Diabetes Type 1 Support Group

NIH Halts Study After Treatment Increases Risk of Death
By Rob Stein
Washington Post Staff Writer
Wednesday, February 6, 2008; 3:55 PM

Aggressively driving blood sugar levels as low as possible in high-risk diabetes patients appears to increase their risk of death from a heart attack or stroke, according to a major government study that stunned and disappointed experts.

The startling discovery, announced today, prompted federal health officials to immediately halt one part of the massive trial so thousands of the type 2 diabetes patients in the study could be notified and switched to less intensive, less risky treatment.

"As always, our primary concern is to protect the safety of our study volunteers," said Elizabeth G. Nabel, director of the National Heart, Lung and Blood Institute, which is sponsoring the study. "We will continue to monitor the health of the study participants and will seek to determine the cause."

Although the reason for increased risk remains a mystery, Nabel and other experts stressed that the benefits of blood sugar control have been well established for diabetics and that patients should not make any changes in their care without consulting their doctors.

But the findings cast doubt on a major assumption about diabetes treatment -- that pushing levels as close to normal as possible would necessarily be better -- and will force experts to reassess their thinking about how to treat one of the nation's leading health problems.

"It's profoundly disappointing," said Richard Kahn, chief scientific and medical officer for the American Diabetes Association. "This presents a real dilemma to patients and their physicians. How intensive should treatment be? We just don't know."

The findings are the second major blow to fundamental assumptions about how to protect against heart disease -- the nation's leading killer. Another recent major study found that driving blood cholesterol levels as low as possible did not necessarily slow the progression of heart disease.

"This is the second big surprise," said Steven Nissen, a Cleveland Clinic cardiologist. "This suggests that there are things drugs do that we don't understand. We have to really ask the question: How low do you go?"

An estimated 21 million Americans suffer from type 2 diabetes, the most common form of the disease, and the number has been increasing because of the obesity epidemic. Diabetes patients' blood sugar levels rise abnormally high, causing a host of serious complications, including nerve damage, amputations, blindness and increased risk for heart attacks and strokes.

Many earlier studies had shown that tightly controlling blood sugar significantly reduced the risk for many complications. The new study, known as the Action to Control Cardiovascular Risk in Diabetes, or ACCORD, trial was designed to convincingly test whether various aggressive treatment strategies reduce the risk for heart disease -- the main cause of death among diabetics.

The study involves 10,251 type 2 diabetes patients ages 40 to 82 at 77 sites in the United States and Canada at high risk for heart disease for any reason, such as having high blood pressure, high cholesterol or being obese. About half the patients were placed on a regimen combining diet and exercise with drugs designed to lower their blood sugar levels to that of the average person with diabetes, while the other half was put on a more intensive regimen designed to drive it closer to that of someone without diabetes. The patients were also divided further into those who also received blood pressure-lowering medication or drugs to improve their cholesterol levels.

After about four years, about half of the participants in the intensive treatment group achieved blood sugar levels close to normal and about half the patients in the standard treatment group achieved levels close to the average diabetic's.

But a special 10-member panel that was monitoring the study alerted the organizers that 257 patients receiving the intensive treatment had died, compared with 203 receiving standard treatment, a difference of 54 deaths -- or three per 1,000 participants per year, officials said. About half the excess deaths were from heart disease.

"We obviously were surprised," Nabel said. "We were hoping for a positive outcome."

Letters were mailed out to all the participants on Monday notifying them of the results so they could consult with their doctors about switching to the less intensive therapy.

Nabel stressed that while the death rate was higher in the intensive group, the rate in both groups was still lower than would have been expected in a group of patients at such high risk receiving standard treatment.

"Although there appears to be some benefit of an overall lower death rate in both groups , the [special panel] recommended stopping the trial," Nabel said. "The harm of the very intensive treatment outweighed the potential benefit."

The researchers stressed that the disturbing findings would not alter treatment for most diabetics.

"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," said Judith Fradkin of the National Institute of Diabetes and Digestive Disorders.

In addition, driving blood sugar levels to very low levels might still prove beneficial for other patients, such as those who are younger, whose diabetes was diagnosed more recently or who are not at high risk for heart disease.

"It is not yet known whether controlling glucose to near-normal levels will prevent heart disease and extend life in other groups," Fradkin said.

Officials defended the study, saying previous research had suggested that intensive blood sugar lowering would be beneficial.

"ACCORD is an important study intended to find new answers to help people with type 2 diabetes reduce their high risk of heart disease," said Denise G. Simons-Morton, the project's director. "Hypotheses about treatments to prevent cardiovascular disease in people with type 2 diabetes need to be tested in clinical trials such as ACCORD."

Despite an intensive analysis, researchers were unable to determine the cause of the excess deaths. Because some of the patients were taking the drug Avandia, which has been the focus of concern that it might increase the risk of heart attacks, the researchers specifically examined whether that might have been a factor. They determined it was not.

"We found no link," said William T. Friedewald of Columbia University, who chairs the study's steering committee, adding that the investigation would continue.
Posted on 02/06/08, 07:02 pm