1. Preventing Type 2 Diabetes Selay Lam PGY1, Internal Medicine October 29, 2008

2. Learning Objectives This program will review the following aspects of type 2 diabetes: –risk factors and potential impact –primary prevention: review lifestyle modification trials review pharmacological trials practical aspects

3. Diabetes Mellitus Type 2 Due to some combination of: 1.Genetics 2.Relative impairment in insulin secretion 3.Insulin resistance

4. Prevalence Lifetime risk of developing diabetes (type 1 or type 2) for individuals born in 2000 –Male = 33% and Female = 39% Average reduction in life years –Male = 12 yrs, and Female = 19 yrs JAMA 2003 Oct 8;290(14):1884-90

5. Impaired Glucose Tolerance: (IGT) –FBS < 7 mmol/l –OGTT 7.8-11 mmol/l Impaired Fasting Glucose: (IFG) –FBS 6.1-6.9 mmol/l Gestational Diabetes: –Dx in pregnancy (Type 1 or 2) Risk Factors for DM2

6. Family History –No family history of DM1 or 2  older onset with preserved endogenous insulin secretion Ethnicity –Asians, Hispanics, and Blacks (RR 2.26, 1.86, and 1.34 respectively) Diabetes Care. 2006 Jul;29(7):1585-90.

7. Risk Factors for DM2 Obesity –increased risk of IGT or DM2b N Engl J Med 1991; 325:147.

8. Risk Factors for DM2 Fat Distribution –degree of insulin resistance and the incidence of type 2 diabetes are highest in those subjects with upper body or abdominal obesity (a waist-to-hip circumference ratio that is >0.95 in men and >0.85 in women) Diabetes Care 1995 Jun;18(6):747-53. Diabetes Care 1994 Sep;17(9):961-9.

10. Risk Factors for DM2 Lifestyle Factors –Exercise –Smoking In a meta-analysis of 25 prospective cohort studies, smokers at increased risk of DM2 compared with nonsmokers with pooled RR 1.4 JAMA. 2007 Dec 12;298(22):2654-64.

11. “Fitness Craze”

12. Risk Factors for DM2 Dietary –western diet high in red meat, processed meat, high fat dairy products, sweets, and desserts Ann Intern Med 2002 Feb 5;136(3):201-9.

13. Type 2 Diabetes Prevention What can be done? –Genetics: choose parents carefully! –Insulin secretion: unknown –Insulin resistance: lots

14. Primary prevention Means the disease never happens Our context today …this means people do not progress to a fasting glucose over 7.0 mM or a 2 hour pc glucose over 11.a mM

15. Secondary prevention Means the disease is prevented from becoming worse Our context today…. Means retinopathy or elevated creatinine do not occur (etc)

16. Tertiary Prevention Means that disease or complications are prevented from getting worse Our context today… this means someone with retinopathy does not become blind; someone with an increase in creatinine does not end up on dialysis (etc)

17. Prevention of Type II diabetes We will concentrate on Primary Prevention this hour

18. Primary Approaches to Prevention Programs targeting: High-risk individuals (i.e. IGT or obesity) High-risk individuals (i.e. IGT or obesity) High-risk subgroups (i.e. ethnic group) High-risk subgroups (i.e. ethnic group) General population (i.e. exercise and healthy diet) General population (i.e. exercise and healthy diet)

19. Evidence for Prevention An epidemiologic analysis projected that if all diabetes could be avoided (Caucasian males in US) through effective primary prevention –All cause mortality ↓ by 6.2% –Cardiovascular mortality ↓ by 9.0% Health Care Manag Sci. 1999;2:223-227.

20. IFG 6090120150180300-30 Minutes Fasting Plasma glucose (mmol/l) 8.3 11.1 IGT Diabetes FPG  7 Normal FPG <5.5 Diabetes  11.1 Normal <7.8 OGTT Impaired Fasting Glucose, Impaired Glucose Tolerance, and Type 2 Diabetes

21. Lifestyle DM Prevention Trials: IGT progression to T2DM Da Qing Study Finnish Prevention Trial Diabetes Prevention Trial (DPP)

22. Da Qing Study 577 lean + overweight IGT (1986-1992, China) were randomly assigned to four groups; at 6 years, incidence of DM2 1.Control 67.7% 2.Diet Only 43.8% 3.Exercise Only41.1% 4.Diet and Exercise 46.0% 31% Risk Reduction

23. Dietary Modification Low calorie Low fat (<30% energy consumed) Low saturated fat (<10% energy consumed) High fibre diet (>15g/1000kcal) Moderate- intensity physical activity of at least 30 minutes/day Resulting in loss of ~5% of initial body wt

24. Finnish Diabetes Prevention Study (DPS) 522 middle aged overweight with IGT (1993-8, Finland) were randomly assigned to one of the following groups: 1.Intensive lifestyle changes 2.Placebo plus information on diet and exercise At 4 yrs, incidence of DM2 –11% in intervention group vs. 23% in control Risk of DM2 ↓ by 58% N Engl J Med, Vol. 344, No. 18, May 3, 2001

