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Leveraging Weight Loss in the Treatment of Type 2 Diabetes

This article explores the impact of weight gain from antihyperglycemic therapies on the control of hyperglycemia, vascular complications, and patient adherence. It discusses the interactions between adipocytes and the vasculature, as well as the effects of weight gain on cardiovascular risk factors and provides an overview of available options for weight loss.

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Leveraging Weight Loss in the Treatment of Type 2 Diabetes

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  1. Leveraging Weight Loss in the Treatment of Type 2 Diabetes Pa Part 3 of 4

  2. Treatment-Induced Weight Gain • Is weight gain from antihyperglycemic therapies the “price paid” for the improved control of hyperglycemia? • What is the impact of weight gain upon vascular complications? • Will individuals accept weight gain? • May be a barrier to adherence • May discourage patients • Appears to be concern for physicians • Glycemic goals may not be reached

  3. Adipocyte and Vasculature Interactions Blood Pressure Visfatin Adipocyte Angiotensinogen Inflammation IL-6 Clotting TNF- PAI-1 Adiponectin Leptin FFA Insulin Sensitivity Insulin Resistance Vascular Inflammation Endothelial Dysfunction FFA = free fatty acids.Lyon CJ et al. Endocrinology 2003; 144:2195-2200. Trayhurn P et al. Br J Nutr. 2004;92:347-355. Eckel RH et al. Lancet. 2005;365:1415-1428.

  4. Impact of Weight Gain on Cardiovascular Risk Factors Type 1 Patients on IIT (n=582), Stratified by Weight Change A B 120 118 116 114 112 110 80 78 76 74 72 70 Systolic BP Diastolic BP mm Hg mm Hg 1st Quartile 2nd Quartile 3rd Quartile 4th Quartile 1st Quartile 2nd Quartile 3rd Quartile 4th Quartile C D 90 85 80 75 70 65 195 190 185 180 175 170 Triglycerides Total Cholesterol mg/dL mg/dL 1st Quartile 2nd Quartile 3rd Quartile 4th Quartile 1st Quartile 2nd Quartile 3rd Quartile 4th Quartile Purnell J. JAMA. 1998;280:140-146.

  5. Systolic Blood Pressure Increases WithWeight Gain in T2DM Treated With Insulin 6 Nonobese Nonobese XXX XXX 20 XX XXX 4 XXX Weight (kg) 10 XXX XXX 2 XXX XXX 0 Change in Systolic BP (mm Hg) 0 6 Obese Obese XXX 20 XXX XX XX XXX XX 4 10 XXX Weight (kg) XXX XXX XXX 2 X 0 XXX 0 12 3 6 9 0 12 3 6 9 0 Insulin Time (months) Time (months) Combination *P<.05; **P<.01 vs 0 months; *** P<.001 vs 0 months. Yki-Jarvinen H, et al. J Clin Endocrinol Metab. 1997;82:4037-4043.

  6.  Total Cholesterol  LDL Cholesterol  HDL Cholesterol  Glycemia  A1C  Systolic BP  Diastolic BP Moderate Weight Loss(5%-10%) Weight Loss and Cardiovascular Risk Obesity Type 2 Diabetes Hypertension Dyslipidemia Muls E, et al. Int J Obes. 1997;21(2):155-158.

  7. Available Options forWeight Loss

  8. Diet + Placebo TID (n=159) Diet + Orlistat 120 mg TID (n=162) Orlistat in Obese Individuals With T2DM:Weight Change From Baseline at 52 Weeks 0 -2 Mean (± SEM) % Change inBody Weight -4 P<.001 -6 -8 -5 0 4 12 20 28 36 44 52 Time (weeks) Hollander PA, et al. Diabetes Care. 1998;21:1288-1294.

  9. Additive Effects of Behavior and Diet Therapy With Pharmacotherapy for Obesity 0 Medication Alone -5 Medication and BehaviorModification -10 * Weight Change (%) -15 * Medication, BehaviorModification, and Meal Replacements -20 -25 0 2 4 6 8 10 12 Time (months) *P<.05 vs medication alone. Wadden TA, et al. Arch Intern Med. 2001;161:218-227.

  10. Multihormonal Control of Body Weight:Role of Fat-, Gut-, and Islet-Derived Signals Clinical-Stage Compounds Leptin (r-met human)(AC164594) Pramlintide(AC137) PYY3-36 (synthetic)(AC162352) Adapted from Badman MK, et al. Science. 2005;307:1909-1914.

  11. Exenatide: An Incretin Mimetic Mimics the actions of a pharmacologic dose of continuously infused GLP-1 by binding to known GLP-1 receptors in vitro Has an extended half-life Not degraded by DPP-4, unlike endogenous GLP-1 Approved for use as an adjunctive therapy to improve glycemic control in individuals with type 2 diabetes who are taking any of the following medications but have not achieved adequate glycemic control: MET TZD, with or without MET SFU MET and SFU DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; MET=metformin; SFU=sulfonylurea; TZD=thiazolidinedione. Nielsen LL, et al. Regul Pept. 2004;117:77-88.

  12. Exenatide Sustained A1C Reduction and Continued to Reduce Weight:3 Year Completers Open-Label Uncontrolled PBO-Controlled Open-Label Uncontrolled PBO-Controlled 1 10 0 Baseline Weight = 99 kg Baseline A1C = 8.2% 9 -1 8 ± ± -1.1 0.1% -1.0 0.1% -2 A1C (%) -3 Change in Body Weight (kg) 7 -4 -5.3 ± 0.4kg 6 -5 5 54% 46% -6 % Achieving A1C ≤7% -7 4 0 26 52 78 104 130 156 0 26 52 78 104 130 156 Time (weeks) Time (weeks) P<.0001 from baseline to 30 weeks and baseline to 3 years. P<.0001 from baseline to 3 years and between 30 weeks and 3 years.No diet and exercise regimen was provided. N=217; Mean (- SE); Data on file, Amylin Pharmaceuticals, Inc. Buse JB, et al. Presented at ADA 67th Scientific Sessions; June 22-26, 2007; Chicago, IL Abstract 0283-OR.

  13. Percent Lipid and Blood Pressure Changes With 3.5 Years of Exenatide 30 +24% 20 10 Change (%) 0 -2% -4% -5% -10 -6% -12% -20 TC TG LDL-C HDL-C Systolic BP Diastolic BP 3.5-year completer cohort N=151; Mean ± SE. Kendall D, et al. Diabetes. 2007:56(suppl 1):A149.

  14. Heine et al1 Nauck et al3 Barnettet al2 Heine et al1 Barnettet al2 Nauck et al3 -1.0% -1.4% -1.1% -1.4% -1.1% -0.9% +6.4 lb +4.0 lb +5.1 lb -4.9 lb -5.1 lb -5.5 lb Changes in Glycemia and Weight in 3 Head-to-Head Studies: Exenatide vs Insulin 10 9 ∆ A1C (%) 8 ADA GOAL 7 6 Glargine, Once Daily Insulin Aspart, 70/30 Exenatide 8 6 4 2 ∆ Weight (lb) 0 -2 -4 -6 1. Heine RJ, et al. Ann Intern Med. 2005;143:559-569. 2. Barnett AH, et al. Clin Ther. 2007;29:2333-2348. 3. Nauck MA, et al. Diabetologia. 2007;50:259-267.

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