Ischemic Heart and Cerebrovascular Disease. Harold E. Lebovitz, MD, FACE Kathmandu November 2010

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1 Ischemic Heart and Cerebrovascular Disease Harold E. Lebovitz, MD, FACE Kathmandu November 2010

2 Relationships Between Diabetes and Ischemic Heart Disease

3 Risk of Cardiovascular Disease in Different Categories of Glucose Tolerance 4 Risk of CVD CHD Stroke PVD 2-3 -fold 2-3 -fold 3-5 -fold Impaired Fasting Glucose Impaired Glucose Tolerance Normoglycemia Prediabetes Type 2 diabetes

4 HYPERGLYCEMIA Atherosclerosis Clinical Event Endothelial dysfunction Endothelial activation Inflammation Apoptosis Fibrous cap formation Angiogenesis Thrombosis Modified from Choudhury RP et al. Nat Rev Drug Disc 3:913-9, 2004

5 Sweden Turku Finland Kuopio East-West Study : Risk Factors for Cardiovascular Disease in Type 2 Diabetes 1059 subjects with type 2 diabetes (Drug Reimbursement Register) 1378 non-diabetic subjects Age at baseline from 45 to 64 years Follow-up data up to 18 years Performed in Turku (Dr. Tapani Rönnemaa) and Kuopio (ML)

6 Type 2 Diabetes is Coronary Heart Disease Equivalent : 7-year Follow-up Study in Finns 1,0 DM+,MI- DM-,MI subjects with type 2 diabetes; 1378 non-diabetic subjects Cumulative Survival, CHD,8,6,4 DM-,MI+ DM+,MI +,2 Haffner S, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. New Engl J Med 339:229-34, ,0 0 5 Year

7 Incidence of Fatal or Nonfatal MI During a 7-Year Follow-up in Relation to History of MI in Nondiabetic vs Diabetic Subjects: East-West Study Incidence During Follow-up (%) Nondiabetics with prior MI Nondiabetics with no prior MI Diabetics with prior MI Diabetics with no prior MI Coronary equivalent Haffner SM et al. N Engl J Med 1998;339:

8 Type 2 Diabetes is Coronary Heart Disease Equivalent : 18-year Follow-up Study in Finns 1,0 DM+,MI- DM-,MI- Cumulative Survival, CHD,8,6,4 DM-,MI+ DM+,MI +,2 Juutilainen A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Diabetes Care 28:2901-7, ,0 0 5 Year

9 Diabetes Patients Requiring Glucose-Lowering Therapy and Nondiabetics With a Prior Myocardial Infarction Carry the Same Cardiovascular Risk A Population Study of 3.3 Million People 7 Cardiovascular Death 6 5 Women Men Relative Risk Prior MI DM DM+Prior MI Prior MI DM DM+Prior MI Schramm TK, et al. Circulation 117: , 2008

10 Relative e Risk Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes: Nurses Health Study 1 Nondiabetic throughout the study Diabetes Care, Vol. 25, 2002; Prior to diagnosis of diabetes 3.71 After diagnosis of diabetes 5.02 Diabetic at baseline

11 EPIC-Norfolk study: risk of CV events or death associated with HbA 1c level HbA 1c level: 5 5.4% % % % 7% Age-adjusted re elative risk 8 Men Women CHD events CVD events All-cause mortality CHD events CVD events All-cause mortality P < for linear trend across HbA 1c categories for all endpoints. Khaw KT, et al. Ann Intern Med 2004; 141:

12 Dysglycemia and coronary artery disease Reliability of OGTT in clinical practice OGTT at discharge OGTT at 3 months OGTT after 1 year IGT 34% DM 33% IGT 41% DM DM IGT 25% 25% 40% 25% NGT 33% NGT 34% NGT 35% Abnormal 67% Abnormal 66% Abnormal 65% (Wallander et al Diabetes Care 2008; 31:36)

13 Cardiovascular events in the GAMI trial OGTT at discharge (n= 168) IGT 34% NGT 33% DM 33% Abnormal 67% Probability of event free survival Time to Major Cardiovascular Event Normal Abnormal two-sided p = Follow-up (months) (Bartnik et al Eur Heart J 2004;25:1990) 1 13

