Meta-analyses of ACE inhibitor trials provide compelling evidence that ACE inhibitors reduce cardiovascular events and mortality related to acute myocardial infarction (MI) and heart failure (90,91). Because diabetes is an independent risk factor for CVD (92) and the RAS and diabetes appear to interact at multiple levels, it is possible that diabetes may affect the efficacy of ACE inhibition on CVD. Several recent reports have provided retrospective analyses of data from diabetic subgroups, which participated in large ACE inhibitor trials. Although some of these trials were not designed to specifically address the effects of ACE inhibition in diabetes, comparison of the relative effects of ACE inhibition in the diabetic and nondiabetic subgroups may provide important insight into the role of the RAS in CVD in diabetes.
An underlying question regarding the vascular protective effects of antihypertensive therapies is whether these effects are mediated via the reduction in BP or whether these drugs may provide additional effects. This issue has been addressed in a number of studies. Comparisons of antihypertensive therapies on cardiovascular outcomes in hypertensive patients with type 2 diabetes have been performed in several trials. In the United Kingdom Prospective Diabetes Study, the effects of tight and less tight BP control by the ACE inhibitor captopril or the ^-blocker atenolol were compared in patients with both hypertension and type 2 diabetes (9,93). This prospective study demonstrated that tight BP control was more effective than less tight control in reducing macrovascular endpoints, including stroke and deaths related to diabetes (9,93). Additionally, this study indicated that the ACE inhibitor and ^-blocker were equally effective in reducing cardiovascular outcomes.
The Appropriate Blood Pressure Control in Diabetes trial compared the effects of moderate and intensive BP control using a dihydropyridine calcium channel blocker (CCB; nisoldipine) and an ACE inhibitor (enalapril) on hypertension in type 2 diabetic patients (94). Although these therapies were similarly effective in controlling BP for both the intensive- and moderate-treatment protocols, the incidence of MI were significantly greater in the CCB-treated group compared with the ACE inhibitor group (95). Although cardiovascular outcomes were a secondary endpoint, this study suggests that ACE inhibition may have protective effects against MI that go beyond BP lowering. Similar results were reported for hypertensive type 2 diabetic patients from the Fosinopril Versus Amlodipine Cardiovascular Events (FACET) randomized trial (12). The FACET trial showed that although ACE inhibition and calcium antagonism were similarly effective on BP reduction and certain biochemical parameters, the risk of major cardiovascular events was significantly lower in the ACE inhibitor-treated group.
The Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO)-Heart Outcomes Prevention Evaluation (HOPE) study was a placebo-controlled trial designed to evaluate the effects of the ACE inhibitor ramipril and vitamin E on the development of diabetic nephropathy and CVD in diabetic patients (5). The ACE inhibitor component of the HOPE trial was discontinued early, after 4.5 years, because there was clear evidence of a beneficial effect on cardiovascular endpoints in the ramipril-treated group (96). Analysis of the composite outcome including MI, stroke, or cardiovascular-related death, revealed that the protective effects associated with ACE inhibition were similar in the absence or presence of diabetes (96). The beneficial effects of ACE inhibition occurred in both type 1 and type 2 diabetic patients and were irrespective of hypertension (5). Interestingly, the results from this study demonstrated that ACE inhibition reduced cardiovascular endpoints beyond that which would be expected from its BP-lowering effects (5,96,97). Although it is likely that multiple mechanisms contribute to the reduction of cardiovascular endpoints following RAS inhibition, a substudy of the HOPE trial has shown that the ACE inhibitor-treated group had a reduced rate of progression in carotid intimal-medial thickness (98), which is consistent with a reduction in atherosclerosis.
A component of the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study compared the effects of losartan and atenolol on diabetic patients with hypertension and signs of left-ventricular hypertrophy (99). Patients were followed for a mean of 4.7 years. This study reported the primary composite cardiovascular endpoint, including cardiovascular death, stroke, and MI, was lower in the patients assigned to the losartan treatment group (RR, 0.76, p = 0.031). Because similar reductions in BP were observed with losartan and atenolol, this study suggests that ATI receptor antagonism could provide beneficial cardiovascular effects beyond BP control.
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