Nateglinide, an insulin secretagogue that lowers postprandial glucose, failed to prevent the development of diabetes and related cardiovascular events among high-risk patients in a large international clinical trial.
The angiotensin-receptor blocker valsartan also failed to prevent cardiovascular events in the same trial, but it did induce an unexpected relative reduction of 14% in the incidence of diabetes, according to the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Study Group.
The results were published online in the New England Journal of Medicine, simultaneously with the planned presentation at the annual meeting of the American College of Cardiology in Atlanta.
In an editorial comment accompanying the two reports, Dr. David M. Nathan of Massachusetts General Hospital, Boston, said, “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.”
Instead, the study findings show that “for now we should steer away from these two drugs” when attempting to forestall diabetes and cardiovascular complications in high-risk patients, Dr. Nathan said (N. Engl. J. Med. 2010 March 14 [doi:10.1056/NEJMe1002322
In NAVIGATOR, 9,306 patients who had impaired glucose tolerance and either known cardiovascular disease or cardiovascular risk factors were randomly assigned to take 60 mg oral nateglinide before meals three times daily, a placebo, or in a 2-by-2 factorial design, oral valsartan or a placebo.
Nateglinide was studied to determine whether it would slow progression to diabetes by restoring a more physiologic insulin response to meals. However, during a mean follow-up of about 6 years, progression to diabetes occurred in 36% of the nateglinide group and 34% of the placebo group, a nonsignificant difference, said Dr. Rury R. Holman of Oxford (England) University's Centre for Diabetes, Endocrinology, and Metabolism, and his associates said (N. Engl. J. Med. 2010 March 14 [doi:10.1056/NEJMoa1001122
Similarly, a composite cardiovascular outcome event occurred in 14% of the nateglinide group and 15% of the placebo group, a nonsignificant difference. There also were no differences between the two groups in any of the individual components of the composite cardiovascular outcome, including mortality rates.
The valsartan results were reported in a separate article. Unexpectedly, the angiotensin-receptor blocker had no effect on combined cardiovascular outcomes. Also unexpectedly, it reduced the incidence of diabetes by 14% relative to placebo, said Dr. Robert M. Califf of the Duke Translational Medicine Institute in Durham, N.C., and his NAVIGATOR colleagues.
It is possible that valsartan did not improve cardiovascular outcomes as it should have because most risk factors were already well controlled, since study subjects were allowed to take nonstudy medications such as ACE inhibitors, they said (N. Engl. J. Med. 2010 March 14 [doi:10.1056/NEJMoa1001121
Also, a “substantial proportion” of study subjects discontinued valsartan during the trial, which may have further mitigated its beneficial effects, they said.
In his editorial comment, Dr. Nathan agreed that “the high rates of loss to follow-up (13%), use of off-study ACE inhibitors or ARBs among participants assigned to placebo (24%), and nonadherence to valsartan (34% by study end) could explain the absence of an effect on cardiovascular disease.”
He went on to question the use of valsartan in the study in the first place. “The rationale behind the choice of valsartan to inhibit the renin-angiotensin axis is less clear, other than the fact that both nateglinide and valsartan are manufactured by the pharmaceutical sponsor, which also designed the study,” he said.