Mechanistic and clinical aspects of renin-angiotensin-aldosterone system blockade in the prevention of diabetes mellitus and cardiovascular disease.

OBJECTIVE: To review the rationale for the use of renin-angiotensin-aldosterone system (RAAS) inhibition to prevent type 2 diabetes mellitus and cardiovascular events and to discuss clinical data evaluating the relationship between RAAS blockade and diabetes prevention.

METHODS: PubMed was searched to identify preclinical and clinical data addressing this aim.

RESULTS: Potential mechanisms of angiotensin II-mediated insulin resistance and type 2 diabetes may include impaired blood flow and sympathetic activity, increased oxidative stress, alterations in insulin signaling, and effects on adipose tissue. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated reduced incidences of new-onset diabetes in patients with prediabetes or hypertension and in other cardiovascular populations; however, insight into the corresponding impact on cardiovascular-related morbidity and mortality has been lacking. A recent trial (NAVIGATOR) was designed to evaluate incident diabetes and cardiovascular outcomes as part of its primary endpoint. In this trial, valsartan-based therapy reduced the incidence of new-onset diabetes by 14% relative to placebo over the 5-year follow-up period (P<.001). Cardiovascular outcomes, however, were not significantly affected by active treatment, which may be attributed to a number of potential confounding factors including the low rate of cardiovascular disease at baseline, concurrent implementation of lifestyle modification in all patients, and the substantial use of other risk-reducing agents.

CONCLUSIONS: Angiotensin II has been implicated in a number of pathophysiologic processes with the potential to indirectly or directly influence the pathogenesis of insulin resistance and type 2 diabetes. Most clinical trials show a reduced risk of new-onset diabetes with RAAS blockade; however, recent results of the NAVIGATOR trial show that the addition of valsartan to lifestyle modification reduces the risk of diabetes, but does not improve cardiovascular outcomes.