1. Diabetes Prevention for a Heterogeneous Population Richard Arakaki, M.D. Professor of Medicine and Chief, Division of Endocrinology and Metabolism John A. Burns School of Medicine September 30, 2011

2. Type 2 Diabetes Prevention: A Few Questions UNEQUIVOCALLY SHOWN TO BE PREVENTED AND/OR DELAYED!UNEQUIVOCALLY SHOWN TO BE PREVENTED AND/OR DELAYED! How should we identify people at-risk?How should we identify people at-risk? What interventions are appropriate?What interventions are appropriate? How do we implement the interventions?How do we implement the interventions?

3. Da Qing IGT and Diabetes Study Screened 110,660 persons in Da Qing, China for IGTScreened 110,660 persons in Da Qing, China for IGT Randomized 577 persons with IGT at 33 local health centersRandomized 577 persons with IGT at 33 local health centers Four arm study over 6 years (group intervention for weight loss)Four arm study over 6 years (group intervention for weight loss) –Diet (modest weight reduction due to low BMI) –Exercise –Diet + –Diet + Exercise –Control Pan et al. Diabetes Care 1997;20:537-44

4. Da Qing IGT and Diabetes Study a Adjusted for BMI and fasting glucosePan et al. Diabetes Care 1997;20:537-44 Mean change in BMI for intervention -0.69; Control -0.34

5. Diabetes Prevention Program Primary Goal:Primary Goal: To prevent or delay the development of type 2 diabetes in persons with impaired glucose tolerance (IGT)To prevent or delay the development of type 2 diabetes in persons with impaired glucose tolerance (IGT) Randomized (3,819 people) Standard lifestyle teaching IntensiveLifestyle (1079 people) Metformin (1073 people) Placebo (1082 people) Troglitazone 585 people Until 6/98 Study Interventions:Study Interventions:

6. Placebo (n=1082) Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Metformin, p<0.001 vs. Placebo) Incidence of Diabetes Risk reduction 31% by metformin 58% by lifestyle N Engl J Med 346:393-403, 2002

7. Effect of Treatment on Incidence of Diabetes Placebo Metformin Lifestyle Placebo Metformin Lifestyle Incidence of diabetes 11.0% 7.8% 4.8% (percent per year) (percent per year) Reduction in incidence ---- 31% 58% compared with placebo/metformin 39% compared with placebo/metformin 39% Number needed to treat ---- 13.9 6.9 to prevent 1 case in 3 years to prevent 1 case in 3 years N Engl J Med 346:393-403, 2002

8. Diabetes Incidence Rates by Ethnicity N Engl J Med 346:393-403, 2002 71% 51%

9. Diabetes Incidence Rates by Fasting Glucose Fasting Plasma Glucose: mg/dl (mmol/l) N Engl J Med 346:393-403, 2002

10. Diabetes Incidence Rates by 2-hr Glucose 2-Hour Plasma Glucose (mg/dl) N Engl J Med 346:393-403, 2002

11. DPPOS Incidence of Diabetes DPP Research Group. Lancet. 2009; 374:1677-1686 (Figure 4)

12. DPPOS Diabetes Risk Reduction Delay in diabetes onset after 10 years follow-up: – –4 years for Lifestyle; 34% lower risk – –2 years for Metformin; 18% lower risk The key factors for lower rate of diabetes development for lifestyle and metformin. – –Weight loss is the predominant factor; 16% RR per kg weight loss – –Metformin compliance

13. Summary of Treatment Effects Lifestyle intervention was beneficial regardless of ethnicity, age, BMI, or sex The efficacy of lifestyle relative to metformin was greater in older persons and in those with lower BMI The efficacy of metformin relative to placebo was greater in those with higher baseline fasting glucose and BMI

14. Li et al. Lancet 2008;317:1783-89 Cumulative incidence of DM during follow-up in China Da Qing Diabetes Prevention Outcome Study

