CardioExchange Archive

We welcome John J. McMurray, MD, lead author of the NEJM article on the valsartan component of the NAVIGATOR trial, to answer our questions about this angiotensin-receptor blocker (ARB). We encourage you to ask yours.

Background: In the NAVIGATOR trial, 9306 patients with impaired glucose tolerance and established cardiovascular disease or CVD risk factors were randomized, in double-blind fashion, to receive valsartan (up to 160 mg daily) or placebo in addition to lifestyle modification. The trial had a 2×2 factorial design, and participants were also randomized to receive nateglinide, a short-acting insulin secretagogue, or placebo; results of this component of the trial are reported in a separate, accompanying NEJM article.* (Nateglinide and valsartan are made by the same company, which funded the study.)

At a median follow-up of 5 years, significantly fewer valsartan than placebo recipients had diabetes (33.1% vs. 36.8%). What mechanisms do you think underlie this effect of valsartan on glycemic control?

There are many postulated mechanisms, including:

• Increased skeletal-muscle blood flow, enhancing glucose uptake and possibly also increasing muscle mass (which may ultimately reduce lipid accumulation)
• Increased insulin sensitivity (i.e., reduction in insulin resistance), as suggested by previous euglycemic hyperinsulinemic clamp studies
  Increased pancreatic blood flow, which may help to preserve beta-cell function
• Increased potassium levels (hypokalemia has been associated with the development of diabetes)
• Angiotensin II production by adipocytes may be elevated in obese patients; in turn, angiotensin II may have effects on adipocytes, such as increasing fat storage, leptin production, or both. (The NAVIGATOR participants’ mean body-mass index was 30.5.)
• Angiotensin II cross-talk with insulin (e.g., angiotensin II may inhibit the action of insulin)

Valsartan had no advantage over placebo with respect to cardiovascular outcomes at a median follow-up of about 6.5 years. That leaves the improvement in glycemic control essentially as a surrogate endpoint. Given that, do you think valsartan would improve the length or quality of the lives of patients like those in the study?

Inhibition of the renin-angiotensin system certainly didn’t reduce the risk for cardiovascular events in NAVIGATOR. But I think it is reasonable to speculate that prevention of diabetes would translate into longer-term reduction in microvascular complications — nephropathy, neuropathy, and retinopathy — which seem firmly linked to hyperglycemia. Whether or not preventing diabetes would reduce the risk for future cardiovascular events is harder to determine because the relationship between glucose and macrovascular disease is less clear-cut.

Do you think these findings are sufficient to argue for using valsartan to prevent diabetes in clinical practice? If so, how would valsartan ideally be incorporated into practice guidelines?

Not generally, no. Lifestyle modification remains the only realistic population-based strategy — and one that is highly effective. However, our findings may influence the choice of antihypertensive therapy, especially in hypertensive patients who are at high risk for developing diabetes. Some of the alternatives to an ARB (e.g., diuretics and beta-blockers) appear to increase the risk for diabetes.

Will you continue to follow the NAVIGATOR participants?

Unfortunately, we will not be following them for the longer term. We had already extended the follow-up because of lower-than-expected cardiovascular event rates.

*Note: Nateglinide showed no advantage over placebo with respect to incident diabetes or cardiovascular outcomes in the NAVIGATOR trial.