Diabetes Prevention for a Heterogeneous Population

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! • How should we identify people at-risk? • What interventions are appropriate? • How do we implement the interventions?

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

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

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

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

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

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

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

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

17. Medication DM Prevention Studies in Asians 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.

18. Genetics Risk for Diabetes • 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 ClinEndocrinolMetab 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

19. Type 2 Diabetes Prevention: A Few Answers? • How should we identify people at-risk? • Pathophysiologicand 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? • 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?

21. Type 2 Diabetes Prevention: A Few Answers? • 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