How to Reduce CVD Complications in Diabetes?

How to Reduce CVD Complications in Diabetes? Chaicharn Deerochanawong M.D. Diabetes and Endocrinology Unit Department of Medicine Rajavithi Hospital, Ministry of Public Health

Framingham Heart Study 30-Year Follow-up CVD Events in Patients With Diabetes Compared with non-diabetes Subjects (Ages 35-64) RR 12 10 Men Women 8 6 4 2 0 Total CVD CHD Cardiac failure Intermittent Claudication Stroke Wilson PWF. Diabetes and Vascular Disease. Oxford;1992

Mortality Rate is Twice as Great in Patients with Diabetes 35 Ratio 2.5 Ratio 2.2 Ratio 2.1 Mortality rate (deaths per 1,000 patient years) 30 25 20 15 10 5 Control Diabetes 0 Whitehall Study Paris Prospective Helsinki Study Policemen Study Balkau B, et al. Lancet 1997; 350:1680.

Causes of Mortality in Patients With Diabetes Malignant Neoplasms 13% Pneumonia/ Influenza 13% Other 4% 5% 10% Heart Disease 55% Diabetes Cerebrovascular Disease Geiss LS, et al. In: Diabetes in America. 2nd ed. NIH Publication No. 95-1468. 1995:233-257.

Type 2 Diabetes and CHD : 7 Year 50 40 Incidence of Fatal/Nonfatal MI P<0.001 (East West Study) Nondiabetic N=1373 Diabetic N=1059 P<0.001 45 30 20 19 20 10 0 4 No prior M I M I No Prior M I M I Haffner.NEJM1998:339;229-34

Diabetes, Metabolic syndrome and prevalence of CHD 25 CHD prevalence 20 15 10 5 8.7% 13.9% 7.5% 19.2% 0 No MS / No DM MS / No DM DM / No MS DM / MS % of population 54.2% 28.7% 2.3% 14.6% Charles M. Diabetes 2003;52:1210-4

Diabetes & Cardiovascular Risks 65% of people with diabetes die from heart disease or stroke. 1 3X more cardiovascular mortality in type 2 DM 2 Risk for heart attack 2, 3 Middle-aged patients with type 2 DM = Patients without DM with history of heart attack. Heart attacks occur at an earlier age in people with DM 4 1.Centers for Disease Control and Prevention. Centers for Disease Control and Prevention: Diabetes Surveillance Report, 1999. Atlanta, GA: US Department of Health and Human Services, 1999. 2.Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. N Engl J Med 1998; 339:229-34. 3.Grundy SM, Benjamin IJ, Burke GL, et al. Circulation 1999; 100:1134-46. 4.Wingard DL, Barrett-Connor E. Heart disease and diabetes. In: National Diabetes Data Group, ed. Diabetes in America. Washington, DC: National Institutes of Health, NIDDK, NIH publication no. 95-1468, 1995.

Why Type 2 Diabetes has Excessive Premature Atherosclerosis? Hyperglycemia : AGE proteins, Oxidative stress Insulin Resistance Atherogenic dyslipidemia Hypertension Haemostatic abnormalities

How to reduce cardiovascular complications in diabetes? Holistic treatment Or Multiple Risks Management

Goals of Therapy in Diabetes Glycemic goal Blood pressure goal ACEI in albuminuria or CVD or CVD risk factor Lipid goal Aspirin in selected cases Quit smoking Approach desriable body weight

Glycemic Control - Intervention Studies Micro and Macrovascular Complications Reduction in risk with intensive therapy Retinopathy Nephropathy Neuropathy Cardiovascular disease DCCT (Type 1) 63% 54% 60% 41%* (p=0.06) Kumamoto (Type 2) 69% 70% - - UKPDS (Type 2) 17-21% 24-33% - 16%* (p=0.052) DCCT Research Group. N Engl J Med.. 1993;329:977-986. 986. Ohkubo Y, et al. Diabetes Res Clin Pract.. 1995;28:103-117. 117. UKPDS 33: Lancet 1998; 352, 837-853. 853.

