Further information: Endocrine Disorders and the Heart (see p2295) and Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

Although published in the two separate papers listed above, the effects of Valsartan and Nateglinide were studied in the same trial entitled, “Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR)” [1, 2]. The double-blind, randomized clinical trial with a two-by-two factorial design was conducted from January 2002 through January 2004, with recruitment occurring at 806 centers in 40 countries. Eligible patients had impaired glucose tolerance, a fasting plasma glucose level of at least 95 mg/dl, but less than 126 mg/dl, and one or more cardiovascular risk factors or known cardiovascular disease, and 9306 participants were enrolled. Patients were randomized to receive either nateglinide, up to 60 mg three times a day, or a matching placebo, and valsartan, up to 160 mg daily, or a matching placebo. In addition, patients were required to participate in a lifestyle program, and a goal was set to maintain a 5% weight loss, an increase in physical activity to an average of 30 min five days a week, and adherence to a low-fat diet. Valsartan, an angiotensin-receptor blocker (ARB), is used to treat high blood pressure, heart failure (HF), and long-term consequences of a heart attack. Valsartan was selected for this trial to evaluate the use of an ARB in the delay or prevention of diabetes and to determine the possibility of its helping the cardiovascular system. In the valsartan group, the cumulative incidence of diabetes was 33.1%, as compared with 36.8% in the placebo group (hazard ratio (HR) with valsartan, 0.86; 95% confidence interval [CI], 0.80–0.92; P<0.001). Compared with placebo, valsartan did not significantly reduce the incidence of either the extended CV outcome (14.5% vs. 14.8%; hazard ratio [HR], 0.96; 95% CI, 0.86–1.07; P=0.43) or the core CV outcome (8.1% vs. 8.1%; HR, 0.99; 95% CI, 0.86–1.14; P=0.85). Although nateglinide is in a class of drugs previously shown to lower post prandial glycemia, the hoped-for effect did not occur in NAVIGATOR, nor was the incidence of cardiovascular disease reduced. Nateglinide compared with placebo did not reduce cumulative incidence of diabetes (36% and 34% respectively; HR, 1.07; 95% CI, 1.00–1.15; P=0.05), the core composite CV outcome (7.9% and 8.3% respectively; HR, 0.94, 95% CI, 0.82–1.09; P=0.43), or the extended composite CV outcome (14.2% and 15.2%, respectively; HR, 0.93%, 95% CI, 0.83–1.03; P=0.16).

In an accompanying editorial [3], the author opined that effective lifestyle interventions should be used to combat the current diabetes epidemic, a critical public health concern, but for now, neither drug evaluated in the NAVIGATOR should be used.

[1] The NAVIGATOR study group.Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362(16):1477-90

[2] The NAVIGATOR study group.Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362(16):1463-76

[3] Navigating the choices for diabetes prevention. Nathan DM. N Engl J Med 2010;362:1533-35

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