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

Endocr Pract. May-Jun 2011;17(3):430-40. doi: 10.4158/EP10106.RA.


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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Angiotensin Receptor Antagonists / pharmacology*
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use
  • Cardiovascular Diseases / prevention & control*
  • Clinical Trials as Topic
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Humans
  • Models, Biological
  • Renin-Angiotensin System / drug effects*
  • Renin-Angiotensin System / physiology
  • Signal Transduction / drug effects
  • Tetrazoles / pharmacology
  • Tetrazoles / therapeutic use
  • Valine / analogs & derivatives
  • Valine / pharmacology
  • Valine / therapeutic use
  • Valsartan


  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Tetrazoles
  • Valsartan
  • Valine