NAVIGATOR Confirms Diet and Exercise Still Best

"Patients randomized to valsartan (Diovan) did achieve a 14% relative reduction in the incidence of diabetes (P<0.001), but even that benefit was less than the 25% to 30% decline in incidence reported in previous trials of ACE inhibitors" stated Robert M. Califf, MD, lead investigator at Duke University Medical Center in Durham, NC.

In order to achieve a 14% reduction in new onset diabetes, it would require treating 1,000 patients with valsartan for five years.

The incidence of MI, stroke, or hospitalization for heart failure was 14.5% in the valsartan arm and 14.8% in the placebo group. For patients randomized to the insulin secretagogue nateglinide (Starlix), the cardiovascular endpoint was 7.9% versus 8.3% in the placebo arm.

NAVIGATOR randomized 9,306 patients with impaired glucose tolerance and either established heart disease or a combination of risk factors that put them at high risk for cardiovascular events to either valsartan, nateglinide, or matched placebo on top of a lifestyle intervention.

The intervention was designed to help patients lose at least 5% of body weight, reduce fat intake, and increase exercise.

Valsartan was dosed at 80 mg daily for two weeks followed by an increase to 160 mg daily. Nateglinide was dosed at 30 mg three times a day before meals for two weeks then increased to 60 mg, three times a day.

The average age of patients was 63 and half were women. About one-quarter of the patients had established cardiac disease as opposed to risk factors for same. There were three coprimary endpoints -- new onset diabetes, a core cardiovascular endpoint that combined MI, stroke, or hospitalization for heart failure, and five-year progression of cardiovascular disease as measured by components of the core cardiovascular endpoint and hospitalization for angina or revascularization.

The most unexpected finding of the study was the failure of nateglinide to prevent progression to diabetes in patients with impaired glucose tolerance.

The NAVIGATOR investigators wrote that they thought nateglinide "might reduce the risk of progression to diabetes by restoring a more physiologic insulin response to meals than that which occurs with sulfonylureas."

But they found, "that nateglinide offers no protection from the progression of impaired glucose tolerance to diabetes or from the progression of cardiovascular disease, and possibly raises glucose levels after a glucose challenge."

One bright note -- nateglinide did not increase cardiovascular risk, which has been a concern with some oral glucose-lowering agents. It did, however, increase the risk of hypoglycemia.

Holman said the study did confirm the value of weight loss, diet, and exercise. Lifestyle intervention, he said, appears to be the best option for primary and secondary prevention.

And the authors wrote that even the slight benefit seen with valsartan may have clinical implications "since the use of both thiazide diuretics and beta-blockers has been associated with an increased risk of diabetes."

But in an editorial that accompanied the journal publication, Harvard's David M. Nathan, MD, didn't buy that argument because while valsartan did not worsen glycemia it "was relatively weak in preventing diabetes, and it did not lower the rates of cardiovascular disease."

Nathan concluded that, for now, "We should steer away from these two drugs and use effective lifestyle interventions and, in selected persons, metformin to combat the epidemic."

One limitation noted in the study was that the valsartan arm had a high rate of patients discontinuing the drug and those in the matched placebo group had a high rate of taking ACE inhibitors or other ARBs.

• Explain to patients that this study demonstrated that a lifestyle intervention aimed at losing at least 5% of body weight, reducing fat intake, and increasing exercise is an effective strategy to reduce the risk of new onset diabetes in high-risk patients.
  
  
• Explain that the two drugs studied in this trial did not reduce the risk of cardiovascular disease, but the angiotensin receptor blocker did reduce the risk of new onset diabetes compared with placebo, which confirms earlier studies that have found a benefit for drugs that target the renin-angiotensin system.

NAVIGATOR study group "Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events" N Engl J Med 2010; 10.1056/NEJMoa1001122.

NAVIGATOR Study Group, "Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events" N Engl J Med 2010; DOI 10.1056/NEJMoa1001121.

Nathan, DM "Navigating the Choices for Diabetes Prevention" N Engl J Med 2010; DOI: 10.1056/NEJMe1002322.