Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy

BACKGROUND Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes. METHODS 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy. FINDINGS The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0.0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0.027). After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (12-36, p=0.0004). INTERPRETATION Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.

[1]  F. Ferris.  Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. , 1992, JAMA.

[2]  S. Yusuf,et al.  Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry. , 1996, The American journal of cardiology.

[3]  A. Neil,et al.  A Prospective Population-Based Study of Microalbuminuria as a Predictor of Mortality in NIDDM , 1993, Diabetes Care.

[4]  A. Maggioni,et al.  Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. , 1997, Circulation.

[5]  R J Jarrett,et al.  Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study. , 1983, British medical journal.

[6]  M. Lishner,et al.  Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. , 1996, Archives of internal medicine.

[7]  T. Hedner,et al.  Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study , 1999, The Lancet.

[8]  A Fournier,et al.  The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. , 1994, The New England journal of medicine.

[9]  J. Medalie,et al.  Factors predictive of long-term coronary heart disease mortality among 10,059 male Israeli civil servants and municipal employees. A 23-year mortality follow-up in the Israeli Ischemic Heart Disease Study. , 1993, Cardiology.

[10]  M. Pahor,et al.  Outcome Results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in Patients With Hypertension and NIDDM , 1998, Diabetes Care.

[11]  C. Mogensen,et al.  Eight to nine year mortality in known non-insulin dependent diabetics and controls. , 1992, Kidney international.

[12]  R. Bain,et al.  The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. , 1993 .

[13]  S. Yusuf,et al.  Anti-ischaemic effects of ACE inhibitors: review of current clinical evidence and ongoing clinical trials. , 1998, European heart journal.

[14]  J. Manson,et al.  A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. , 1991, Archives of internal medicine.

[15]  M. Laakso,et al.  Hyperglycemia and cardiovascular disease in type 2 diabetes. , 1999, Diabetes.

[16]  Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. , 1996 .

[17]  J. Neaton,et al.  Diabetes, Other Risk Factors, and 12-Yr Cardiovascular Mortality for Men Screened in the Multiple Risk Factor Intervention Trial , 1993, Diabetes Care.

[18]  M. Harris,et al.  Diabetes and decline in heart disease mortality in US adults. , 1999, JAMA.

[19]  Illiam,et al.  THE EFFECT OF NISOLDIPINE AS COMPARED WITH ENALAPRIL ON CARDIOVASCULAR OUTCOMES IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES AND HYPERTENSION , 2000 .

[20]  S. Yusuf,et al.  Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. , 1994, Circulation.

[21]  Philip D. Harvey,et al.  Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39 , 1998, BMJ.

[22]  E. Barrett-Connor,et al.  Chapter 19 Heart Disease and Diabetes , 2022 .

[23]  H. Parving,et al.  Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. , 1992, Kidney international.

[24]  A. Sjølie,et al.  Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes , 1998, The Lancet.

[25]  E. Ritz,et al.  Nephropathy in patients with type 2 diabetes mellitus. , 1999, The New England journal of medicine.

[26]  W. Kannel,et al.  Diabetes and cardiovascular disease. The Framingham study. , 1979, JAMA.

[27]  E. Barrett-Connor,et al.  Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. , 1991, JAMA.