25. Sustainability of DPS The Lancet; Nov 11-Nov 17, 2006; 368, 9548

26. Diabetes Prevention Program (DPP) 3234 obese subjects (1996-9, US) with IFG/ IGT were randomly assigned to one of the following groups: 1.Intensive lifestyle changes with the aim of reducing weight by 7 percent through a low-fat diet and exercise for 150 minutes per week. 2.Treatment with metformin (850 mg twice daily) plus information on diet and exercise metformin 3.Placebo plus information on diet and exercise N Engl J Med, Vol. 346, No. 6. February 7, 2002

27. DPP Results 53% of DPP participants had metabolic syndrome (ATP III criteria) at baseline. At avg f/u of 3 yrs, % developed DM2 –Intensive lifestyle group 14% –Metformin 22% –Placebo 29% At avg f/u of 3 yrs, % developed metabolic syndrome –Intensive lifestyle 34% –Metformin 45% –Placebo 51%

28. Diabetes Prevention Program Progression to Type 2 Diabetes Placebo Metformin Intensive Lifestyle Cases / 100 person-years Average follow-up of 2.8 years  31% *  58% * *All pair-wise comparisons significantly different by group sequential log-rank test The Diabetes Prevention Program Research Group. New Engl J Med 2002;346:393-403. Younger Obese subjects All Groups

29. Pharmacological Prevention Diabetes Prevention Program (DPP) United Kingdom Prospective Diabetes Study (UKPDS) Study to Prevent NIDDM (STOP-NIDDM) Xenical in the Prevention of DM2 in Obese Subjects (XENDOS) Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM)

30. Diabetes Prevention Program (DPP) Metformin (850mg BID) arm for an average of 2.8yrs significantly decreased progression to DM2 by 31% No significant effects in older age (>60y/o) and less obese (BMI 60y/o) and less obese (BMI<35) subjects

31. United Kingdom Prospective Diabetes Study (UKPDS) Metformin may reduce diabetes-related end points. –sudden death, hypo- or hyperglycemia causing death, MI, angina, heart failure, stroke, renal failure, amputation, retinopathy, monocular blindness or cataract extraction, and all cause mortality

32. Study to Prevent NIDDM (STOP- NIDDM) 1429 subjects with IGT Acarbose 100mg TID with avg f/u 3.3yrs Overall 25% reduction with 1 OGGT, 36% reduction with 2 OGGT (not affected by age or BMI) However, when drug was discontinued, effect did not persist 49% reduction in CV events, 50% reduction in progression of carotid intima-media thickness

34. Xenical in the Prevention of DM2 in Obese Subjects (XENDOS) Effect of orlistat in combination with an intensive lifestyle modification program 3305 obese individuals with or w/o IGT (4 yrs) –Orlistat 120mg TID –Placebo TID 37% reduction BUT, high dropout rates (48%, 66%) and last observation carried forward was used for analysis Diabetes Care; Jan 2004; 27, 1.

36. Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) 5269 IGT and/or IFG randomized to following groups: –Rosiglitazone 8 mg OD (3 yr) –Control Rosiglitazone ↓ incidence of DM2 by 60%, but whether effect persists after drug withdrawal is unknown. No strong evidence that TZDs reduce CVD endpoints, and in particular there are no data on such risk reduction for people with metabolic syndrome. Rosiglitazone may even be associated with an increased incidence of myocardial infarction. The Lancet; Sep 23-Sep 29, 2006; 368, 9541; N Engl J Med 2006;355:1551-62.

38. Ramipril 15mg ODRamipril 15mg OD Results suggest effect of ramipril on glucose metabolism, but use for preventing DM2 is not indicatedResults suggest effect of ramipril on glucose metabolism, but use for preventing DM2 is not indicated

39. Completed Diabetes Prevention Trials in Type 2 Diabetes Treatment Relative Risk Treatment Relative Risk Finnish Diabetes Intensive D&E vs Control  58% Finnish Diabetes Intensive D&E vs Control  58% Prevention Study Prevention Study DiabetesIntensive D&E vs Placebo  58% DiabetesIntensive D&E vs Placebo  58% Prevention Metformin vs Placebo  31% Prevention Metformin vs Placebo  31% Program Troglitazone vs Placebo*  75% Program Troglitazone vs Placebo*  75% STOP-NIDDMAcarbose vs Placebo  25% STOP-NIDDMAcarbose vs Placebo  25% TRIPODTZD vs Placebo in GDM  56% TRIPODTZD vs Placebo in GDM  56% DREAMTZD vs Placebo  60% Trial * Troglitazone vs placebo discontinued after 10 months.  Data collected after the 1st year of the study.

40. Elliott Lancet 2007; 369: 201–07 Can we prevent or delay diabetes?

41. Key Messages Intensive and structured lifestyle modification (↓5% of initial body weight) can reduce the risk of progression from impaired glucose tolerance to type 2 by ~60% Progression from prediabetes to DM2 can also be reduced by pharmacologic therapy with metformin (~30% reduction), acarbose (~30% reduction) and TXD (~60% reduction)

42. CDA Recommendations A structured program of lifestyle modification that includes moderate weight loss and regular physical activity should be implemented to reduce progression to DM2 In IGT, metformin or acarbose should be considered In IGT and/or IFG and no know CVD, TZD could be considered to reduce risk of developing DM2