NAVIGATOR Off Course to Diabetes Prevention With Valsartan, Nateglinide

March 14, 2010

March 13, 2010 (Atlanta, GA) — Daily therapy with an angiotensin receptor blocker (ARB) had a significant but weak dampening effect on the risk of incident diabetes in a population with impaired glucose tolerance and either cardiovascular (CV) disease or CV risk factors, but no such effect was seen in the same group with a different drug, a short-acting promoter of insulin secretion [1,2].

Neither valsartan (Diovan, Novartis) nor nateglinide (Starlix, Novartis), respectively, had any significant effect on cardiovascular risk in the trial, which compared them with placeboes in separate randomizations and followed participants for a median of five years. Everyone in the study, called Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR), also followed a lifestyle-intervention program aimed at reducing the risk of diabetes.

The findings are published online today in the New England Journal of Medicine, the valsartan and nateglinide components of the trial appearing in separate reports, to coincide with their presentation here at the American College of Cardiology 2010 Scientific Sessions/i2 Summit.

We don't know if the drug was effective at all. Not only was it a negative study, but we can't even begin to understand why.

The 14% decrease in risk of diabetes in the valsartan group is modest compared with the benefits of lifestyle modification alone in other studies, although those were shorter and involved different populations, observed the authors of the valsartan report, led by Dr John J McMurray (University of Glasgow, Scotland).

"The effect of valsartan was also smaller than that of acarbose, metformin, or rosiglitazone, medications that have a recognized glucose-lowering action, although none of these drugs were tested in addition to lifestyle modification or for as long as valsartan," according to the group.

Valsartan was tested in NAVIGATOR because of evidence in past studies that using ARBs or angiotensin-converting enzyme (ACE) inhibitors to reduce cardiovascular risk might also prevent diabetes; those including valsartan generally used higher dosages than the "up to 160 mg daily" in NAVIGATOR.

The group notes that "no safety concerns were identified" in the trial.

In the nateglinide group, however, the results hint at a possibly increased risk of incident diabetes that could at least be called a trend at p=0.05.

"The results of the NAVIGATOR study are largely negative," according to Dr David M Nathan (Massachusetts General Hospital, Boston) in an accompanying editorial [3]. "The finding that valsartan failed to have an effect on either of the cardiovascular-disease outcomes but had a positive effect on the incidence of diabetes is surprising," he writes, because other studies suggest ARBs and ACE inhibitors improve cardiovascular outcomes in diabetics.

Valsartan vs Placebo: NAVIGATOR Co-Primary End-Point Outcomes

Co-primary end points Valsartan, n=4631 (%) Placebo, n=4675 (%) HR (95% CI) pa
Progression to diabetes 33.1 36.8 0.86 (0.80–0.92) <0.001
Composite CV events, extendedb 14.5 14.8 0.96 (0.86–1.07) 0.43
Composite CV events, corec 8.1 8.1 0.99 (0.86–1.14) 0.85

a. two-sided test

b. cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization from unstable angina, heart failure, or arterial revascularization

c. cardiovascular death, nonfatal MI, nonfatal stroke, or heart-failure hospitalization

Possibly, Nathan writes, the "high rates of loss to follow-up," a substantial rate of ACE-inhibitor and ARB use by participants in the valsartan placebo group, and ultimately a 34% rate of "nonadherence to valsartan" by those assigned to it "could explain the absence of an effect on cardiovascular disease."

To heartwire , Nathan said he'd expect NAVIGATOR to have "zero impact on clinical practice," although it's conceivable that Novartis might seek and the US Food and Drug Administration (FDA) grant an expanded indication for valsartan to cover prevention of diabetes.

But of the medications that have been studied for diabetes prevention, he said, valsartan "is the weakest of all. And it's probably one of the more expensive of the medications that could be used. It's not a drug I would use to prevent diabetes, because it demonstrably had much less of an effect than, for example, metformin--which is a cheap generic drug, and we have tons of experience with it as a preventive treatment."

The 9306 patients in NAVIGATOR's primary analyses, recruited in 40 countries, had impaired glucose tolerance, as determined by plasma glucose >140 mg/dL but <200 mg/dL after an oral glucose load, and at least one cardiovascular risk factor if they were >55 years old or known cardiovascular disease if they were >50 years old.

They had been randomized double-blind and separately to both valsartan vs placebo and nateglinide vs placebo. In addition, all participants were "required to participate in a study-specific lifestyle-modification program designed to reduce the risk of diabetes" through weight loss, dietary fat reduction, and increased exercise.

Nateglinide, a short-acting insulin secretagogue, attenuates postprandial elevations in glucose, note the authors of the nateglinide report, led by Dr Rury R Holman (Churchill Hospital, Oxford, UK). The drug was given "up to 60 mg three times daily," their report notes. "It was hypothesized that nateglinide might reduce the risk of progression to diabetes by restoring a more physiologic insulin response to meals than that which occurs with sulfonylureas such as glyburide." It also might, based on some trial data, improve CV risk, they write.

Not only did nateglinide fail to be cardioprotective or cut the risk of diabetes in NAVIGATOR, "it possibly raises glucose levels after a glucose challenge," Holman et al write. They report that two hours after a glucose load, glucose levels were a mean 4.37 mg/dL higher (p<0.001) in the nateglinide group than their corresponding controls.

Nateglinide vs Placebo: NAVIGATOR Co-Primary End-Point Outcomes

Co-primary end points Nateglinide, n=4645 (%) Placebo, n=4661 (%) HR (95% CI) pa
Progression to diabetes 36.0 33.9 1.07 (1.00–1.15) 0.05
Composite CV events, extendedb 14.2 15.2 0.93 (0.83–1.03) 0.16
Composite CV events, corec 7.9 8.3 0.94 (0.82–1.09) 0.43

a. two-sided test

b. cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina, heart failure, or arterial revascularization

c. cardiovascular death, nonfatal MI, nonfatal stroke, or heart-failure hospitalization

Holman et al point out that "the study medication was withheld on mornings before oral glucose-tolerance testing," so it is possible that the post–glucose-challenge jump in glycemia in the nateglinide group represents a rebound effect following the drug's withdrawal. They acknowledge, however, that another possibility is "long-term diminution in the beta-cell response to an acute glucose challenge."

There is some enthusiasm over the idea that lowering postprandial glucose levels might also cut CV risk, "generated to a great extent by drug companies that have products that lower postprandial glucose, because there is an association between postprandial glucose levels and heart disease, more so than there is between fasting glucose and heart disease," Nathan said. He added that the effect has been observed predominantly in prediabetics. "There's been great interest in determining whether it's actually a causal association."

NAVIGATOR, Nathan said, was supposed to be the "put-up-or-shut-up" trial for advocates of the strategy in people with abnormal glucose tolerance. That the drug was withheld on glucose-tolerance-test days "was a very disappointing feature of the study."

The goal of treatment with nateglinide, as a short-acting agent, is specifically to lower postprandial glucose, Nathan noted. "But we don't know if the drug was effective at all. Not only was it a negative study, but we can't even begin to understand why."

NAVIGATOR was funded by Novartis Pharma, which markets both valsartan and nateglinide and "collaborated with an academic executive committee" to design the trial. Among the trial's coauthors were at least three Novartis employees. Nathan had no financial relationships to disclose. Disclosures for the coauthors are listed online .


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