UKPDS Risk Reduction:Glucose Control Study Mean HbA1c 7.8% vs 8.5% and FU PSM 5yr = 8.0% During Study Including PSM Any DM related end pt. 12%, p=0.029 10%, p=0.033 DM related death 10%, p=0.340 16%, p=0.028 All cause mortality 6%, p=0.440 11%, p=0.071 Myocardial infarction 16%, p=0.052 14%, p=0.042 Stroke +11%, p=0.520 5%, p=0.660 PVD 35%, p=0.520 32%, p=0.089 Microvascular dis. 25%, p=0.009 28%. P=0.001

Goals of Glycemic Control ADA ACCE EASD IDF HbA1c (4.0-6.0%) < 7.0% 6.5% 6.5% 6.5% FPG (preprandial( preprandial)< 130 110 110 110 Postprandial < 180 140 135 135

Is Lower the Better of Glycemic control in Diabetes? There is no lower limit of HbA1c at which further lowering does not reduce risk of complications, at the risk of increased hypoglycemia The risks and benefits of an HbA1c goal of < 6% are currently tested in type 2 diabetes ( ACCORD )

Compare Met vs Intens. vs Conv. in Overweight pts. Any diabetes related endpoint Metformin Intensive Diabetes related deaths Metformin Intensive All cause mortality Metformin Intensive Myocardial infarction Metformin Intensive M v Int RR p p=0.0034 p=0.11 p=0.021 p=0.12 0.68 0.93 0.58 0.80 0.64 0.92 0.61 0.79 0.0023 0.46 0.017 0.19 0.011 0.49 0.01 0.11 RR (95% CI) 0.2 1 5 Favours metformin or intensive favours conventional

Goals of Therapy in Diabetes Glycemic goal Blood pressure goal ACEI in albuminuria or CVD or CVD risk factor Lipid goal Aspirin in selected cases Quit smoking Approach desriable body weight

The goal of BP in DM is < 130/80mmHg

Major CV events in patients with diabetes at randomisation in relation to target blood pressure groups Major CV events/ 1000 patient years 25 20 p=0.005 for trend HOT STUDY 15 10 5 0 < 90 < 85 < 80 Target DBP mm Hg

Association of Systolic BP and Cardiovascular Death in Type 2 DM 250 225 200 Cardiovascular 175 mortality rate/10,000 150 person-yr 125 100 75 50 25 0 Nondiabetic Diabetic < 120 120 139 140 159 160 179 180 199 > 200 Systolic blood pressure (mm Hg) Stamler J et al. Diabetes Care 1993;16:434-444.

Number of Antihypertensive Drugs Therapy Requirement in UKPDS number of antihypertensive agents None one two > two 100 LessTight Control Policy Tight Control Policy % of patients 80 60 40 20 0 1 2 3 4 5 6 7 8 Years from randomisation 1 2 3 4 5 6 7 8

Effects of Antihypertensive Drugs on Cardiovascular dis.. in Diabetic Patients Comparative drugs in Diabetes patients ABCD and FACET : ACEI vs DCCB CAPP : ACEI vs conventional UKPDS : ACEI vs Beta Blocker STOP2 : ACEI vs DCCB vs convent. LIFE : ARB vs Beta Blocker ALLHAT : Diuretic vs ACEI vs DCCB RENALL : ARB vs convent. IDNT : ARB vs CCB

Goals of Therapy in Diabetes Glycemic goal Blood pressure goal ACEI in albuminuria or CVD or CVD risk factor Lipid goal Aspirin in selected cases Quit smoking Approach desriable body weight

MICRO-HOPE or HOPE STUDY DIABETES SUBGROUP ( Lancet 2000;355: 253-9 )

MICRO-HOPE - Objective Does the addition of ramipril and/or vitamin E to the ongoing medication of 'high-risk' diabetic patients reduce the risk of renal and CV events?

