ACE Inhibition for Diabetics: HOPE or Hype?

abstract & commentary

Synopsis: Ramipril significantly lowers the risk of major cardiovascular events by 20-30% in a wide range of middle-aged and elderly diabetics at high risk.

Source: The HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.

The heart outcomes prevention evaluation (HOPE) Trial, presented at the American Heart Association meetings in November 1999, has achieved considerable favorable publicity (Clin Cardiol Alert 1999;18:89-90). The publication of the primary study was released on the New England Journal of Medicine Web page, and published in the New England Journal of Medicine simultaneously with the results of the HOPE diabetic analysis subset, MICRO-HOPE.1 The diabetic substudy consists of approximately 40% of the entire 9541 HOPE cohort; 3577 subjects with diabetes were included. All patients were prospectively randomized to ramipril or placebo, as well as vitamin E or placebo. The results of the vitamin E arm were neutral (N Engl J Med 2000;342:154-160). The HOPE study was terminated six months early because of a 22% reduction in the primary composite endpoint of myocardial infarction, stroke, and cardiovascular death. Mean follow-up was 4.5 years. Subjects were randomized to a 2- to 5-mg dose of ramipril or placebo, with a target of 10 mg daily. At four years, 12% and 15% of the ramipril and placebo groups, respectively, were taking open-label ACE inhibitors. The major side effect was cough, approximately 5% more frequent with ramipril than placebo. A variety of endpoints were prespecified, including assessment of diabetic and microvascular disease. The diabetic cohort was comparable to the main study group, with a high burden of cardiovascular risk. Fifty-seven percent had a history of hypertension, two-thirds had elevated cholesterol, 15% were current smokers, and 50% were ex-smokers. Sixty percent had a diagnosis of coronary disease, 7.5% had a history of stroke or carotid endarterectomy, and 18.5% had peripheral vascular disease. Approximately 30% of all diabetics had no vascular disease, but by study protocol, were 55 years of age or older and had one additional major coronary artery disease (CAD) risk factor. The primary and secondary macrovascular endpoint results in MICRO-HOPE were similar to the entire HOPE group. A robust reduction in the primary endpoint was demonstrated, with risk reduction of 25% (P = 0.0004). Each component of this endpoint was significantly reduced. The curve separation was noted by 1-1.5 years. The benefits of ramipril were found whether individuals had a history of cardiovascular disease, hypertension, or microalbuminuria. Glucose control, as measured by HBA1C, was comparable between ramipril and placebo. There was a small decrease in blood pressure in the ACE inhibitor cohort compared to placebo of approximately 2 mmHg. A small but statistically significant decrease in overt nephropathy in diabetics with and without baseline microalbuminuria was documented (6.5% vs 8.4%; P = 0.03). The need for dialysis or new laser eye therapy was not significantly reduced by ramipril, but a combined endpoint of nephropathy, dialysis, and laser therapy was decreased by 16% (P = 0.04). Albuminuria was reduced by ramipril.

Thus, it was concluded that ramipril significantly lowered the risk of major cardiovascular events by 20-30% in a wide range of middle-aged and elderly diabetics at high risk. Pre-existing cardiovascular disease, hypertension, type of diabetic therapy, or microalbuminuria had no effect on the outcome. The HOPE investigators believe that the effect of ramipril could not be attributed to its effects on lowering blood pressure and believe that "the observed benefits . . . may be due largely to a protective effect of ACE inhibitors on the arterial wall." They point out that other hypertension studies with ACE inhibitors have confirmed efficacy for these agents, with a suggestion of perhaps greater benefit compared to other antihypertensive agents. Prior observations have confirmed a benefit of ACE inhibitors in type II diabetics on nephropathy and renal failure, and possibly retinopathy in type I diabetics. The HOPE investigators conclude that "ACE inhibition with ramipril is most appropriately viewed . . . as a preventive intervention with multiple mechanisms of benefit," and that ACE inhibitors should be added to other prevention strategies in diabetics, such as antihypertensive agents, glucose control, lipid lowering, smoking cessation, and aspirin.

Comment by Jonathan Abrams, MD

HOPE and MICRO-HOPE represent a significant advance in the prevention of vascular disease and its complications. Furthermore, MICRO-HOPE suggests that there is a modest benefit of ramipril in reducing microvascular complications of diabetes, concordant with other previously published observations. It is important to stress that HOPE and MICRO-HOPE enrolled individuals who were not prima facie candidates for an ACE inhibitor. While there were large numbers of hypertensives in the study, these were presumably controlled on medication and, by study design, could not be on an ACE inhibitor at entry. Analysis of the blood pressure data supports the HOPE investigators’ contention that the benefits of ramipril were not directly related to improved blood pressure control.

A number of questions are raised by these results, particularly related to whether one can extrapolate or extend the HOPE trial observations to other diabetic populations. It may be that ACE inhibition would be beneficial for diabetics without a major additional coronary risk factor, or those younger than the age of 55 with a similar risk profile. Another question is whether ramipril is a surrogate for all ACE inhibitors. While there are no definitive data available, an educated guess would support the fact that all drugs in this class would be beneficial due to their effect on blocking angiotensin II, as well as increasing bradykinin and nitric oxide availability. HOPE did not enroll individuals with impaired left ventricular function. Thus, the role of ACE inhibitors can now be substantially extended with respect to secondary prevention in individuals who have CAD, peripheral vascular disease, or previous stroke, as well as primary prevention in the middle-aged diabetic population with other risk factors. Because of the high burden of atherosclerosis in the diabetic, I would cautiously suggest that ACE inhibitors should be considered for many more diabetics than were eligible for the HOPE trial, particularly younger individuals. In addition, HOPE supports the initial use of an ACE inhibitor for diabetics with hypertension, an extremely common situation. The UKPDS hypertension study showed that a beta-blocker appeared to be as effective as captopril, and there are ample data supporting the beneficial role of a beta-blocker for conventional indications. However, ramipril was used as an additional measure irrespective of blood pressure control in HOPE, and this is an important aspect of this trial. One cannot stress too firmly the imperative to monitor all diabetics extremely closely, with aggressive hypertensive and lipid control. HOPE suggests that an ACE inhibitor will become part of the standard treatment for individuals with long-standing diabetes or middle-aged adult diabetics irrespective of blood pressure and lipid levels.

Reference

1. The HOPE Study Investigators. Effects of cardiovascular and microvascular outcomes in people with diabetes mellitus. Lancet 2000;355:253-259.

In diabetics older than age 55 with one additional major coronary artery disease risk factor, the ACEI ramipril:

a. reduced the incidence of nephropathy.

b. decreased blood pressure significantly.

c. improved glucose control.

d. reduced cardiovascular endpoints.