic effects of pregnancy on insulin sensitivity were described, and in a symposium entitled Metformin in Pregnancy–Is It Safe? Does it Work?, leading authorities attempted to elucidate the role of metformin in these patients examined the relationship between the rate of weight change during the six years before pregnancy and GDM in a case control 114 GDM cases and 94 controls, multicenter cohort of 13,798 women aged 20-44 years who delivered between 1996 and 1998 and were screened for GDM at 24-28 weeks Women were categorized according to quartiles of rate of weight
change Compared to women who lost weight -82 to -067 kg/year, women whose weight changed by -067 to 039 kg/year had an increased risk of GDM OR 23 Women who gained 039 to 162 kg/year had a corresponding relative risk of 34 for GDM, and women in the highest quartile 18 to 84 kg/year had a striking relative risk of 57 for GDM, compared to women in the lowest quartile sure to drugs or chemicals is implicated in only 3 of cases, with over 40 being of unknown cause Among diabetics, determining teratogenicity is especially difficult as these patients already have a three- to seven-fold higher background rate of structural defects between 9 and 14 In the case of metformin, rat and rabbit studies using doses of metformin two- to 10-times higher than those administered to humans produced no evidence of impaired fertility, structural defects, fetal abnormalities, or any effects on lactation Embryo toxicity has been seen in rats at a dose of 10 times the human doses based on body surface area, thus placing metformin in the moderate risk category
Metformin in PCOS and GDM Physiologic Effects of Pregnancy on Insulin Sensitivity
The changes in insulin sensitivity that occur during pregnancy
may be in part due to changes in adipose tissue and adiponectin levels according to the findings of Catalano et al from Cleveland 1917-P Ten healthy women were evaluated prior to conception and again in early 12-14 wks and late 34-36 wks pregnancy Maternal adiponectin decreased by 20 p 001 in late, as compared to early, pregnancy 125 to 100 g/l There was a strong positive correlation between adiponectin concentrations and insulin sensitivity, as measured by the euglycemic insulin clamp technique, at all three timepoints, but most especially during late gestation However this correlation was no longer significant after adjustment for maternal fat mass, with an impressive negative correlation between adiponectin and maternal body fat p 0008 Weight gain, even during the years prior to pregnancy, increases the risk for diabetes as well as GDM as revealed in a study by Henderson et al from California 1914-P The investigators
Metformin During Gestation
In the opening presentation of the symposium, Dr Clifford Bailey from Birmingham, UK, an international authority on metformin, reviewed the drugs cellular and metabolic mechanisms of action Briefly, metformin counters insulin resistance
by both insulin-dependent and -independent actions and may therefore have a potential role in the pregnant, insulin-resistant woman It also appears to exert favorable cardiovascular effects without causing hypoglycemia or weight gain Among women with insulindependent GDM, the addition of metformin often results in a 30 to 60 reduction in insulin dose In those with a history of GDM, metformin therapy is thought to delay the onset of diabetes as well as its associated complications
Determining Drug Safety During Pregnancy
Safety is of significant concern when prescribing any agent during pregnancy, as reviewed during a symposium presentation by Dr Gerry Briggs of California Of all fetal structural defects, expo-
In subsequent symposium presentations, Drs Charles Glueck of Cinncinati and Janey Rowan of New Zealand reviewed the results of studies using metformin in women with polycystic ovary syndrome PCOS and GDM Glueck reported that 80 of non-ovulatory women with PCOS responded to metformin Among the nonresponders, the addition of pioglitazone further promoted ovulation Additional studies have found that metformin treatment significantly decreases the risk of spontaneous abortions
