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

2. Overview Overweight/obesity health risks associated with type 2 diabetes American Diabetes Association (ADA) guidelines for medical nutrition therapy (MNT) and lifestyle changes Glycemic benefits and additional advantages of weight loss in type 2 diabetes Application to clinical practice

3. Body Weight (lb) 200 220 240 260 280 300 320 Adapted from Kendall DM, et al. © 2004 International Diabetes Center, Minneapolis, MN. All rights reserved. Years Diabetes Diagnosis Onset Prediabetes (IFG, IGT) Metabolic Syndrome Fasting Glucose Postmeal Glucose Glucose (mg/dL) 50 100 150 200 250 300 350 Obesity, Inactivity, Genetics Relative Function -10-5051015202530 Insulin Resistance Insulin Response 0 50 100 150 200 250 -15 Progressive  -Cell Defect (glucose specific) Amylin Response Oral Agents/Incretin Enhancers Basal Insulin Basal/Bolus Insulin Amylin Replacement Natural History of Type 2 Diabetes and Obesity

4. Prevalence of Overweight and Obesity Among Adults Diagnosed With Diabetes BMI = body mass index. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2004;53:1066-1068. www.cdc.gov/mmwr/preview/mmwrhtml/mm5345a2.htm. Accessed April 9,2008. 20-64 ≥65 0 20 40 60 80 100 Age (years) % Obese (BMI ≥30) Overweight or Obese (BMI ≥25)

5. Health Risks of Obesity Increased morbidity – Hypertension – Dyslipidemia – Coronary heart disease – Type 2 diabetes – Stroke – Cancer (endometrial, breast, colon) – Impairments in health-related quality of life and psychosocial well-being – Sleep apnea – Osteoarthritis Increased mortality NIH-NHLBI. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. 1998.

6. Excess Weight in Individuals With Type 2 Diabetes Increases Mortality Risk Comorbidities of Obesity TC = total cholesterol; Ref category = normal weight without the risk factor. Wei M, et al. JAMA. 1999;282:1547-1553. Relative Risk of All-Cause Death by BMI Categories for Selected Mortality Predictors Ref CategoryNormal Overweight Obese Relative Risk Adjusted for Age and Exam Year 0 0.5 1 1.5 2 2.5 3 3.5 TC >239DiabetesHypertensionSmoker

7. Additional Problems Associated With Obesity in Individuals With Type 2 Diabetes Exacerbation of metabolic risk factors – Hyperglycemia – Dyslipidemia – Increased thrombogenic risk (eg, increased PAI-1) Increased insulin resistance and glucose intolerance Increased risk of hypertension and cardiovascular disease Increased mortality – Mortality ratio for individuals with diabetes whose body weights are 20% to 30% above ideal is 2.5 to 3.3 times higher than those of normal body weight PAI-1 = Plasminogen activator inhibitor-1. Maggio CA, et al. Diabetes Care. 1997;20:1744-1766.

8. Additional Problems Associated With Obesity in Individuals With Type 2 Diabetes Exacerbation of metabolic risk factors – Hyperglycemia – Dyslipidemia – Increased thrombogenic risk (eg, increased PAI-1) Increased insulin resistance and glucose intolerance Increased risk of hypertension and cardiovascular disease Increased mortality – Mortality ratio for individuals with diabetes whose body weights are 20% to 30% above ideal is 2.5 to 3.3 times higher than those of normal body weight PAI-1 = Plasminogen activator inhibitor-1. Maggio CA, et al. Diabetes Care. 1997;20:1744-1766.

9. Standards of Medical Care in Type 2 Diabetes: 2008 ADA Glycemic Goals A1C <7.0% – Preprandial glucose 70-130 mg/dL – Postprandial glucose (PPG) <180 mg/dL At diagnosis: Metformin (MET) and lifestyle changes (MNT) – Add therapy to reach A1C of <7% – Add therapy to maintain an A1C of <7% Target PPG if A1C goals are unmet, despite reaching preprandial glucose American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54.

10. Standards of Medical Care in Type 2 Diabetes: 2008 ADA Weight Recommendations Weight loss is an important therapeutic objective 1 – 85% of individuals with type 2 diabetes are obese/overweight 2 Physical activity and behavior modification are important 1 Moderate weight loss (5% in short-term studies) 1 – Decreased insulin resistance – Improved measures of glycemia and lipemia – Reduced blood pressure “The importance of controlling body weight in reducing risks related to diabetes is of great importance…” but sustaining weight loss is difficult 1 1. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S78. 2. www.cdc.gov/mmwr/preview/mmwrhtml/mm5345a2.htm. Accessed April 9,2008.

11. Modest Weight Loss Can Drastically Reduce Abdominal Visceral Fat Before Weight Loss (95 kg, BMI 32) After 10% Weight Loss (85 kg, BMI 29) Després J-P. Baillière’s Clin Endocrinol Metab. 1994;8:629-660.

12. Weight Loss in Type 2 Diabetes: Study Objective and Design Objective: Determine if modest weight loss would provide a long-term benefit Weight Control Program Group treatment Individualized treatment goals to produce a 1-kg/wk weight loss Calorie/food restriction with focus on reduced fat intake Gradual increase of exercise goals with final goal of 3.2 km/d, 5 days per week Behavior-modification strategies 1-Year Follow-up Physical Wing RR, et al. Arch Intern Med. 1987;147:1749-1753. N=114 Type 2 diabetes treated with insulin, orals, diet only, or insulin plus oral medications

13. Weight Loss in T2DM Dramatically Improves Glycemia and Metabolic Risk Factors Δ Body Weight (%) Δ A1C Δ Body Weight (kg) -2 to -4.9 -5 to -9.9 0 -0.4 0.4 0.8 0 0 to -1.9 > -10 -0.8 -1.2 -1.6 -20 -40 0 Δ Triglycerides (mg/dL) 0 0 to -2.3 -2.4 to -6.8 -6.9 to -13.6 > -13.6 -60 -80 -100 Δ HDL-C (mg/dL) 8 6 10 12 4 2 0 0 0 to -2.3 -2.4 to -6.8 -6.9 to -13.6 > -13.6 Δ Body Weight (kg) Wing RR, et al. Arch Intern Med. 1987;147:1749-1753.

14. Hamdy O, et al. Diabetes Care. 2003;26:2119-2125. Monzillo LU. Obes Res. 2003;11:1048-1054. Change From Baseline (%) IL-6 TNF-  hCRP PAI-1 Leptin P<.05 NS NS P<.001 P<.01 NS Adiponectin -16.3 -17.4 -18.7 -25.5 -15.7 4.3 -30 -25 -20 -15 -10 -5 0 5 Benefits of Weight Reduction on Cytokines in Type 2 Diabetes and Prediabetes