14 Aspects on prevalence and detection Euro Heart Survey Diabetes and the Heart n= % 29% NGT IFG IGT DM (new) 12% 25% 3% DM (known) (Bartnik et al Eur Heart J 2004; 26:1880) 1 14

15 Glycemic control Experiences from the Euro Heart Survey Glucose lowering drugs at follow up in patients with newly detected diabetes Newly detected diabetes n = % 1% 16% <1% Prescribed glucose lowering drugs 77 (17%) Insulin Oral drugs Combinations No prescription Not prescribed glucose lowering drugs 375 (83%) (Anselmino et al Eur Heart J 2008;29:177)

16 Euro Heart Survey diabetes and the heart Impact of glucose-lowering lowering drugs in newly detected diabetes Cumulative event free rate 1,00 0,98 0,96 0,94 0,92 0,90 Glucose-lowering drug Log rank test p=0.047 Yes No Time of follow up (days) (Anselmino et al Eur Heart J 2008;29:177) 1 16

17 CV Risk Factors Cluster Together The Diabetic Population DYSLIPIDAEMIA 8% of US population has diabetes and dyslipidaemia OBESITY 7% of US population has diabetes and obesity 2% 1% 1% 3% 3% 1% 0% HYPERTENSION 6% of US population has diabetes and HBP 11% of the US adult population has diabetes, but only 0.1% has no co-morbidity

18 Pathogenesis of CHD in Patients with Type 2 diabetes Pancreas Hyperinsulinemi a Insulin Resistance in Skeletal Muscle FFAs, Glucose Adiponectin Atherosclerosis TNF-α, IL-6 Insulin Resistance in Adipose tissue FFA Insulin Resistance in Endothelium NO synthesis Adhesion molecules Aging, Smoking, LDL-C Elevated blood pressure Genetic factors Thrombosis Plaque rupture PAI-1 Fibrinogen CRP ROS AGEs Hyperglycemia Dyslipidemia HDL, VLDL Modified from Libby P, Plutzky J. Circulation 106:2760-3, 2002 Insulin Resistance in Liver

19 Insulin Resistance- and Hyperglycemia-Related Cardiovascular Disease Risk of CVD LDL cholesterol, smoking and elevated blood pressure are similar risk factors for CVD in non-diabetic and type 2 diabetic subjects Insulin resistance-related CVD Hyperglycemiarelated CVD 0 Normoglycemia Prediabetes Type 2 diabetes

20 Prevalence of CHD Is Increased With the Metabolic Syndrome NHANES III; age 50 years Prevalence, 13.9 age-adjusted 10 (%) No metabolic syndrome No diabetes No metabolic syndrome With diabetes With metabolic syndrome No diabetes With metabolic syndrome With diabetes % of total population NHANES = National Health and Nutrition Examination Survey Alexander CM et al. Diabetes. 2003;52:

21 CARDS: Primary Prevention of CVD with Atorvastatin in Patients with Type 2 15 Diabetes placebo (n=1410) atorvastatin 10 mg (n=1428) Major co oronary events (%) % relative risk reduction (P=0.001) placebo: ATV: Years Colhoun HM et al. Lancet 2004; 364:

22 Aggressive Statin Intervention in Patients with Diabetes CHD event rat te in diabetic patients (%) S 1 Previous Statin Trials in Diabetes CARE 2 LIPID 3 HPS 4 TNT 0 1 Haffner SM, et al. Arch Intern Med. 1999;159: ; 2 Goldberg RB, et al. Circulation. 1998;98: ; 3 Keech A, et al. Diabetes Care. 2003;26: ; 4 HPS Collaborative Group. Lancet. 2003;361:

23 Diabetes 58: , 2009

24 VA-DT Study: Intensive vs ordinary glycemic control: Effects on CV outcomes as a function of baseline coronary artery calcification Glycemic Control Diabetes 58: , 2009

25 VA-DT Study: Intensive vs ordinary glycemic control: Effects on CV outcomes as a function of baseline coronary artery calcification Diabetes 58: , 2009

26 VA-DT Study: Intensive vs ordinary glycemic control: Effects on CV outcomes as a function of baseline coronary artery calcification Diabetes 58: , 2009

27 Hypertension Optimal Treatment Trial Effect on Major Cardiovascular Events - 4 years 30 Events/ pt-years % Risk Reduction vs. < 90 group < 90 < 85 < 80 < 90 < 85 < 80 Diabetic Patients n=1501, P=0.005 Lancet 351: , 1998 Non-Diabetic Patients n=18790, P=NS

