Nateglinide failed to prevent the development of diabetes and related CV events in high-risk patients in a large international clinical trial.
In the same trial, the angiotensin-receptor blocker valsartan also failed to prevent CV events. However, valsartan induced 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 simultaneously their at the annual meeting of the American College of Cardiology in Atlanta.
In an editorial accompanying the two reports, Dr. David M. Nathan of Massachusetts General Hospital's Diabetes Center, 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.”
However, this trial's single positive finding was only a “weak” reduction in diabetes with valsartan—not enough to support such a recommendation. The totality of the study findings show instead that “for now we should steer away from these two drugs” when attempting to forestall diabetes and its associated 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 CV risk factors were assessed at 806 medical centers in 40 countries during January 2002–January 2004. They were randomly assigned to take 60 mg of the insulin secretagogue nateglinide before meals three times daily, a placebo, or in a 2-by-2 factorial design, oral valsartan or placebo.
All the study subjects also were required to participate in a lifestyle modification program aimed at achieving a 5% weight loss, reduced dietary fats, and increased physical activity.
Nateglinide, which lowers postprandial glucose, was studied to determine whether it would slow progression to diabetes by restoring a more physiologic insulin response to meals. But 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. There also were no differences between the two groups in any of the individual components of the composite CV outcome, including mortality rates.
The valsartan results, reported in a separate article, showed that the ARB had no effect on combined CV outcomes. Furthermore, it reduced the incidence of diabetes by 14% relative to placebo. This “would translate into 38 fewer cases of diabetes per 1,000 patients treated for 5 years,” 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 CV 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]).
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.”
Overall, the NAVIGATOR results “do not support the contention that reducing postprandial hyperglycemia has a specific role in preventing diabetes or reducing cardiovascular disease. Other than increasing the rate of hypoglycemia by a factor of two, nateglinide had little effect,” Dr. Nathan commented.
The study was sponsored and designed by Novartis Pharma, manufacturer of both drugs. Novartis also collected, managed, and analyzed the data. In addition to support from Novartis, the NAVIGATOR researchers reported receiving financial support from Sanofi-Aventis and Merck. Dr. Nathan reported no financial conflicts of interest.
RAS Inhibition, Lifestyle Modification Affirmed
The NAVIGATOR trial was an ambitious effort to assess the ability of nateglinide and valsartan to prevent the onset of diabetes and adverse cardiovascular outcomes. Given our growing diabetes epidemic, meaningfully positive findings for either outcome with either intervention would have been welcome.
Unfortunately, both treatments were disappointing with regard to each of the co-primary end points. Furthermore, nateglinide was also linked to greater weight gain and increase in waist circumference, likely foreboding a higher rate of future diabetes.
Although valsartan did not prevent CV events or any of its other component events, it was associated with a significantly lower incidence of new onset diabetes, compared with placebo.