Socorro Juan Vargas, M.D., F.A.C.P., F.A.C.E Section of Diabetes and Endocrinology

1. Effects of Diabetes, Obesity, Metabolic Syndrome on Cardiovascular HealthFilipino American Cardiovascular Health Summit July 9, 2011 Washington, D.C. Socorro Juan Vargas, M.D., F.A.C.P., F.A.C.E Section of Diabetes and Endocrinology St. Francis Hospital and Medical Center Assistant Professor of Medicine University of Connecticut School of Medicine

2. Disclosure of Conflicts of Interest • Nothing to disclose

3. Outline • Diabetes: • Definition • Complications • Burden of disease • Cardiometabolic risk factors • Metabolic Syndrome • Effects of intensive glycemic control on cardiovascular risk • Primary prevention of cardiovascular risk in diabetes patients • Treatment goals

4. What is Diabetes? • Diabetes is a state characterized by an absolute or relative deficiency of insulin relative to the physiological needs of a given individual GI Hormones Too much Glucagon Not enough insulin Hyperglycemia

5. Prevalence and Incidence of Diabetes and Pre-diabetes in the U.S.A. • 25.8 million people have diabetes • Diagnosed: 18.8 million people • Undiagnosed: 7.0 million people • A total of 1.9 million new cases of diabetes were diagnosed in 2010 in the United States among people aged 20 years and older • 79 million U.S. adults ages 20 and older have pre-diabetes National Diabetes Fact Sheet, CDC, 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm.

6. Diabetes in Asian Americans and Pacific Islanders • 8.4% of all Asian Americans have diagnosed diabetes • Prevalence data for diabetes among Pacific Islanders is limited National Diabetes Fact Sheet, CDC, 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm.

7. Diabetes Care 2001; 24:2054-2058

8. Diagnostic Criteria for Pre-diabetes and Diabetes American Diabetes Association. Diabetes Care 2011; 34;(Suppl.1):S11-61.

9. Diabetes Complications • Diabetes is the leading cause of: • kidney failure • 48,374 people with diabetes began treatment for end stage kidney disease in 2008 • new cases of adult blindness • 4.2 million people with diabetes aged 40 and older had diabetic retinopathy in 2005-2008 • nontraumatic lower-limb amputations • Over 65,000 nontraumatic lower-limb amputations were performed in people with diabetes in 2006 National Diabetes Fact Sheet, CDC, 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm.-

10. Diabetes Complications The risk of periodontal disease is two to three times higher in adults with diabetes About one-third of people with diabetes have severe periodontal disease 60% to 70% of people with diabetes have mild to severe nervous system damage Almost 30% of people with diabetes aged 40 years and older have impaired sensation in the feet People with diabetes are twice as likely to have depression National Diabetes Fact Sheet, CDC, 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm.

11. Cardiovascular disease is leading cause of death in patients with Type 1 and Type 2 Diabetes • Framingham study: CVD incidence in diabetics 1 • Males: 2-fold increase • Females: 3-fold increase • Women had greater cardiovascular mortality • CVD morbidity and mortality greater for diabetic women than non-diabetic men 2 • MRFIT: Absolute risk of CVD death 3X higher in diabetic men at every age, race, income, cholesterol and blood pressure 3 1 Kannel WB, McGee DL. Diabetes Care 1979; 2:120-126 2 Lee WL et al. Diabetes Care 2000; 23:962-968 3 Stamler J et al. Diabetes Care 1993;16:434-444

12. Diabetes is a CVD Risk Equivalent • Subjects with diabetes have the same 7-year risk for future MI as nondiabetic individuals who have had a previous MI Haffner SM et al. N Engl J Med 1998;339:229-234

13. Diabetes and Risk for Cardiovascular Disease (CVD) • Cardiovascular disease (CVD) a major complication of diabetes and leading cause of death in patients with diabetes • In adults with diabetes • 68% die of heart disease or stroke • the risk for stroke is 2 to 4 times higher • 67% have high blood pressure • smoking doubles the risk for heart disease National Diabetes Fact Sheet, CDC, 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm.

14. Type 1 Diabetes and CVD • The prevalence of coronary artery disease is 10 times greater among patients with Type 1 diabetes than age- and gender-matched individuals without diabetes • Insulin resistance is not a characteristic feature of T1DM • Is hyperglycemia a direct risk mediator?