15. StudyN Study population Duration of intervention Cumulative incidence in controls Risk reduction (95% CI) DPP Research Group API Subgroups 1079 active 1082 control 57 L/S, 49 P IGT BMI 34 BMI 29.3 2.8 years 28.9% at 3 years 36% at 3 yrs 58% (48-66) 71% Da Qing IGT and DiabetesStudy 133 control; 130 diet;141 ex; 126 both IGT BMI 26 6 years 68 % (15.7% per year) 31% (diet) 46% (ex) 42% (both) Japan Diabetes Study 356 control 102 active IGT (*) BMI 24 4 years 9.3 (FPG >140mg/dl) 67.4% Indian Diabetes Prevention Programme 133 active 136 control IGT BMI 26 3 years55 % 28.5% (20-37) Zensharen Study 330 control 311 active IFG, IGT BMI 27 3 years16.6 %44% Lifestyle Intervention/Prevention DM Asian Studies Knowler W et al, N Engl J Med 2002;346:393-403, 2002; Pan XR et al, Diabetes Care 1997;20:537-544; Kosaka Diabetes Res Clin Pract 2005;67:152-62K et al,; Ramachandran A et al, Diabetologia 2006;49:289-97; Saito T et al Arch Intern Med 2011;171:1352-60.

16. Saito T et al Arch Intern Med 2011;171:1352-60. Zensharen Study: Cumulative Diabetes Incidence by baseline glucose tolerance status

17. Study and Medication N Study population Duration of intervention Cumulative incidence in controls Risk reduction (95% CI) DPP Research Group Metformin 850 BID API Subgroup 1073 active 1082 placebo 36 Met, 49 Pla IGT BMI 34 BMI 29.3 2.8 years 28.9% at 3 years 36% at 3 yrs 31% 38% Chinese Diabetes Metformin 250 TID 42 active 43 control IGT BMI 26 1 year14.0 %50% Indian Diabetes PP Metformin 250 BID 133 active 136 control IGT BMI 26 2.5 years55%26% Indian Diabetes PP Pioglitazone 30 + LS 204 active 203 control IGT BMI 26 3 years31.6 %8% (NS) DREAM Trial Indian Cohort Rosiglitazone 8 mg 330 active 332 placebo IGT /IFG/both BMI 28 3.0 years8 % per year40 % Japan DiabetesStudy Voglibose 0.2 mg TID 110 control 112 active IGT BMI 26 3 years9.3 %58 % Knowler W et al, N Engl J Med 2002;346:393-403, 2002; Ramachandran A et al, Diabetologia 2009;52:1019-26; Li, CL et al Diabetic Med 1999;16:477-481; DREAM Trial Investigators Lancet 2006;368:1096-1105; Kawamori R et al, Lancet 2009;373:1607-14. Medication DM Prevention Studies in Asians

18.  10% Estimate of diabetes associated with known genetic risk (Jablonski K et al Diabetes 2010)  Primarily related to beta-cell function  Overall genetic markers (SNPs by GWAS) associated with increased rates of DM are similar across all ethnic groups (Europeans, Asians, etc; Tan JT et al, J Clin Endocrinol Metab 2010;95:390-397).  Allele frequency may reduce usefulness of SNPs for screening at-risk individuals  TCF7L2 Polymorphisms and progression to diabetes in the Diabetes Prevention Program (N Engl J Med, July 2006);  high risk SNP but still responsive to lifestyle intervention Genetics Risk for Diabetes

19. Type 2 Diabetes Prevention: A Few Answers? How should we identify people at-risk?How should we identify people at-risk? Pathophysiologic and physical characteristics low insulinogenic index (beta cell function) high HOMA IR (insulin resistance) higher BS levels; fasting > 110 mg/dl; A1c>6.0% Zensharen Study- need for OGTT GWAS; look for multiple SNPs, additive risk

20. Type 2 Diabetes Prevention: A Few Answers? What interventions are appropriate?What interventions are appropriate? ANY effective Weight loss interventions Lower BMI group More weight loss-greater effect Effective Exercise interventions 150 min/week or more? Medications Metformin 250 BID/TID (lower doses) TZDs at high dose Alpha-glucosidase inhibitors-preferred?Alpha-glucosidase inhibitors-preferred?

21. Type 2 Diabetes Prevention: A Few Answers? How do we implement the interventions?How do we implement the interventions? Community-Based Interventions Physicians/physician’s groups Medicare/ Other Insurers Government-Federal/State Are we even there yet?

22. Thank you for your attention