1. Type 2 Diabetes in the Elderly: Lessons from the Diabetes Primary Prevention Program Andrew P. Goldberg, MD Baltimore VA GRECC University of Maryland School of Medicine 410-605-7183 agoldber@grecc.umaryland.edu

2. Oral Glucose Tolerance Test Fasting (2-Hour Glucose During OGTT) (mg/dL) (mg/dL) Normal<110<140 Impaired110-125140-199 Diabetes>125>199 Glucose Tolerance Categories Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

3. High Prevalence of Type 2 Diabetes Among Elderly People Harris MI, et al. Diab Care. 1998;21:518-524. Resnick HE, et al. Diab Care. 2000;23:176-180. Percentage of Population NHANES III

4. BMI (kg/m 2 ) <22 22-25 26-30 31-35 >35 <22 22-25 26-3031-35 >35 Percent Diabetic Age (years) 20 - 54 60 - 74 Prevalence of Diabesity by Age

5. Increased adiposity Age effects on insulin action Medications Age effects on Muscle metabolism and  cells Coexisting illness Genetics INSULIN RESISTANCE Impaired adaptation: No  insulin Progressio n to IGT and type 2 diabetes DECREASED INSULIN SECRETION Diabetes Risk Factors in Aging Model for Age-Related Hyperglycemia Decreased physical activity * Chang & Halter. AJP 284:E7-E12, 2003

6. Compensatory hyperinsuline mia Maintenance of euglycemia Insulin resistance (of any cause) Adaptation of  -cell function Normal Adaptation to Insulin Resistance

7. Aging and Diabetes Comparison Aging Diabetes Inactivity/Deconditioning ++  Body Fat,  Muscle++ Central Adiposity++ Atherosclerosis++ Renal failure++ Vision problems++ Cognitive problems++ Neuropathy++ Hypertension++ Insulin signaling/resistance++ Mortality ++ Response to CR++

8. National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995. Atherosclerosis in Diabetes ~80% of all diabetic mortality – 75% from coronary atherosclerosis – 25% from cerebral or peripheral vascular disease >75% of all hospitalizations for diabetic complications >50% of patients with newly diagnosed type 2 diabetes have CHD

9. SMC=smooth muscle cell. Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656. Mechanisms of Atherogenesis in Diabetes Abnormal lipoproteins and apolipoproteins Hypertension Glucose toxicity – Protein glycosylation and glycation – Glycoxidation and oxidation Insulin resistance and hyperinsulinemia Procoagulant state Hormone-, growth-factor–, and cytokine- enhanced SMC proliferation and foam cell formation

10. Aging  Energy Flux  Energy Intake  Body Fat  Energy Flux  Energy Expenditure Maintain Muscle Mass “Health-Related Fitness” Exercise Hypocaloric Diet Weight LossExercise Nutritional Balance Age, Physical Inactivity, and Obesity

11. Physical Characteristics of Subjects Normal Lean Men (10) Insulin Resistant Men ( 17) VariableBaselineAfter Intervention Age (yr) Weight (kg) Percent body Fat (%) Fat-Free Mass (kg) Waist:Hip Ratio Waist Girth (cm) Maximal Oxygen Uptake: Lmin -1 mLkg -1 min -1 62 ± 2 75 ± 3 19 ± 2 61 ± 3 0.88 ± 0.02 86 ± 3 2.6 ± 0.1 35 ± 2 57 ± 1 † 97 ± 4 † 32 ± 1 † 66 ± 3 0.96 ± 0.01 † 106 ± 3 † 2.7 ± 0.2 28 ± 1 † 88 ± 4** † 25 ± 1** † 66 ± 3 0.93 ± 0.01** † 96 ± 2** † 3.1 ± 0.2** 36 ± 2** Dengel, DR. et al. Metabolism, 1998;47(9):1075-1082 Significantly different from Normal Lean men † P < 0.01, Significantly different from Baseline value: * P < 0.05; ** P < 0.01.