15. Estimated Costs of Diabetes and CVDin the U.S. † Disability, work loss, premature mortality ‡ Totals do not add up because of rounding and overlap National Diabetes Fact Sheet, CDC, 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm. American Heart Association. Circulation 2010; 121:e46-e215

16. The Evolution of Mankind

17. The Evolution of Mankind 50 years Environment 2.5 Million years Genes

18. Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes Obesity BMI ≥ 30 kg/m2 1994 2000 2008 Diabetes 1994 2000 2008 Centers for Disease Control and Prevention: National Diabetes Surveillance System http://www.cdc.gov/diabetes/statistics

20. Definitions of Metabolic Syndrome AHA/NHLBI Circulation 2005;112:2735-2752 IDF Lancet 2005;366:1059-1062

21. Glycemic Control and CV RiskClinical Trials • Hypothesis: Treatment that normalizes blood glucose will prevent or delay the long term complications of diabetes mellitus

22. Diabetes Control and Complications Trial (DCCT) • Improved control of blood glucose reduced the risk of clinically meaningful: DCCT. N Engl J Med 1993; 329: 977-986 DCCT/EDIC. N Engl J Med 2005;353:2643-2653

23. EDIC Findings: Cardiovascular Events Cumulative Incidence of First of Any Event 0.12 0.10 Risk reduction 42% 95% CI: 9% to 63% P = 0.02 Conventional 0.08 0.06 Cumulative Incidence 0.04 Intensive 0.02 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Non-Fatal MI, Stroke, or CVD Death 0.12 0.10 Risk reduction 57% 95% CI: 12% to 79% P = 0.02 0.08 0.06 Conventional 0.04 Cumulative Incidence 0.02 Intensive 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years from Study Entry DCCT/EDIC N Engl J Med 2005;353:2643-2653

24. 12% 14% 16% 19% 37% 43% Micro-vascular Disease PVD MI Stroke Heart Failure Cataract Extraction United Kingdom Prospective Diabetes Study (UKPDS) Risk reduction with 1% decline in annual mean A1C P <.0001 P = .035 P = .021 P = .0001 0% 15% 30% 45% UKPDS. BMJ 2000;321:405-412

25. UKPDS: Follow-Up Study Differences in A1C between intensive & standard glycemia control treatment groups were lost after one year UKPDS. N Engl J Med 2008;359:1577-1589

26. ACCORD, ADVANCE and VADT ACCORD Study Group. N Engl J Med 2008;358:2545-2559 ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572 VADT. N Engl J Med 2009;360:129-139

27. Effects of Intensive Glycemic Control UKPDS. Lancet 1998; 352:837-853 UKPDS. N Engl J Med 2008; 359:1577-1589 DCCT. N Engl J Med 1993; 329: 977-986 DCCT/EDIC. N Engl J Med 2005;353:2643-2653 ACCORD. N Engl J Med 2008; 358(24):2545-59 ADVANCE. N Engl J Med 2008; 358 (24): 2560-72 VADT. N Engl J Med 2009;360:129-139 Initial Trial Long-term Follow-up

28. Effects of Intensive Glycemic Control • Benefit from intensive therapy when initiated earlier in the course of disease • CV benefit may be evident only after an extended period of time • Effect may be sustained for period longer than 10 years after intensive therapy is discontinued

29. Intensive Glycemic Control in Diabetes:Implications of ACCORD, ADVANCE and VADT • Clinical implication = individualized goals and care • General A1c goal of <7% • For microvascular disease prevention • Reasonable for macrovascular risk reduction, pending more evidence • A1c goals closer to normal for some patients • Short duration of diabetes, long life expectancy, no significant CVD • Levels reached without significant adverse treatment effects ADA/ACC/AHA Position Statement. Diabetes Care 2009;32:187-192

30. Intensive Glycemic Control in Diabetes:Implications of ACCORD, ADVANCE and VADT • Less stringent goals for some patients • History of severe hypoglycemia • Limited life expectancy • Advanced micro- or macrovascular complications • Extensive comorbid conditions • Long-standing diabetes with difficulty achieving glycemic goals ADA/ACC/AHA Position Statement. Diabetes Care 2009;32:187-192

31. Targets for Glycemic, Blood Pressure and Lipid Control American Diabetes Association. Diabetes Care. 2011;34(suppl 1):S11-S61 American College of Endocrinology. Endocr Pract. 2007;13(suppl 1):1-68

32. Glucagon Secretion ↓ Incretins ↓ Amylin Insulin Secretion ↑ Sulfonylureas ↑ Meglitinides ↑ Incretins GI Effects Incretins Amylin α Glucosidase inhibitors Bile acid sequestrant Appetite Control Incretins Amylin HYPERGLYCEMIA Glucose reabsorption ↓SGLT2 Inhibitors Hepatic Glucose Output ↓ Metformin ↓ Thiazolidinediones Lipotoxicity Thiazolidinediones Glucose uptake and utilization ↑Thiazolidinediones ↑ Metformin

33. Primary Prevention of CVD in People with Type 1 and Type 2 Diabetes AHA/ADA Circulation 2007;115:114-126

34. Primary Prevention of CVD in People with Type 1 and Type 2 Diabetes AHA/ADA Circulation 2007;115:114-126

35. Summary • A comprehensive approach to the prevention and management of cardiovascular disease in diabetes patients is best accomplished through a combination of lifestyle modification and targeting of multiple cardiometabolic risk factors and comorbidities • Focus on individualizing therapy: choose the appropriate A1c target, cardiometabolic goals and proper drug regimen for each patient

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