Deaths Halt Part of Large Diabetes Trial
WEDNESDAY, Feb. 6 -- A large North American trial designed to aggressively lower the blood sugar of type 2 diabetics at risk of heart disease has been halted because of an unexpected number of deaths among those receiving the drug therapy.
Federal health officials announced Wednesday that 257 people who received the intensive therapy had died, compared with 203 in patients in a standard treatment group. But they could not pinpoint the reason for the heightened risk, and they appeared to rule out any of the diabetes drugs that were used.
A segment of the trial, called the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, was stopped 18 months early because of the findings.
"After thoroughly reviewing the data collected to date, ACCORD investigators found that among these adults with type 2 diabetes who are at especially high risk of cardiovascular disease, a medical treatment strategy to intensively lower their blood sugar levels below the current guidelines increased the risk of death compared to standard blood sugar lowering treatment." Dr. Elizabeth G. Nabel, director of the U.S. National Heart, Lung, and Blood Institute (NHLBI), said during a teleconference.
The ACCORD trial, sponsored by the NHLBI, began in 2001 at 77 sites in the United States and Canada with the enrollment of 10,251 patients with type 2 diabetes who were at high risk for heart attack or stroke because they had at least two risk factors, including high blood pressure, high cholesterol or obesity. Those in the trial received either medications to aggressively lower their blood sugar below recommended levels, or standard treatment to control their disease.
Among the 257 deaths in the aggressive therapy group, 50 percent were due to heart attacks or other cardiovascular causes, said Dr. William Friedewald, a clinical professor of public health and medicine at Columbia University and the chairman of the ACCORD Steering Committee.
While these death rates were lower than those seen in similar groups in other studies, the NHLBI decided to follow the recommendation of the study's data safety monitoring board and stop the aggressive therapy part of the trial. Patients in that part of the trial will now receive standard care until the study ends in 2009, Nabel said.
Officials stressed that it's not clear why people in the intensive therapy group were at higher risk of death. But the researchers did not find that the combination of medications used for the trial -- and approved by the U.S. Food and Drug Administration to lower blood sugar -- was responsible for the increased risk.
The halting of the trial segment follows recent reports that one of those medications, Avandia (rosiglitazone), has been linked to an increased risk of heart attack. But Friedewalt said the drug was not responsible for the deaths.
"Because of the recent concerns raised with regard to rosiglitazone, we specifically analyzed the data to try and determine whether there was any link between this particular medication and the increased deaths we were seeing in the ACCORD intensive treatment group," Friedewald said. "At this time, we have found no link, and thus the use of rosiglitazone does not seem to explain the increased mortality."
Most of the people in the intensive treatment group were taking high doses of several medications to lower their blood sugar. Other drugs used in the trial included metformin, thiazolidinediones, insulins, sulfonylureas, exenatide, and acarbose.
Reaction to the news was generally cautious.
One federal health expert said the findings should not affect the current treatment of type 2 diabetes.
"The ACCORD findings are important, but will not change therapy for most patients with type 2 diabetes. Few patients with high cardiovascular risk like those studied in ACCORD are treated to blood sugar levels as low as those tested in this study, " Dr. Judith Fradkin, director of the National Institute of Diabetes and Digestive and Kidney Diseases' division of diabetes, endocrinology, and metabolic diseases, said in a prepared statement. "People with diabetes should never adjust their treatment plan or goals without consulting their health care providers."
Nabel also urged those with diabetes " to consult with their health-care professional before making any changes to their treatment."
And the American Diabetes Association echoed his words.
"The American Diabetes Association looks forward to more analysis of the data from ACCORD, as well as other ongoing studies that may shed more light on this issue," the group said in a prepared statement. "However, at this time, the American Diabetes Association advises people with diabetes who have existing cardiovascular disease (CVD), or multiple CVD risk factors, to consult with their health care team about their treatment goals and to ensure that their blood pressure and cholesterol are appropriately managed."
Wednesday's announcement stunned at least one doctor who specializes in diabetes treatment.
"This is a mindblower," said Dr. Mary Ann Banerji, a diabetes expert at SUNY Downstate Medical Center in New York City. "We absolutely did not expect this."
"If we do have an increase in mortality, then we absolutely have to stop it," said Banerji, who has nearly 100 patients in the trial. "Of course, nobody knows why it happened. And everybody would like to know why it happened.
"It may be that these patients were a very high risk group to start with, because every other study suggested that intensive glucose [blood sugar] control was actually better for you," Banerji added. "This study flies in the face of that."
Type 2 diabetes is the most common form of diabetes. An estimated 21 million Americans have type 2 diabetes and 284,000 die from it each year. Sixty-five percent of those deaths are related to cardiovascular causes. Type 2 diabetes increases the risk for heart disease two to four times, according to the NHLBI.
Posted: February 2008