2. Diabetes – A 21 st Century Epidemic Diagnosis and what is it A common disease An expensive disease A serious disease A treatable disease A preventable disease

3. Diagnosis and what is it Glucose Tolerance Categories Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197. FPG 126 mg/dL 100 mg/dL 7.0 mmol/L 5.7 mmol/L Impaired Fasting Glucose Normal 2-Hour PG on OGTT 200 mg/dL 140 mg/dL 11.1mmol/L 7.8mmol/L Diabetes Mellitus Impaired Glucose Tolerance Normal Diabetes Mellitus

4. What is it ? Diabetes is a Vascular Disease Background Retinopathy 100 125 150 175 200 Fasting Plasma Glucose % Affected

5. Natural History of Type 2 Diabetes Adapted from: International Diabetes Center (Minneapolis, Minnesota). Insulin resistance Relative Functio n (%) Gluco se (mg/d L) Years of Diabetes -15-10-50510152025 -15-10-50510152025 Fasting glucose Post-meal glucose ß-cell IGT Diabetes 75 50 25 0 100 125 350 250 100 300 200 150

6. Etiologic Classification of Diabetes Mellitus Type 1  -cell destruction with lack of insulin Type 2Insulin resistance with insulin deficiency Other specific typesGenetic defects in  -cell function, exocrine pancreas diseases, endo- crinopathies, drug- or chemical- induced, and other rare forms GestationalInsulin resistance with  -cell dysfunction Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197.

7. 23.6 million (10.7% ≥ 20 y.o) at a cost of $174 billion in 2007 –57 million with prediabetes 6th disease specific cause of death. Leading cause of: –Kidney failure. –Adult blindness. –Nontraumatic limb amputation. –Cardiovascular disease. ADA. Diabetes Care 31:596-615, 2008 Diabetes in the U.S.

8. Diabetes is a Common Disease : Estimated Prevalence of Diabetes in the US: Adult Men and Women Harris, et al. Diabetes Care. 1998;21:518-524, with permission. 0 10 20 30 75+60-7450-5940-4920-39 Age (y) 1.61.7 6.8 6.1 12.9 12.4 20.2 17.8 21.1 17.5 Men Women Percent of Population

9. Estimated Prevalence of Diabetes in the US: Breakdown by Ethnicity Data from Harris, et al. Diabetes Care. 1998;21:518-524. 4.8 2.5 8.2 3.6 9.3 4.5 0 2 4 6 8 10 Hispanic American African American Non-Hispanic White Diagnosed Undiagnosed Percent of Population

10. Diabetes – An expensive disease Direct and indirect costs of diabetes estimated to be $174 Billion annually in the USA in 2007 Costs to most health systems is 2-3 fold greater annually for patients with diabetes

11. 1997 Per Capita Health Care Costs: Persons With and Without Diabetes Data from American Diabetes Association. Diabetes Care. 1998;21:296-309. Annual Costs ($1000s) 0 5 10 15 20 25 Outpatient Drugs Office Visits EROutpatient Services Inpatient 23.5 12.2 2.5 1.5 0.7 0.4 0.7 0.4 0.7 0.2 Diabetes No diabetes

12. Diabetes – A serious but treatable disease Microvascular complications Blindness, renal failure and nerve dysfunction Macrovascular complications Atherosclerosis –MI, Stroke and amputations Hypertension - Stroke, CHF, CAD

13. Conduit Artery ResistancePrecapillaryCapillaries Arterioles Arterioles The Arterial Tree in Diabetes Atherosclerosis Hypertension Retinopathy Neuropathy Nephropathy

14. Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) 10 9 20 11 9638 19 3* 30 0 2 4 6 8 10 Age-adjusted annual rate/1,000 MenWomen Total CVD CHDCardiac failure Intermittent claudication Stroke Risk ratio P<0.001 for all values except *P<0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.