14 among those treated with metformin vs 68 in controls as well as reduces the development of GDM by 50 with no increased incidence of pre-eclampsia It also promotes lactation in women with inadequate breast milk production and produces no difference in infant height, weight, or motor social development scores during 18 months of follow-up In a study comparing metformin with a sulfonylurea or insulin, a higher risk of pre-eclampsia was noted in the metformin group; however, these women were older and heavier than those in the other treatment groups The reduction in spontaneous
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Diabetes2005
American Diabetes Association
San Diego, CA
Volume 11
Issue 4
June 13, 2005
Mommy and ME-tformin Continued from page 3
abortion rates with metformin is thought to be associated with a decrease in the activity of plasminogen activator inhibitor-1 PAI-1 activity, an antifibrinolytic factor that is an independent determinant of miscarriage Children born to women with GDM are at three to four-fold higher risk of developing obesity and diabetes The ability of metformin to modify insulin sensitivity suggests that it may play a protective role when used in GDM
Rowan described the results of a retrospective study performed in a diverse ethnic population of diabetic/insulin-resistant women that found a lower risk of hypoglycemia in neonates of mothers given metformin compared to those given insulin and glibenclamide This finding suggests that the use of metformin during pregnancy, although it is not FDA-approved for this indication, may improve the metabolic milieu of both the mother and fetus
Table 2 Mortality Risk by Diabetes and Child-Bearing Category
Mortality Rate Ratio
Nondiabetic, parous Nondiabetic, nulliparous Diabetic, nulliparous Diabetic, parous Diabetic in pregnancy 100 243 187 238 281
95 CI
reference group 126 467 093 377 145-394 173-459
p-value
001 008 001 001
Long-Term Effects on Mortality
Little is known about the long-term impact of diabetes during pregnancy on maternal mortality Curtis et al from Phoenix studied this association in a longitudinal health study involving Pima Indians, a population known to have a high prevalence of both insulin resistance and Type 2 diabetes 158-OR Women between the ages of 20-34 years during the period 1965-1979 n 840 were followed until death or through 2001 Diabetes and parity
were determined at
baseline and then up until age 35, after which time these variables were fixed for analysis As shown in Table 2, the highest mortality was seen in women with a history of pregnancy complicated by diabetes before the age of 35 years, as compared to those who had given birth but did not develop diabetes Of note, nulliparous, nondiabetic women also had increased mortality rates GDM is clearly important to identify and treat The role of metformin in this regard continues to evolve
Feeling Low?
Hypoglycemia poses the major barrier to tight glycemic control of diabetes Numerous presentations highlighted the risk factors associated with this feared complication and its potential prevention Few studies have evaluated potential risk factors for occurrence of severe hypoglycemia in insulin treated Type 2 diabetes subjects Akram et al from Denmark evaluated 401 patients who completed a questionnaire about occurrence of hypoglycemia awareness and socio-demographic factors 632-P In the preceding year total number of episodes of severe hypoglycemia was 178, corresponding to an incidence rate of 044 episodes/person-years The risk of any severe event was increased with
impaired hypoglycemia awareness OR 295, long duration of insulin therapy OR 197/10 years, and marital status OR 239, while treatment with an angiotensin converting enzyme inhibitor/angiotensin receptor blocker ACEI/ARB decreased the risk OR 05 For those who had one event, the risk of repeated events was increased with presence of neuropathy RR 299 and macrovascular complications RR 20, while diabetes duration prior to insulin commencement decreased the risk RR 035/10 years Thus, the incidence of severe hypoglycemia in insulin-treated Type 2 diabetes is one third of that in Type 1 diabetes, and impaired awareness is the most important risk factor Severe hypoglycemia in Type 1 diabetes has been associated with high renin-angiotensin system RAS activity Hoi-Hansen et al from Denmark studied nine patients with high RAS activity and nine patients with low RAS activity mean age 40 years, diabetes duration 183 yrs, HbA1c 83 to test whether high activity may predispose to cognitive dysfunction during hypoglycemia 622-P In a cross-over study, patients were subjected to hypoglycemia and euglycemia using IV insulin infusion or IV insulin-glucose infusion, respectively Cognitive function and
