Better glucose control no help for cardiovascular risk

Three major studies comparing intensive glucose control to standard treatment in Type 2 diabetes brought mixed messages to those who recently attended the American Diabetes Association's 68th Scientific Sessions in San Francisco.

The good news: Tight glucose control clearly reduces the incidence and the risk of renal disease and other microvascular complications of diabetes.

The bad news: Tight glucose control does not reduce the risk of cardiovascular disease and may increase the risk of mortality in the highest-risk patients.

On the positive side, ADVANCE found that intensive glucose control reduced the risk of renal disease by 21%. Patients in the intensive treatment arm reduced hemoglobin A1c levels from 7.5% at enrollment to a mean of 6.5% using an open drug regimen that included Diamicron MR (gliclazide MR, Servier), a sulfonylurea that is not available in the United States.

He said patients in the standard arm went from 7.5% to 7.3% using an open drug regimen that did not include Diamicron MR. Servier funded the trial, but he said he would expect similar results using any similar agent.

"We were testing a strategy, not a drug," he explained.

Two other trials produced equally mixed messages. The worst news came from ACCORD (Action to Control Cardiovascular Risk in Diabetes). Researchers found a 35% increase in fatal or non-fatal heart attacks, strokes, or cardiac arrhythmias and a 22% overall increase in mortality among patients with intensive glucose-lowering regimens. The trial enrolled more than 10,000 patients in the United States and Canada.

The intensive intervention arm was halted in February 2008 after 3.5 years of treatment due to excess mortality. The standard treatment arm will continue for the planned 5.6 years.

"We concluded that the strategy used is what caused these results," said Elizabeth Nabel, M.D., director of the National Institutes of Health National Heart, Lung, and Blood Institute, which sponsored ACCORD. "For these [highest-risk] individuals, intensively lowering blood sugar to near-normal levels appears to be too risky."

Nabel said that subgroup analyses has not identified any association between mortality and age, gender, ethnicity, comorbidities, glycemic control, hypoglycemia, or drug used, including rosiglitazone (Avandia, GlaxoSmithKline). Rosiglitazone has been linked with excess cardiovascular risk in other studies.The intensive control goal was A1c below 6%. The standard control goal was 7% to 7.9%. At termination, the intensive group had reached 6.4% and the standard group 7.5%.

ACCORD also included studies on the effects of blood pressure control and lipid lowering on cardiovascular disease. Approximately 45% of patients received either intensive or standard blood pressure control and 55% received fenofibrate (Tricor, Abbott) or placebo to raise HDL and lower triglycerides. The blood pressure and lipid trials will close in June 2009.

The Veterans Affairs Diabetes Trial produced less challenging results. Researchers found that intensive glucose control using a variety of oral agents plus insulin had no statistically significant effect on cardiovascular disease or mortality.

"While we found that intensive treatment of patients with Type 2 diabetes suggested some benefits from glucose control, it did not reach significance for a composite of specified cardiovascular disease events in this population," said trial co-director William Duckworth, M.D., director of diabetes research at the Carl Hayden VA Medical Center in Phoenix.

"The key advice we would give Type 2 patients is that lowering A1c may not affect cardiovascular events, but it will protect against microvascular disease," MacMahon concluded.