12. ATPIII Criteria for Metabolic Syndrome Metabolic Syndrome if 3 or More: Abdominal Obesity: Waist >102 cm (men), > 88cm (women)  Triglyceride: >150 mg/dl  HDL-C: < 40 mg/dl (men), < 50 mg/dl (women)  BP: >135/85 mm Hg  Fasting Glucose: >100 mg/dl

13. AEX + WL in Metabolic Syndrome Improves Oral Glucose Tolerance

14. AE + WL in Metabolic Syndrome Improves Lipid Profiles VariableBaselineAEX + WL Cholesterol 177 ± 7154 ± 7* Total HDL-C 30 ± 134 ± 1* HDL 2 -C 2 ± 0.45 ± 0.8** HDL 3 -C 29 ± 1 LDL-C 119 ± 6103 ± 6* Triglyceride 137 ± 1892 ± 11** Data are Mean ± SEM, mg/dl; *p < 0.05; **p < 0.01 vs Baseline

15. AEX+WL in Metabolic Syndrome Reduces Blood Pressure  = -8%  = -10%

16. Effects of Exercise and Weight Loss on Components of Metabolic Syndrome Metabolic AbnormalityBaselineAEX+WL Central Obesity1710 Hypertension176 ­ Insulin 1710 Glucose Intolerance105 Low HDL-C1710 ­ TG 63 Totals8444

17. There are now a large number of prevention trials—some limited to life-style intervention, some limited to anti-diabetic drug trials; however, only rarely do studies include both types of potential prevention. Da Qing IGT and Diabetes Study (Pan et al. Diabetes Care 1997). Randomized 577 IGT subjects (283M/247F) mean age 45yrs –diabetes incidence: control (15.7%) v diet (10%) v exercise (8.3%) v diet + exercise (9.6%). Finnish Diabetes Prevention Trial (Tuomilehto et al., NEJM 2001). Randomized 422 IGT subjects age 40-64 ( 350F/172M, mean 55 yrs ) to diet counseling and circuit-type weight training vs. control. F/U 3.2 yrs. Diabetes incidence: 58% reduction (19.8% control vs. 8.3% intervention. Of importance to this talk, the Diabetes Prevention Program (NEJM, 2002) is the only one that includes old subjects (60–85 yr). Diabetes Prevention Trials

18. Diabetes Prevention Program (DPP) A Randomized Clinical Trial at 27 sites to Prevent Type 2 Diabetes in Persons at High Risk

19. To prevent or delay the development of type 2 diabetes in persons with impaired glucose tolerance (IGT). DPP Primary Goal

20. Age > 25 years Plasma glucose – 2 hour glucose 140-199 mg/dl (7.8- <11.1 mmol/L) and – Fasting glucose 95-125 mg/dl (5.3- <7.0 mmol/L) Body mass index > 24 kg/m 2 All ethnic groups Goal of up to 50% subjects from high risk populations – old, African American, American Indian, Hispanic, Asian Eligibility Criteria NEJM 346:393-403, 2002

21. Study Interventions Eligible Participants Randomized Standard Lifestyle Recommendations Intensive Metformin Placebo Lifestyle (n = 1079) (n = 1073) (n = 1082)

22. DPP Population Sex Distribution Age Distribution 25-44 31% > 60 20% 45-59 49% Men 32% Women 68% The DPP Research Group, Diabetes Care 23:1619-29, 2000

23. Base-Line Characteristics of the Study Participants CharacteristicPlacebo (N=1082 ) Metformi n (N=1073) Lifestyl e (N=1079 ) Sex – Male/Female (%)31/6934/6632/68 Race or ethnic group (%) White/African American54/2056/215419 Hispanic/American Indian/ Asian16/6/515/5/317/6/5 Family history of diabetes (%)706870 History of gestational diabetes (%)16 Age – yr50 ± 1051 ± 1051 ± 11 Weight – kg94 ± 20 94 ± 21 Body-mass index34 ± 7 Waist circumference – cm105 ± 14 105 ± 15 Plasma glucose – Fasting107 ± 8 106 ± 8 Two hours after an oral glucose load 165 ± 17 164 ± 17 Glycosylated hemoglobin - %6 ± 1 Leisure physical activity – MET- hr/wk¶ 17 ± 2916 ± 2616 ± 22 *Values are means ± SD ¶Data are based on responses to the Modifiable Activity Questionnaire N Engl J Med, 2002; 346(6):393-403

24. Lifestyle Intervention Structure 16 session core curriculum Long-term maintenance program Supervised by a case manager & lifestyle support staff – Dietician – Behavioral specialist – Exercise physiologist / trainer

25. Lifestyle Intervention Exercise Component Moderate intensity aerobic exercise Structured classes offered 1-2 x per week Tool box strategies – Pedometers, exercise videos, health club memberships Activity assessed by self-report – LoPAR (habitual physical activity) – MAQ (leisure activity)