hypoglycemic symptoms were recorded during the experiment Despite a similar hypoglycemic stimulus nadir plasma glucose 43 mg/dl, only the group with high RAS activity showed significant deterioration in cognitive performance reaction time for tasks requiring use of working memory The high RAS group reported a lower increase in autonomic symptoms scores during hypoglycemia The investigators concluded that in patients with Type 1 diabetes high RAS activity is associated with increased cognitive dysfunction and a blunted autonomic symptom response during mild hypoglycemia compared to patients with low RAS activity In another study, the same researchers, Hoi-Hansen et al from Denmark, assessed the relationship between conventional risk factors for hypoglycemia and the occurrence of silent hypoglycemia using continuous glucose monitoring CGMS 621-P A cohort of 119 patients with Type 1 diabetes mean age 46 years, diabetes duration 22 years, HbA1c 83, 89 on multiple injections, 21 treated with ACEI or ARB participated in six days of continuous glucose monitoring Valid monitoring time was 621 days, with total number of episodes less than 40 mg/dl of 39 per week, including silent
hypoglycemia 3 per week, symptomatic hypoglycemia 08 per week, and severe hypoglycemia 006 per week There was no relationship between hypoglycemia and known risk factors, such as HbA1c, hypoglycemia awareness, diabetes duration, age, Cpeptide status, ACE activity, and late diabetic complications Patients not being treated with an ACEI or ARB had two times more episodes of silent hypoglycemia p 001, as compared to patients taking one of these medications After excluding patients on ACEI/ARB treatment, patients with impaired awareness were 16 times more likely to have episodes of silent hypoglycemia as compared to patients with normal awareness In conclusion, silent hypoglycemia is quite common and was not related to known risk factors of severe hypoglycemia ACEI/ARB therapy may confer protection against silent hypoglycemia To avoid severe hypoglycemia, frequent glucose monitoring is mandatory In addition, comprehensive diabetes education is important, particularly in insulin-treated patients, so that dosing can be modified appropriately during periods of increased physical exertion and decreased caloric intake The data provided this week concerning the RAS system are quite
interesting
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Diabetes2005
American Diabetes Association
EXT RA
San Diego, CA
Volume 11
Issue 4
June 13, 2005
EXTR A
Late Breaking Clinical Trials
Figure 3 Vascular Event Rates in the TNT Study
50 — 40 –
of Patients
Diabetes Group Total TNT Population
Results and/or updates on five clinical trials were featured in a crowded Sunday afternoon symposium The first, Intensive Lipid Lowering with Atorvastatin in Patients with Diabetes and Stable Coronary Disease, was presented by Dr James Shepherd of Glasgow Results of the Treating to New Target TNT study were presented earlier this year at the annual meeting of the American College of Cardiology and revealed that atorvastatin 80 mg reduced the relative risk of vascular events by 22 in all patient types At this meeting, Dr Shepherd shared the results for the diabetes subset of TNT A total of 1,501 patients with diabetes randomized to receive atorvastatin 10 mg daily n 753 or atorvastatin 80 mg daily n 748 were followed for 49 years The average LDL-cholesterol at the completion of the trial was 100 mg/dl and 77 mg/dl in the 10 mg and 80 mg atorvastatin groups, respectively Patients receiving 80 mg had a 25 relative
risk reduction in the time to first major cardiovascular event p 0026 The total number of events were 135 in the 10 mg group and 103 in the 80 mg group Cerebrovascular events decreased by 31 in the 80 mg group p 0037 As would be expected, event rates were higher in the diabetes subset versus total TNT group Figure 3 Dr Shepherd remarked that this trial confirms that aggressive lipid lowering therapy should become standard for all patients with diabetes In the second late-breaking trial, Dr David Kendall of Minnesota shared information related to two double-blind, randomized studies evaluating muraglitazar, a dual PPAR / agonist The first, a two-year trial, demonstrated maintenance of an average HbA1c of 65, a decrease in triglycerides ranging from 13-39, and an increase in HDLcholesterol of greater than 20 at muraglitazar doses of 05 mg to 20 mg The second trial compared muraglitazar 5 mg daily to pioglitazone 30 mg per day, each in combination with metformin The muraglitazar group demonstrated a statistically significantly greater improvement in HbA1c, triglycerides, and HDL-cholesterol when compared with pioglitazone p 0001, each parameter One criticism of the trial is the 30
