Diabetes trial stops treatment arm in wake of death risk

Washington -- The halting on Feb. 6 of an arm of the large type 2 diabetes trial, ACCORD, sent shock waves through the medical community. The lower-the-better conventional wisdom for blood glucose levels was questioned when it was found that those getting the most intensive glucose-lowering treatments were more likely to die.

But treatment strategies -- keeping blood glucose, blood pressure and cholesterol levels in check -- are likely to remain unchanged for the vast majority of the millions of people with type 2 diabetes. What might change is an overly aggressive pursuit of low blood glucose levels in patients with or at risk for cardiovascular disease.

The overall trial, which had enrolled more than 10,000 people at high risk for heart attacks and strokes, will continue. The adjustment will occur among those who received the most aggressive glucose-lowering treatment, designed to achieve A1c levels of less than 6%. They will now receive the standard treatment, with an A1c goal of 7% to 7.9%. This level is, on average, achieved by type 2 diabetics in the United States, according to the study's sponsor, the National Heart, Lung and Blood Institute.

With a growing rate of diabetes in the nation, researchers have been striving to find ways to lower the disease's death toll. An estimated 21 million Americans have diabetes, and 284,000 die from it each year. The majority, or 65%, die because of cardiovascular causes, the NHLBI said.

The ACCORD -- Action to Control Cardiovascular Risk in Diabetes -- trial was an attempt to determine whether this toll could be reduced through more intensive control of blood glucose levels, a goal already endorsed by many physician groups.

Most type 2 diabetes treatment guidelines recommend A1c goals of less than 7%, including those of the American Diabetes Assn. After the news broke, NHLBI Director Elizabeth Nabel, MD, said, "First and foremost, individuals with diabetes should not change their diabetes treatment without consulting their health care provider."

"Second," she added, "we concur with the general recommendation of the ADA that advises people with diabetes to aim for an A1c level of less than 7%. But for this special group of individuals with diabetes, as exemplified in the ACCORD population, which were average age of 62, had diabetes for an average of 10 years and had known heart disease or were at high risk [for heart disease], less-stringent A1c goals are likely appropriate, with an aim of around 7%."

Guideline recommendations

The ADA reiterated its less-than-7% recommendation for patients with type 2 diabetes, although it underscored that treatment should be tailored to the individual, according to a statement the groups released after the ACCORD announcement.

Meanwhile, the American Assn. of Clinical Endocrinologists, which recommends in its guidelines A1c levels of 6.5% or lower, offered some cautions. "A target of an A1c of 6.4% or less may not be either possible, wise or safe in type 2 patients with a higher risk of cardiovascular disease or those with established cardiovascular disease."

The NHLBI decided to end the intensive treatment arm of the study when a review of the data revealed that 257 people enrolled in that part of the study had died compared with 203 in the standard treatment group.

Most participants in the intensive treatment group had achieved their lower A1c levels with a combination of approved diabetes medications. For both the intensive and standard treatment groups, clinicians in the study could use all the major classes of medications available: metformin, thiazolidinediones (primarily rosiglitazone), insulins, sulfonylureas, exenatide and acarbose.

Given recent concerns about possible cardiovascular risks from rosiglitazone, that medication was particularly scrutinized to see if there was any link to the increased deaths, said William T. Friedewald, MD, the trial's steering committee chair and clinical professor of medicine and public health at Columbia University in New York City. None was found, he noted.

ACCORD researchers will continue to monitor participants and conduct additional analyses to try to explain the findings, Dr. Friedewald said. The trial is scheduled to conclude in June 2009.