NAVIGATOR: Valsartan slowed progression to diabetes, no effect on CV events

Use of nateglinide following meals also did not reduce incidence of diabetes or CV events.

American College of Cardiology 59th Annual Scientific Sessions

ATLANTA – Valsartan reduced the progression to diabetes in patients with impaired glucose tolerance and cardiovascular risk factors, but did not reduce the rate of CV events, new study results indicated.

Researchers for the NAVIGATOR trial enrolled 9,306 patients with glucose intolerance in the randomized, double blind, 2×2 factorial study. Patients were assigned to receive either up to 160 mg valsartan daily (n=4,631; Diovan, Novartis) or placebo (n=4,675). In a separate arm, patients were also randomly assigned to receive up to 60 mg nateglinide (Starlix, Novartis) after meals or a matching placebo. All patients also participated in a lifestyle modification program with the goal of increasing physical activity to an average of 30 minutes per day five days per week, achieving 5% weight loss and following a low-fat diet.

The co-primary outcomes were the development of diabetes; an extended composite of death from CV causes, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization, arterial revascularization or hospitalization for unstable angina; and a core composite that excluded unstable angina and revascularization. Patients were followed for a mean of five years for the development of diabetes and 6.5 years for CV disease.

According to results presented today at the American College of Cardiology 59th Annual Scientific Sessions, the cumulative incidence of diabetes was 33% (n=1,531) in the valsartan group vs. 36.8% (n=1,722) in the placebo group (P<.001). When compared with placebo, the researchers also reported that valsartan did not reduce the incidence of either the composite CV outcome (14.8% vs. 14.5%; HR=0.96; 95% CI, 0.86-1.07) or the core CV outcome excluding unstable angina and revascularization (8.1% vs. 8.1%; HR=0.99; 95% CI, 0.86-1.14).

The researchers further reported that nateglinide did not reduce the incidence of diabetes (P=.036% vs. 34%; HR=1.07; 95% CI, 1.00-1.15), the extended composite endpoint (14.2% vs. 15.2%; HR=0.93; 95% CI, 0.83-1.03) or the core composite endpoint (7.9% vs. 8.3%; HR=0.94; 95% CI, 0.82-1.09) vs. placebo. However, nateglinide increased the risk for hypoglycemia.

“In our view, these results put to rest an argument that’s been going on in the CV community about renin-angiotensin system blockers, ACE inhibitors and angiotensin receptor-blockers, where a number of trials that did not have a reduction in diabetes as a primary endpoint found a reduction in diabetes but could not ‘prove’ it because it was not a primary endpoint,” Robert M. Califf, MD, vice chancellor for clinical research at Duke University Medical Center in Durham, N.C., said in a press conference. “The fact that valsartan did not reduce CV endpoints was surprising, but there is a lot more analysis to be done in this database.”

The NAVIGATOR data were published in the New England Journal of Medicine today. – Eric Raible

The NAVIGATOR trial is, unfortunately, essentially a negative trial. Sometimes in medicine, we tend to say that more is better. In this case, we are attacking the renin axis and attacking it in several ways. The study drug may not have been conducive to an overall morbidity and mortality benefit. We saw similar results in several other trials in the HF sector about 10 years ago, such as in the VAL-HEFT trial, and we are seeing similar things with renin access. In this case, we should continue the current management, where we attack it from multiple levels, from the renin-modifying access to the beta adrenergic access. Right now, these results will not have a large impact on practice. We take a scientific view of it, but how does it go from guidelines to practice? We need to bridge the knowledge gap and the practice gap, and I’m not sure this study will impact the practice gap, other than to reinforce that modifying the renin access is still necessary. The angiotensin receptor-blocker would still be beneficial.

– Paul Mather, MD

Professor of Medicine, Jefferson Medical College,
Philadelphia Co-Chair, American College of Cardiology 59th Annual Scientific Sessions

For more information:

Califf R. LBCT I. Presented at: American College of Cardiology 59th Annual Scientific Sessions; March 14-16, 2010; Atlanta.

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