While neither nateglinide (Starlix, Novartis) nor valsartan (Diovan, Novartis) reduced incidence rates of cardiovascular (CV) outcomes in patients with impaired glucose levels, valsartan reduced rates of diabetes by 14 percent, according to results from two separate studies of the NAVIGATOR trial published April 22 in the New England Journal of Medicine.
The valsartan study was led by John J. McMurray, MD, of the University of Glasgow in the U.K., while Rury R. Holman, FRCP, of the University of Oxford in the U.K., led the nateglinide study.
Patients were administered valsartan, an angiotensin-receptor blocker, and nateglinide, a blood glucose lowering drug in the meglitinide class, to test their effectiveness to lower glucose levels and CV events.
“Patients with impaired glucose tolerance have an increased risk of type 2 diabetes mellitus and CVD,” the authors wrote. “Interventions that might reduce the incidence of diabetes and associated rates of death and complications from CV causes in such patients are therefore of importance.”
Researchers from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) study group evaluated 18,612 patients who received either 60 mg of nateglinide, up to 160 mg of valsartan or placebo.
Patients were enrolled between January 2002 and January 2004, from 806 centers in 40 countries. Eligible patients had fasting glucose levels of at least 95 mg/dL but less than 126 mg/dL and had one or more CV risk factors or CVD.
In the nateglinide arm of the study, 4,645 patients were administered the drug, while 4,661 received a placebo, while in the valsartan study arm, 4,631 patients received the drug while 4,675 received a placebo.
Both were double-blind, randomized clinical trials that observed primary outcomes including diabetes and CV outcomes including nonfatal MI, stroke and hospitalization for heart failure.
Results showed that incidence of diabetes between the placebo group and nateglinide arm were similar, 36 and 34 percent, respectively. Additionally, the rates of both composite CV outcomes for the two groups were also similar, 7.9 percent and 8.3 percent, respectively.
These data also showed that the risk of hypoglycemia increased for patients administered nateglinide.
Though the incidences of CV events were similar in the placebo group and those administered valsartan, rates of diabetes differed significantly, 36.8 versus 33.1 percent, respectively.
“The relative reduction of 14 percent in the risk of diabetes in the valsartan group would translate into 38 fewer cases of diabetes per 1,000 patients treated for five years, a reduction that was consistent across all subgroups that were examined,” the authors wrote.
The researchers speculated that because only 24 percent of the patients administered valsartan had CVD and all had well controlled blood pressure, this could be one reason why the rate of CV outcomes did not decline.
“Although lifestyle modification should remain the primary intervention to reduce the risk of diabetes in the general population, our findings may have implications for the treatment of hypertension, since the use of both thiazide diuretics and beta-blockers has been associated with an increased risk of diabetes,” the authors concluded.
In an accompanying editorial, David M. Nathan, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, wrote that “the results of the NAVIGATOR study are largely negative.”
Nathan said that researchers should better focus on lifestyle interventions, rather than drug treatment. “The lifestyle intervention program was not effectively implemented, as evidenced by the trivial weight loss over the course of the study and the 8 percent annual incidence of diabetes in the placebo group, which was close to the rates found in control groups from other studies.”
“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," Nathan concluded.