28 Multi-factorial Intervention in Type 2 Diabetes

29 STENO 2 TRIAL: Targets achieved during the intervention trial Gaede et al. N Engl J Med 2008; 358:

30 Gaede et al. N Engl J Med 2008; 358:

31 Cumulative Incidence of Death Cumulative Incidence of CV Events Gaede et al. N Engl J Med 2008; 358:

32 Gaede et al. N Engl J Med 2008; 358:

33 Stroke in Diabetes 2-4 times increased prevalence May account for 12-16% of all diabetic deaths As high as 20% of people with diabetes have evidence of carotid artery occlusive disease BP control can reduce risk by 44% Cholesterol reduction can reduce risk by 28%

34 Risk Ratios of CV Events in Adults with Diabetes Age Men Women Total CVD CHD Cardiac Failure Intermittent Claudication Stroke JAMA 259: , 1988

35 Death Rate in MRFIT: 12-Year Follow-up* Cause of Death Diabetes No Diabetes n = 5,163 n = 342,815 mortality rate per 10,000 person/year Relative Risk (95% CI) Cardiovascular Disease ( ) CHD ( ) Stroke ( ) Other ( ) All Other ( ) * Age-adjusted. Relative risk adjusted for age, race, income, systolic BP, and smoking. All male cohort. Ann Int Med 124: , 1996

36 UKPDS: Glucose Control Study Results Intensive Blood Glucose Control Produced a HbA1c Improvement of 0.9% which Resulted in: Change in risk P value Any diabetes-related endpoint -12% Diabetes-related deaths -10% NS Myocardial infarction (fatal/nonfatal) -16% Stroke (fatal/nonfatal) -11% NS Microvascular disease -25% UKPDS Group. Lancet. 1998;352:

37 UKPDS Blood Pressure Study Tight vs. Less Tight Control BP lowered to avg. of 144 / 82 mmhg (controls: 154/87); 9 year follow-up 1,148 Type 2 patients Endpoint Risk Reduction (%) P value Any diabetes-related endpoint Diabetes-related deaths Heart failure Stroke Myocardial infarction 21 NS Microvascular disease BMJ 317: , 1998

38 Risk Reduction (Ramipril vs. Placebo) 0% -5% -10% -15% -20% -25% -30% -35% -40% -25% -20% -32% -15% -30% CVD Death Non-Fatal MI Stroke CABG/PTCA New Onset Diabetes The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:

39 Effects of Simvistatin Treatment on CV Endpoints Type of Major Vascular Event Coronary Events Simvastatin-allocated (10,269) Placebo-allocated (10,267) Non-fatal MI 357 (3.5%) 574 (5.6%) Coronary Death 587 (5.7%) 707 (6.9%) Subtotal: Major Coronary Event 898 (8.7%) 1212 (11.8%) Strokes Non-fatal Stroke 366 (3.6%) 499 (4.9%) Fatal Stroke 96 (0.9%) 119 (1.2%) Subtotal: Any Stroke 444 (4.3%) 585 (5.7%) Heart Protection Study Collaborative Group, Lancet 2002; 360:7-22.

40 Diab Med: 24: , 2007 CARDS: Reduction of Strokes

41 TNT Study: Diabetic Population 1500 known diabetics 5 years treatment 753 Atorvastatin 10 mg/day; 748 Atorvastatin 80 mg/day Baseline: HbA1c 7.4 % ; BMI kg/m² ; BP 135/77 mm Hg LDL cholesterol 98.6 vs 76.7 mg/dl Triglyceride vs mg/dl HDL cholesterol 44.9 vs 44.0 mg/dl Outcomes: Composite CV events 135 vs 103 (RRR = 25 % Cerebrovascular events RRR = 31 % N Engl J Med 352: , 2005

42 N Engl J Med 352: , 2005 Slide37

43 SUMMARY Coronary Heart Disease and Stroke are increased 2 to 4 fold in patients with diabetes Early intensive glycemic control reduces coronary heart disease Lipid management and blood pressure control have major effects in reducing coronary heart disease The major factors in reducing strokes are angiotensin converting enzyme inhibitors, bllood pressure control and staten therapy

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