Diabetes, and its subsequent cardiovascular (CV) complications, is a growing epidemic in the United States. Some studies have shown that inhibition of the renin-angiotensin aldosterone system (RAAS) by the use of angiotensin receptor blockers (ARBs) may reduce the risk of diabetes and cardiovascular complications. However, most of the trials to date have not studied incidence of diabetes as a primary outcome.1
ARBs block the angiotensin II receptor at target organs. Angiotensin II is a potent vasoconstrictor and releases the hormones aldosterone and vasopressin, or ADH. Aldosterone allows for reabsorption of sodium in the kidney, while vasopressin allows for the reabsorption of water and causes vasoconstriction of blood vessels, all of which, increase blood pressure. Thus, by blocking angiotensin II receptor, the net effect of ARBs is decreased blood pressure. Hypertension (HTN) over a long period of time can result in increased risk of diabetes, kidney damage, stroke and cardiovascular disease.2
The recent NAVIGATOR trial was a double blind, prospective, randomized clinical trial that compared valsartan (up to 160mg daily) to placebo in patients with impaired glucose tolerance and established CV disease or CV risk factors. Both groups were also randomized to receive nateglinide; those results were not presented in this study article. Study patients were recruited from January 2002 to January 2004 from 806 centers in 40 countries. All patients with IGT of 140 to <200 mg/dL, fasting plasma glucose of 95 to <126 mg/dL, and one or more CV risk factors or established CV disease were eligible for the study. Exclusion criteria included lab irregularities or disease states that could interfere with assessment of safety/efficacy of the study medication, use of angiotensin converting enzyme (ACE) inhibitor or ARB for treatment of HTN (ACE inhibitors were permitted for other indications), and use of any antidiabetic medication during the previous 5 years. 4631 patients received valsartan and 4675 patients received placebo. Valsartan was initiated at 80 mg daily then titrated to 160 mg daily after 2 weeks. After titration of valsartan, patients were seen every 6 months for fasting plasma glucose measurements for the first 3 years and then annually, while OGT tests were performed yearly. All patients were required to adopt lifestyle modifications to help patients achieve and maintain a 5% weight loss, decrease dietary saturated and total fat intake, and complete at least 150 minutes of physical activity weekly. The trial had two co-primary outcomes: incidence of diabetes and an extended cardiovascular outcome consisting of a composite of death from CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina. A third co-primary core CV outcome was added, which included a composite of death from CV causes, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. Baseline characteristics were similar between the two treatment groups.
After a median follow-up of 5 years, there was a statistically significant difference in the incidence of diabetes between the valsartan group compared to placebo group. Only 33.1% of patients in the valsartan group developed diabetes compared to 36.8% of patients in the placebo group (P<0.001). There was not a statistically significant difference with extended CV outcomes and core CV outcomes between the valsartan cohort as compared to placebo. 14.5% of valsartan participants experienced extended CV outcomes versus 14.8% of placebo participants (P= 0.43); 8.1% of participants in both the valsartan and placebo groups experienced core CV outcomes (P= 0.85). The most commonly reported adverse effects were nasopharyngitis, back pain, and arthralgia. Throughout the study, 12% of participants in the valsartan group versus 11.4% of participants in the placebo group discontinued therapy due to adverse effects, which was not statistically significant (P= 0.33).
The authors concluded that valsartan up to 160 mg daily, when added to lifestyle modification, reduced the risk of diabetes, but did not reduce CV events in patients with impaired glucose tolerance and established CV disease or risk factors. It was surprising that valsartan use did not reduce CV outcomes within the study. These results are in contrast to the HOPE trial which showed that treatment with the angiotensin converting enzyme (ACE) inhibitor, ramipril, reduced rates of death, MI, and stroke in high risk patients without a history of low ejection fraction or heart failure.3 Therefore, more studies are needed to determine if inhibiting the RAAS pathway with an ARB reduces the incidence of CV disease in patients who have impaired glucose tolerance.
1. McMurray JJ, Holman RR, Haffner SM, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362:1477-90.
3. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53.