mg pioglitazone dose versus 45 mg was used as the comparator Despite the trial limitations, muraglitazar appears to be promising new therapeutic agent Dr Richard Herman, University of Colorado, presented retinopathy screening results from the Diabetes Prevention Program DPP This study was designed to address: 1 the level at which diabetic retinopathy DR occurs; and 2 the time course of development of DR in Type 2 diabetes
Figure 4 Prevalence of Diabetic Retinopathy by Disease Duration
14 — 12 — 10 — 8– 6– 4– 2– 0– of Patients
30 — 20 — 10 — 0–
Atorvastatin 10 mg Atorvastatin 80 mg
No Diabetes
Diabetes 1 year
Diabetes 1-2 years
Diabetes 2-3 years
Patients previously enrolled in the DPP, now DPP Outcomes Study DPPOS were followed for development of DR The prevalence of non-proliferative retinopathy was significantly higher in patients with diabetes versus those without 154 vs 96, p0015 Similarly, proliferative diabetic retinopathy was greater in those with diabetes 125 vs 76 in non-diabetics, p 0028 Prevalence of DR by duration of diabetes did not show a linear relationship Figure 4 The study indicates that even individuals with impaired glucose tolerance can
have detectable DR, suggesting that DR may begin before the clinical diagnosis of diabetes The study also demonstrates that DR occurs very early in the clinical course of Type 2 diabetes Rimonabant, a cannabinoid receptor-1 antagonist previously shown to decrease food intake and body weight in laboratory animals and humans, was evaluated in obese or overweight patients with Type 2 diabetes Dr Andre Scheen of Belgium presented results of the RIO-Diabetes trial, a randomized, double-blind study, showing a statistically significant improvement in several parameters with rimonabant 20 mg as compared with placebo Table 3 Scheen also reported that rimonabant was well tolerated with an incidence of adverse drug events similar to placebo Cutting edge trial results culminated with the update provided by Dr David Nathan from
Harvard who reported on Effects of Intensive Diabetes Management on Cardiovascular Events in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications DCCT/EDIC He reminded the audience that it has been greater than 22 years since the DCCT and 12 years since the results demonstrated intensive insulin control prevents long-term
microvascular complications DCCT evolved into EDIC, a long-term observational group that has shown a persistent benefit of intensive insulin therapy despite convergence of HbA1c values at year five The primary outcome of the current study is aggregate cardiovascular events between the groups previously identified as intensive versus conventional insulin control The 20-year cumulative incidence of a first event was 6 in the intensive group and 11 in the conventional group p 0018 Overall risk reduction for the intensive arm was a statistically significant 47 Even when adjusted for differences in renal disease and microalbuminuria, risk reduction was still impressive at 38 and 42, respectively HbA1c during the DCCT was the major independent predictor of cardiovascular events The mechanism remains to be established for the continued protective effects or metabolic memory, as the benefit of early intensive insulin therapy on cardiovascular disease has persisted for almost two decades
Table 3 Rimonabant versus Placebo in Patients with Type 2 Diabetes
Parameter
Body weight kg Waist circumference cm Patients with 5 weight loss Patients with 10 weight loss HbA1c HDL-cholesterol mg/dl
Triglycerides mg/dl Silvio E Inzucchi, MD Robert S Sherwin, MD
Placebo
-14 -19 195 214 01 3 4
Rimonabant 20 mg
-53 -52 559 30 -06 6 -31 Editors, Yale University, New Haven, Connecticut
p-value
0001 001 0001 001 0001 0001 0001
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Source:cnhs.umb.edu
