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Type 2 Diabetes in the Elderly: Lessons from the Diabetes Primary Prevention Program

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. Glucose Tolerance Categories.

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Type 2 Diabetes in the Elderly: Lessons from the Diabetes Primary Prevention Program

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  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. Glucose Tolerance Categories Oral Glucose Tolerance TestFasting (2-Hour Glucose During OGTT)(mg/dL) (mg/dL) Normal<110<140 Impaired110-125140-199 Diabetes>125>199 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 NHANES III Percentage of Population Harris MI, et al. Diab Care. 1998;21:518-524.Resnick HE, et al. Diab Care. 2000;23:176-180.

  4. Prevalenceof Diabesity by Age Percent Diabetic BMI (kg/m2) <22 >35 <22 >35 22-25 26-30 22-25 26-30 31-35 31-35 20 - 54 60 - 74 Age (years)

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

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

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

  8. 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 National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.

  9. 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 SMC=smooth muscle cell. Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656.

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

  11. Physical Characteristics of Subjects 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 SyndromeImproves Oral Glucose Tolerance

  14. AE + WL in Metabolic Syndrome Improves Lipid Profiles Data are Mean ± SEM, mg/dl; *p < 0.05; **p < 0.01 vs Baseline

  15. 170 110 160 100 150 Systolic Blood Pressure (mm Hg) Diastolic Blood Pressure (mm Hg) 140 90 130 80 120 110 70 AEX+WL in Metabolic Syndrome Reduces Blood Pressure  = -8%  = -10%

  16. Effects of Exercise and Weight Loss on Components of Metabolic Syndrome Metabolic Abnormality Baseline AEX+WL Central Obesity 17 10 Hypertension 17 6 ­ 17 10 Insulin Glucose Intolerance 10 5 Low HDL-C 17 10 ­ 6 3 TG Totals 84 44

  17. Diabetes Prevention Trials 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).

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

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

  20. Eligibility Criteria • 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/m2 • All ethnic groups • Goal of up to 50% subjects from high riskpopulations – old, African American, American Indian, Hispanic, Asian 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. Sex Distribution Age Distribution DPP Population > 60 20% Men 32% 25-44 31% 45-59 49% Women 68% The DPP Research Group, Diabetes Care 23:1619-29, 2000

  23. Base-Line Characteristics of the Study Participants N Engl J Med, 2002; 346(6):393-403 *Values are means ± SD ¶Data are based on responses to the Modifiable Activity Questionnaire

  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 Lifestyle Metformin Placebo The DPP Research Group, NEJM 346:393-403, 2002

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

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

  29. Intensive Lifestyle (ILS) Activities by Age 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 p = 0.007 ILS by age p= 0.067 metformin by age Age (years) NEJM 346:393-403, 2002

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

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

  35. 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 DPP : Age 60+ Intensive Lifestyle Group

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

  37. Change in Non-traditional CVD Risk Markers LifestyleMetforminPlacebo Percent Change at 1 year p< 0.01 Met v Placebo p<0.001 ILS v 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 Older, more sedentary Younger, fitter ? Post-challenge Hyperglycemia Fasting Hyperglycemia >intensity? + + ILS Metformin DIABETES

  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 AmputationStents, Bypass Whole BodyQuarterly HbA1c Vascular, Cardiac,Exercise/WL, NeuropathicIntensive ComplicationsGlucose Control

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