Elsevier

The Lancet

Volume 355, Issue 9200, 22 January 2000, Pages 253-259
The Lancet

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

https://doi.org/10.1016/S0140-6736(99)12323-7Get rights and content

Summary

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% Cl 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.

Introduction

People with diabetes mellitus are at high risk of cardiovascular disease. Epidemiological studies show that the risk of cardiovascular mortality is two to three times higher in men with diabetes and three to five times higher in women with diabetes than in people without diabetes.1, 2, 3, 4, 5, 6 The age-adjusted prevalence of coronary heart disease in white adults who have diabetes is about 45%, compared with about 25% in individuals without diabetes,7 and cardiovascular disease accounts for about 70% of all deaths in people with diabetes mellitus.8

The presence of other risk factors increases the risk of cardiovascular disease in people with diabetes mellitus. The absolute annual risk of fatal and non-fatal cardiovascular disease in middle-aged and elderly people with type 2 diabetes is 4-5%.1, 9, 10, 11, 12, 13 Despite decreases in the incidence of heart disease in the general population, the decline is much smaller in people with type 2 diabetes, and may even be rising in women with diabetes.13

Experimental studies, epidemiological studies, and clinical trials suggest that inhibitors of angiotensin-converting enzyme (ACE) may delay or prevent cardiovascular outcomes. For patients with diabetes, such benefit has been seen after acute myocardial infarction,14 in the presence of hypertension,15, 16, 17, 18, 19 and in the presence of a low ejection fraction or heart failure.20 ACE inhibitors may also prevent overt nephropathy and other microvascular outcomes in patients with type 1 or type 2 diabetes.17, 21, 22

Although studies suggest that ACE inhibitors may prevent or delay serious events in some subgroups, their role in a broader group of people with diabetes who are at high risk of cardiovascular events remains unknown. The Heart Outcomes Prevention Evaluation (HOPE) study investigated whether the addition of the ACE inhibitor ramipril to the current medical regimen of high-risk patients with diabetes mellitus can lower the risk of cardiovascular events. In the microalbuminuria, cardiovascular, and renal outcomes (MICRO) HOPE substudy, the effect of this intervention on the risk of overt nephropathy was investigated. We present here the results from these two studies for patients with diabetes mellitus.22

Section snippets

Participants

The HOPE and MICRO-HOPE study protocol has been published.23, 24 Briefly, people with and without diabetes were recruited, who were aged 55 years or older, and who had a history of cardiovascular disease (coronary artery disease, stroke, or peripheral vascular disease) or diabetes plus at least one other cardiovascular risk factor (total cholesterol > 5·2 mmol/L, HDL cholesterol ≪0·9 mmol/L, hypertension, known microalbuminuria, or current smoking). Key exclusion criteria were dipstick-positive

Results

Of all 9541 participants in the HOPE study, 3654 (39·3%) had diabetes at randomisation. 77 people who participated in another substudy in which they received only 2·5 mg ramipril or placebo were excluded from the analysis. Therefore, 3577 people with diabetes were included. The mean age was 65·4 years, 1322 (37%) were women, and 1996 (56%) had a history of hypertension. Baseline characteristics of participants in the ramipril and placebo groups were similar (table 1).

Of surviving participants

Discussion

Ramipril significantly lowered the risk of major cardiovascular outcomes by 25–30% in a broad range of high-risk middle-aged and elderly people with diabetes mellitus. The benefit was apparent irrespective of whether participants had a history of cardiovascular events, hypertension, or microalbuminuria, were taking insulin or oral antihyperglycaemic agents, or had type 1 or type 2 diabetes mellitus. The study had, however, low power to detect different effects in the subgroups. Since adherence

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