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ACE Inhibitors Prevent Diabetes and Cardiovascular Disease by Multiple Mechanisms

Angiotensin-converting enzyme (ACE) inhibitors improve markers of cardiovascular disease and prevent diabetes, renal disease, and cardiovascular disease, according to a review of the latest data that explores the potential mechanisms of this class of antihypertensives.

Samy I. McFarlane, MD, State University of New York, Health Science Center, Brooklyn, New York, United States, and colleagues describe in their article the mechanisms whereby ACE inhibitors influence the cardiometabolic syndrome, the symptoms of which include central obesity, insulin resistance/hyperinsulinaemia, dyslipidaemia, hypercoagulability, enhanced cardiovascular inflammation, hypertension, and albuminuria.

ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, and thereby block the actions of the renin-angiotensin system (RAS). Angiotensin II increases the production of reactive oxygen species and has several vasoconstrictive effects, including opposition of the vasorelaxant actions of nitric oxide and stimulation of plasminogen activator inhibitor-1, according to Dr. MacFarlane and colleagues. In turn, increased plasminogen activator inhibitor-1 production impairs fibrinolysis, "which may help explain why ACE inhibitor therapy has been demonstrated to improve the fibrinolytic balance in high-risk patients," the authors note.

Angiotensin II, furthermore, increases arterial stiffness by a variety of mechanisms. "The most positive data on vascular compliance come from studies with ACE inhibitors," Dr. McFarlane and colleagues point out, adding that: "study findings showed ACE inhibition therapy improved arterial compliance, primarily by increasing distensibility." In contrast, fewer studies have evaluated the effects of angiotensin receptor blockers (ARBs), although these agents may also exert beneficial effects and may act synergistically with ACE inhibitors.

The researchers next discussed the role of ACE inhibitors in diabetes prevention. They note that interruption of the RAS system may improve insulin sensitivity. Several trials, beginning with the Captopril Prevention Project (CAPPP), demonstrate that ACE inhibitors reduce the incidence of type 2 diabetes in hypertensive patients.

Two large randomised trials of antihypertensive are currently underway in patients with type 2 diabetes: the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) trial and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. These trials will evaluate the benefits of an ACE-inhibitor and an ARB, respectively, in combination with antidiabetic drugs.

The authors note that, regarding the role of ACE inhibitors in diabetic renal disease, with the exception of ARBs, ACE inhibitors "have been shown to be more effective in reducing proteinuria than any other antihypertensive agents."

"Thus, therapeutic strategies that interrupt the RAS reduce both cardiovascular disease and renal disease in type 2 diabetes," the authors conclude.
Am J Cardiol. 2003;91:12A:30H-37H "Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease"

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