26. Mean Change in Leisure Physical Activity Placebo Metformin Lifestyle The DPP Research Group, NEJM 346:393-403, 2002

27. 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 The DPP Research Group, NEJM 346:393-403, 2002

28. Placebo Metformin Lifestyle Mean Weight Change The DPP Research Group, NEJM 346:393-403, 2002

29. Intensive Lifestyle (ILS) Activities by Age 25-4445-5960+ p Weight change (kg) -4.09-5.03-6.42 < 0.001 WC change (cm)-4.30-4.68-6.69 < 0.001 % at wt. loss goal33.438.955.7 < 0.0001 Recreational activity (met- hr/wk) 4.45.818.7 <0.001 % at exercise goal 687481 < 0.05 Age in years

30. Changes in Body Fat Distribution ● Placebo; ▲ Metformin; ■ Lifestyle Intervention Diabetes. 2007 Jun;56(6):1680-5.

31. Hazard Rate for Development of Diabetes in Relation to Weight Change

32. Diabetes Incidence Rates by Age Age (years) NEJM 346:393-403, 2002 p = 0.007 ILS by age p= 0.067 metformin by age

33. Diabetes Risk Reduction by Age * p< 0.05 ILS v. Metformin Age in Years ILS Metformin NEJM 346:393-403, 2002 Percent Risk Reduction *

34. Percent Achieving Normal Glucose Tolerance by Age p=0.01 Metformin by age Percent with NGT ILS Metformin Placebo Age in Years

35. DPP : Age 60+ Intensive Lifestyle Group Better success in achieving exercise goals Better success in achieving weight loss goals More likely to complete self-monitoring records Achieved greatest reduction in diabetes risk This suggests there are benefits from including older subjects in clinical trials to prevent diabetes

36. Change in CVD Risk Factors * p <0.001 ILS v P, M Diabetes 2003; Suppl 1:A169 Lifestyle Metformin Placebo Blood pressure mm Hg mg/dl Lipids * * * p<0.001 ILS v P, M *

37. Change in Non-traditional CVD Risk Markers Percent Change at 1 year p< 0.01 Met v Placebo p<0.001 ILS v Placebo Lifestyle Metformin Placebo Diabetes 2003; Suppl 1:A169

38. Weight Loss vs. Exercise in Diabetes Prevention Weight loss was strongest variable associated with reduced diabetes and CVD risk. For every kg lost, 16% reduction in diabetes risk. Increased activity, in the absence of weight loss, had minimal effect on diabetes prevention in DPP. In contrast, Finnish DPS reported those who met physical activity goal, but not wt loss goal, had 70% reduction in DM risk. NEJM 2001;344:1343-50; Cox, et al. Am J Clin Nutr 2004:80:308-16

39. Summary - DPP Lifestyle modification can prevent diabetes in high risk older adults The robust effect in 60+ older subjects was due to greater ILS participation (intensity too low in young and middle-age?) ILS program preferred over medication in older individuals Additional benefits of ILS – lower CVD risk factors

40. Progression to Diabetes Distinct Phenotypes? IGT Fasting Hyperglycemia Post-challenge Hyperglycemia DIABETES Metformin ILS Older, more sedentary Younger, fitter ? + + >intensity?

41. Prevention of Diabetes Weight Loss and Exercise : Increase Aerobic Capacity Reduce Obesity (central) Decrease Hyperglycemia Lower Blood Pressure Benefit Dyslipidemia Increase Insulin Sensitivity But also, Stop Cigarette smoking Insulin Sensitizers – TZDs, Metformin

42. Treatment of Type 2 Diabetes OrganGoalLong-Term EffectAction EyesAnnual ExamPrevent RetinopathyLaser Heart, BrainSemiannual  CVA, CAD, PADEx+WL Blood Pressure,MI, DeathsACE-I, Lipid Rx Lipids KidneyAnnual Microalbumin  ESRDACE-I  DialysisLipid Rx  Transplant LegsCheck Feet  Charcot JointFootcare, Pulses, Doppler  Revascularize Exercise, Sensory Exam  Amputation Stents, Bypass Whole BodyQuarterly HbA1c  Vascular, Cardiac,Exercise/WL, NeuropathicIntensive ComplicationsGlucose Control