CLINICAL DIABETES
VOL. 18 NO. 3 Summer 2000


LANDMARK STUDIES


Hope for the Diabetic Heart


Reviewed by Anne Peters, MD


STUDY
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on death from cardiovascular causes, myocardial infarction, and stroke in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145-53, 2000.

SUMMARY
Objective. To evaluate whether the angiotensin-converting enzyme (ACE) inhibitor, ramipril, reduces cardiovascular (CV) events in high-risk adults.

Design. A randomized, blinded, controlled 2 X 2 factorial trial.

Subjects. Subjects included 9,297 adults selected from 129 centers in Canada, 27 centers in the United States, 76 sites in Western Europe, 5 centers in Mexico, and 30 centers in Argentina and Brazil. All subjects were >55 years of age and had a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes and one or more CV risk factor. Subjects with congestive heart failure and an ejection fraction of <0.4, who were using an ACE inhibitor or who had uncontrolled hypertension were excluded. Of the subjects, 3,577 had diabetes.

Methods. Patients were randomized to ramipril, 10 mg per day, or placebo and followed for a mean of 5 years. The primary outcome measure consisted of one of the following events: myocardial infarction (MI), stroke, or death from cardiovascular cause.

Results. Adults in the ramipril group had lower rates of MI, stroke, CV mortality and all-cause mortality (P < 0.006 for all comparisons). These positive findings led to early termination of the study. The benefits were seen in diabetic and older patients and occurred whether or not patients were taking aspirin, beta.gif (968 bytes)-blockers, lipid-lowering agents, or other antihypertensive agents. Complications related to diabetes were also reduced (6.4% in the ramipril group vs. 7.6% in the placebo group, P = 0.03).

Conclusions. The HOPE trial provides evidence that ACE inhibitor therapy can improve cardiovascular outcomes in high-risk patients, including those with diabetes.

COMMENTARY
This ambitious, multicenter study provides further evidence for the positive role of ACE inhibitors in preventing CV events as well as reducing diabetic complications. ACE inhibitors reduce CV mortality in patients with left ventricular dysfunction and congestive heart failure.1 The HOPE trial included patients who were not as severely impaired but still at high risk for a CV event.

Interestingly, the diabetic patients included were not necessarily known to have coronary heart disease. For inclusion, these patients had to have one or more risk factors that included hypertension, increased total cholesterol, low high-density lipoprotein cholesterol, cigarette smoking, or microalbuminuria. Although event rates were somewhat lower in the diabetic patients, a significant benefit was still seen from treatment, suggesting that diabetic patients behave much like patients with known coronary heart disease and should be treated as such.

In this study, blood pressure was only minimally decreased (3 mmHg for systolic blood pressure and 2 mmHg for diastolic blood pressure).

The effects of ACE inhibitors on the cardiovascular system are multiple, and many potential mechanisms have been postulated. In addition to blocking the effects of angiotensin II on vasoconstriction, ACE inhibitors cause a decrease in proliferation of smooth muscle cells and stabilize plaque, improve vascular endothelial function, enhance fibrinolysis, and decrease left ventricular hypertrophy. The incidence of microalbuminuria was decreased in patients treated with ramipril (relative risk of 0.8). In addition, a decrease in overall diabetic complications (urinary albumin excretion of >300 mg/24 h, the need for dialysis, or the need for laser therapy) was seen as well as fewer cases of newly diagnosed diabetes (102 in the ramipril group vs. 155 in the placebo group, relative risk 0.66, P < 0.001). Whether treatment with ACE inhibitors prevents the development of diabetes needs to be further substantiated, but this study raises an interesting possibility.

In addition to the use of ACE inhibitors for prevention of CV and renal disease, it is important to keep in mind the need for tight control of blood pressure in this population. Many studies have shown that patients with diabetes benefit maximally from blood pressure lowering, often more than do other patient populations.2-5 This holds true for treatment with ACE inhibitors as well as with dihydropyridine calcium channel blockers.

In several trials in which calcium channel blockers have been used to aggressively lower blood pressure (often in conjunction with an ACE inhibitor as second-line therapy), highly significant reductions in CV events have been seen.2,3 For example, in the Hypertension Optimal Treatment (HOT) Study,2 patients were treated following a five-step regimen starting with felopidine to achieve a diastolic blood pressure of <90, <85, and <80 mmHg. In the patients with diabetes, there was a 51% reduction in major CV events in the target group with diastolic blood pressure <80 mmHg versus <90 mmHg.

In the Syst-Eur trial, which treated isolated systolic hypertension, a post hoc analysis was done of the diabetic versus nondiabetic patients.3 The primary agent used was nitrendipine followed by enalapril and a thiazide as a second-line agent. End point reductions in total mortality, CV mortality, and all CV end points in diabetic patients exceeded those found in nondiabetic patients and were significantly reduced compared to placebo.

On the other hand, other studies have shown greater benefits for CV events from ACE inhibitors compared to calcium channel blockers. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial6 compared nisoldipine with enalapril as first-line antihypertensive therapies. After 5 years of follow-up, patients assigned to receive enalapril had fewer CV events than patients assigned to nisoldipine, although the rate of MI in the latter group was similar to that found in other patients with type 2 diabetes. This result suggests that enalapril provided further benefit in this study but does not prove that nisoldipine has negative effects in this population.

The Fosinopril Versus Amlopdipine Cardiovascular Events Trial (FACET)7 also showed greater benefits for CV outcomes from ACE inhibitors compared to calcium channel blockers. However, the combination of the two drugs was associated with a very low rate of CV events.

The benefits of ACE inhibitors in patients with type 2 diabetes have become increasingly clear. A recent meta-analysis found that using ACE inhibitors in all patients with type 2 diabetes could be considered cost-effective solely on the basis of renal protective effects.8 However, >80% of diabetic patients treated for hypertension will require the use of two or more agents,5,9 necessitating an understanding of combination therapy as well as monotherapy.

Treating patients with diabetes is a complex challenge, necessitating aggressive treatment of their hypertension as well as maintenance of near-euglycemia and correction of the commonly present dyslipidemia. Drugs that negatively impact any of these factors should be avoided if possible. On the other hand, increasing data show the benefits of ACE inhibition on both microvascular and macrovascular complications in diabetic patients, and these drugs should be used frequently in this high-risk population.


REFERENCES

1Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CP, Pitt B: Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 90:2056-69, 1994.

2Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial: HOT Study Group. Lancet 351:1755-62, 1998.

3Tuomilehto J, Rastenyte D, Thisj L, Staessen JA: Reduction of mortality and cardiovascular events in older diabetic patients with isolated systolic hypertension in Europe treated with nitrendipine-based antihypertensive therapy (Syst-Eur Trial). Diabetes 47 (Suppl 1):A54, 1998.

4Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N: Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 276:1886-92, 1996.

5U.K. Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Brit Med J 317:703-13, 1998.

6Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW: The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 338:645-52, 1998.

7Tatti P, Pahor M, Byington RP, Mauro PD, Guarisco R, Strollo G, Strollo F: Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 21:597-603, 1998.

8Golan L, Birkmeyer JD, Welch G: The cost-effectiveness of treating all patients with type 2 diabetes with angiotensin-converting enzyme inhibitors. Ann Int Med 131:660-67, 1999.

9Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmakik K, Dahlof B, de Faire U, Morlin C: Effect of angiotension-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPP) randomized trial. Lancet 353:611-16, 1999.


Anne Peters, MD, is an associate professor at the University of California, Los Angeles School of Medicine.


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