15. Kannel WB. Am Heart J. 1985;110:1100-1107. Abbott RD et al. JAMA. 1988;260:3456-3460. Women, Diabetes, and CHD Diabetic women are at high risk for CHD Diabetes eliminates relative cardioprotective effect of being premenopausal –risk of recurrent MI in diabetic women is three times that of nondiabetic women Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women

16. 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

17. 4S:Major CHD Event Reduction in a Patients With Diabetes Pyörälä K et al. Diabetes Care. 1997;20:614- 620. Proportion without major CHD event Yr since randomization - P=0.002 - P=0.0001 Diabetic, simvastatin Diabetic, placebo Nondiabetic, simvastatin Nondiabetic, placebo 32% 55%

18. Conduit Artery ResistancePrecapillaryCapillaries Arterioles Arterioles The Arterial Tree in Diabetes Atherosclerosis Hypertension Retinopathy Neuropathy Nephropathy

19. blood pressure control reduced risk for Any diabetes-related endpoint 24% p=0.0046 diabetes-related deaths 32% p=0.019 stroke 44% p=0.013 microvascular disease 37% p=0.0092 heart failure 56% p=0.0043 retinopathy progression 34% p=0.0038 deterioration of vision 47% p=0.0036 UKPDS Blood Pressure Control

20. Diabetes and CHD HOPE Study –9297 pts >55y.o. with DM or vascular disease + 1 CVD risk factor (~3578 DM ) –Placebo or Ramipril 10 mg qd followed ~ 4 yrs –Significant reductions in cardiovascular events (MI, stroke and CV death) –Changes seen in both DM and non-DM groups

21. MICRO-HOPE No clinical proteinuria, CHF or diminished EF and not on ACE. 3577 patients with DM and either known CHD or one additional risk factor. Ramapril 10 mg/d or placebo. Study stopped at 4.5 yrs by DSMB

22. ACE Inhibition in DM

23. Conduit Artery ResistancePrecapillaryCapillaries Arterioles Arterioles The Arterial Tree in Diabetes Atherosclerosis Hypertension Retinopathy Neuropathy Nephropathy

24. Glucose Control Study Summary The intensive glucose control policy maintained a lower HbA 1c by mean 0.9 % over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: 12%for any diabetes related endpointp=0.029 25%for microvascular endpoints p=0.0099 16%for myocardial infarctionp=0.052 24%for cataract extractionp=0.046 21%for retinopathy at twelve yearsp=0.015 33%for albuminuria at twelve years p=0.000054

25. Quality of Life: Effect of Improved Glycemic Control Quality-of-Life Analog Rating Mental Health Cognitive Function General Perceived Health Symptom Distress Extended- release glipizide Improved Worsened Testa & Simonson, JAMA, 1998;280;1490-1496. P<.05 P<.01 P<.001

26. Glucose Control and Costs of Care A 6 year comparison between patients who improved glucose control (decline in HgbA1C >1%) or not has shown that improved glycemic control reduced annual health care costs for affected individuals Reductions due to fewer physican and emergency room visits Cost saving of $600-1000 annually.

27. Diabetes a preventable disease Several trials of diabetes prevention have been conducted for type 1 diabetes using vaccine strategies. None have yet been successful For Type 2 diabetes, multiple trials successfully demonstrated that both lifestyle changes and pharmacologic interventions can delay or prevent diabetes among individuals at high risk

28. Prevention of DM 2 F/U DMIncidence Risk Reduction StudyControlDiet Exercise Da Qing6 Yr68%44%31% DPS4 Yr23%11%58% DPP3 Yr29%14%58%

29. Prevention of Diabetes with Lifestyle Modification

30. Effect of Metformin and Lifestyle Modification on New Onset Diabetes - Lifestyle changes work better as we age Subject Age % Decline in Diabetes Incidence

31. 161 island archipelago, most live on main island, pop 1.3 m “Galapagos of the East” Lowest age-adjusted mortality (CHD, stroke, cancer) Longest disability-free life expectancy of 47 Japanese prefectures (states) Highest centenarian prevalence Okinawa

32. Centenarians in the World (by prevalence) Willcox DC et al AGE 2006

33. Diabetes – A model for intervention in chronic disease As the population ages: –Diabetes becomes more common –Diabetes itself is more preventable by a healthy lifestyle –Complications of diabetes while common can be prevented

34. Ushi Okushima 106 Years Young and Still Diggin’ Life Thank you ! Domo Arigato!