METHODS 3,577 people with diabetes ( 98% type 2 ) Age > 55 years Had a previous cardiovascular event or At least one other cardiovascular risk factor 1. TC > 200 mg/dl, HDL < 35 mg/dl 2. Hypertension (>160/90) 3. Known microalbuminuria 4. Current smoking No clinical proteinuria, heart failure or low EF Randomly assigned Ramipril 10 mg or placebo

MICRO-HOPE (ramipril( ramipril) - baseline characteristics Variable Ramipril (n = 1808) Placebo (n = 1769) Men/women 1112 (62%)/696 (38%) 1143 (65%)/626 (35%) Age (years)* 65.3 65.6 SBP/DBP (mm Hg)* 141.719 142.3 ± 19.5/79.3 BMI (kg/m2) * 28.9 28.6 Waist-hip ratio* 0.93 0.93 Waist circumference (cm)* 99.9 99.6 History of CAD 1046 (58%) 1093 (62%) Stroke/endarterectomy 124 (7%) 150 (8%) PVD 311 (17%) 361 (20%) No history of CV disease 604 (33%) 515 (29%) Hypertension 1045 (58%) 951 (54%) Type 2 diabetes 1774 (98%) 1722 (97%) Duration of diabetes (years) * 11.1 ± 10.2 11.8 ± 10.7 Current smokers 274 (15%) 270 (15%) Elevated total cholesterol level 1174 (65%) 1161 (66%) Serum creatinine ([m]mol/l)* 93.8 94.0 MA 553 (31%) 587 (33%)

MicroHOPE: : Benefit of Ramipril in DM patient Effects Beyond Baseline Therapy %RR 0-5 -10-15 -20-25 -30-35 -37 Stroke 33%* CV Death 37%* Nonfatal MI 22%* Overt Kidney Disease 24% * P = 0.0001

0.16 MICRO-HOPE (ramipril( ramipril) All causes mortality RRR 24% p=0.0004 Placebo Placebo Kaplan-Meier rates 0.12 0.08 0.04 Ramipril 200 200 400 400 600 600 800 800 1000 1000 1200 1200 1400 1400 1600 1600 1800 1800 HOPE Study Investigators Lancet 2000;355:253-259. Duration of follow up (days)

Goals of Therapy in Diabetes Glycemic goal Blood pressure goal ACEI in albuminuria or CVD or CVD risk factor Lipid goal Aspirin in selected cases Quit smoking Approach desriable body weight

Lipid Goals NCEP & ADA 2007 LDL-C < 100 mg/dl ( < 70 mg/dl in CAD pts. ) Triglycerides < 150 mg/dl Non HDL-C < 130 mg/dl HDL-C > 40 mg/dl

ACP 2004 Recommendations Do not recommend a specific LDL-C target level No strong evidence support exact thresholds for initiating treatment or treating to specific target LDL-C or TC in type 2 diabetic patients HPS and CARDS study showed benefit of statin in diabetic patients Ann Intern Med 2004;140:650-8

Treatment Effect on the Primary Endpoint by Subgroup Subgroup* Placebo** Atorva** Hazard Ratio Risk Reduction (CI) LDL-C 120 66 (9.5) 44 (6.1) 38% (9-58) LDL-C < 120 61 (8.5) 39 (5.6) 37% (6-58) p=0.96 HDL-C 54 62 (8.4) 36 (5.2) 41% (11-61) HDL-C < 54 65 (9.6) 47 (6.4) 35% (5-55) p=0.71 Trig. 150 67 (9.6) 40 (5.5) 44% (18-62) Trig. < 150 60 (8.4) 43 (6.1) 29% (-5-52) p=0.40.2.4.6.8 1 1.2 * units in mmol/l (mg/dl) ** N (% of randomised) Favours Atorvastatin Favours Placebo

ACP 2004 Recommendations All adults with type 2 diabetes and CAD should receive statins All adults with type 2 diabetes and other cardiovascular risk factors, including HT, smoking, LVH, age > 55 yr, should receive statins Statin should take at least moderate dose Patients with low LDL-C and low HDL-C, fibrate may be used as first line therapy Ann Intern Med 2004;140:650-8

Goals of Therapy in Diabetes Glycemic goal Blood pressure goal ACEI in albuminuria or CVD or CVD risk factor Lipid goal Aspirin in selected cases Quit smoking Approach desriable body weight

