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
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