The New England Journal of Medicine has featured outcomes of the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study in which nateglinide and valsartan were evaluated for the reduction in risk of diabetes or cardiovascular events, in patients with impaired glucose tolerance. Data on the two drugs have been presented as separate studies.

The double-blind trial involved 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors, who were randomised in a 2-by-2 factorial design, to receive nateglinide (up to 60 mg three times daily) or placebo, with valsartan (up to 160 mg daily) or placebo, in addition to participation in a lifestyle modification programme. Patients were evaluated for the following three co-primary endpoints:

• the development of diabetes
• a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for heart failure, and,
• an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalisation for unstable angina, or arterial revascularisation.
 

Participants were followed for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status).

The following results were reported:
• Nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94,  0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16).
• The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 0.80 to 0.92; P<0.001).
• Valsartan, as compared with placebo, did not statistically significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 0.86 to 1.14; P=0.85).

The researchers concluded that whilst nateglinide did not reduce the incidence of diabetes or the co-primary composite cardiovascular outcomes, valsartan led to a reduction in the incidence of diabetes but did not reduce the rate of cardiovascular events.

In a related editorial discussing both the studies, the author writes:
“The results of the NAVIGATOR study are largely negative. Neither drug (nor the combination, keeping in mind that one quarter of the study cohort took both drugs) reduced the two coprimary cardiovascular-disease outcomes. The only positive result was a weak, albeit statistically significant, reduction in the incidence of diabetes with valsartan.5 The relative reduction of 14% and the absolute reduction of 3.7 percentage points in incident diabetes with valsartan, as compared with placebo, over a mean follow-up of 5 years make valsartan the weakest of the drugs studied to date.”

Furthermore, the author concludes:
“Although the authors suggest that the prevention of diabetes with valsartan might make it a preferred drug as compared with antihypertensive drugs that potentially worsen glycemia, valsartan was relatively weak in preventing diabetes, and it did not lower the rates of cardiovascular disease. The prevention of diabetes remains a critical public health priority, but for now we should steer away from these two drugs and use effective lifestyle interventions and, in selected persons, metformin to combat the epidemic.”