Aspirin therapy in Diabetes Use aspirin therapy ( 75-325 mg/day ) in all adult patients with diabetes and macrovascular disease. Consider beginning aspirin therapy ( 75-325 mg/dl ) for primary prevention in patients > 40 years of age with diabetes and one or more other cardiovascular risk factors Patients at ages below 30 years, when the risk of CVD is low, there is no evidence of benefit of aspirin for primary prevention

Goals of Therapy in Diabetes Glycemic goal Blood pressure goal ACEI in albuminuria or CVD or CVD risk factor Lipid goal Aspirin in selected cases Quit smoking Approach desriable body weight

INTERHEART:Risk of AMI with Multiple Risk Factors 512 2.9 2.4 1.9 3.3 13.0 42.3 68.5 182.9 333.7 256 128 OR (99% CI) 64 32 16 8 4 2 1 Smk DM HTN APoB/A 1+2+3 all4 +O +PS All RFs

INTERHEART: Decreased Risk of AMI with Avoidance of Smoking; Daily Fruits/Veg Veg, Reg Phys Activity & Alcohol 1.0 0.35 0.70 0.86 0.91 0.24 0.21 0.19 OR (99% CI) 0.5 0.25 0.125 no smk Frt/Veg Exer Alc Nosmk+fvg +exer +alc

Modest weight loss has beneficial health effects Modest weight loss of >5% in obese individuals with type 2 diabetes, hypertension or hyperlipidaemia resulted in: Improved glycaemic control Reduced blood pressure Improved lipid profile 20% reduction in premature mortality in overweight women with obesity-related health conditions Goldstein DJ. Int J Obesity 1991; 16: 397 415

Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 DM ( STENO 2 ) Peter Gaede et al. NEJM 2003; 348:383-393

STENO 2 Randomized study to evaluate effect on CVD of an intensified, targeted, multifactorial intervention in type 2 diabetes with microalbuminuria 160 patients follow up means 7.8 years Interventions: dietary, exercise, ACEI, vitamin mineral supplement, 150 mg ASA, tight glycemic, BP and lipid control

Treatment Goals Variable Conventional Therapy 1993-1999 Intensive Therapy 2000-2001 1993-1999 2000-2001 Systolic blood pressure (mmhg) <160 <135 <145 <130 Diastolic blood pressure (mmhg) <95 <85 <85 <80 Glycosylated hemoglobin (%) <7.5 <6.5 <6.5 <6.5 Fasting serum total cholesterol (mg/dl) <250 <190 <190 <175 Fasting serum triglycerides (mg/dl) <195 <180 <150 <150 Treatment with ACE inhibitor irrespective of blood pressure Aspirin therapy No Yes Yes Yes For patients with known ischemia Yes Yes Yes Yes For patients peripheral vascular dis No No Yes Yes For patients without coronary heart disease or peripheral vascular disease No No No Yes

Percentage of patients who reached the intensive-treatment goals at a mean of 7.8 yr Patients % 80 70 60 50 40 P <0.001 intensive therapy P =0.19 P =0.001 Conventional therapy P =0.21 30 20 P=0.06 10 0 G Hb < 6.5% Cholesterol <175 mg/dl Triglycerides <150 mg/dl Systolic BP <130 mmhg Diastolic BP <80 mmhg

Primary Composite End Point (%) 60 50 40 30 20 10 0 No. at Risk Conventional80 therapy Intensive 80 therapy P=0.007 Hazard ratio = 0.47 NNT = 5 patients to prevent 1 CVD event 0 12 24 36 48 60 72 84 96 72 78 70 74 Months of Follow-up 63 71 59 66 Conventional therapy 50 63 Intensive therapy 44 61 41 59 13 19

STENO 2 A long term, targerted, intensive intervention involving multiple risk factors with continued patient education and motivation reduces the risk of both cardiovascular and microvascular events by about 50 percent among patients with type 2 diabetes and microalbuminuria Such patients may represent about 1/3 of the population of patients with type 2 DM

Conclusions CVD is very common in diabetes and is the leading cause of death in type 2 diabetes To reduce the cardiovascular complications of diabetes need long term targeted intensive multiple risk factors intervention ACEI, Ramipril, proved to reduce CVD complications in diabetes with CVD or with CVD risk factor