Diabetes Study Partially Halted After Deaths

Diabetes Study Partially Halted After Deaths

02/07/2008

By GINA KOLATA, The New York Times

For decades, researchers believed that if people with diabetes lowered their blood sugar to normal levels, they would no longer be at high risk of dying from heart disease. But a major federal study of more than 10,000 middle-aged and older people with Type 2 diabetes has found that lowering blood sugar actually increased their risk of death, researchers reported Wednesday.

The researchers announced that they were abruptly halting that part of the study, whose surprising results call into question how the disease, which affects 21 million Americans, should be managed.

The study’s investigators emphasized that patients should still consult with their doctors before considering changing their medications.

Among the study participants who were randomly assigned to get their blood sugar levels to nearly normal, there were 54 more deaths than in the group whose levels were less rigidly controlled. The patients were in the study for an average of four years when investigators called a halt to the intensive blood sugar lowering and put all of them on the less intense regimen.

The results do not mean blood sugar is meaningless. Lowered blood sugar can protect against kidney disease, blindness and amputations, but the findings inject an element of uncertainty into what has been dogma — that the lower the blood sugar the better and that lowering blood sugar levels to normal saves lives.

Medical experts were stunned.

“It’s confusing and disturbing that this happened,” said Dr. James Dove, president of the American College of Cardiology. “For 50 years, we’ve talked about getting blood sugar very low. Everything in the literature would suggest this is the right thing to do,” he added.

Dr. Irl Hirsch, a diabetes researcher at the University of Washington, said the study’s results would be hard to explain to some patients who have spent years and made an enormous effort, through diet and medication, getting and keeping their blood sugar down. They will not want to relax their vigilance, he said.

“It will be similar to what many women felt when they heard the news about estrogen,” Dr. Hirsch said. “Telling these patients to get their blood sugar up will be very difficult.”

Dr. Hirsch added that organizations like the American Diabetes Association would be in a quandary. Its guidelines call for blood sugar targets as close to normal as possible.

And some insurance companies pay doctors extra if their diabetic patients get their levels very low.

The low-blood sugar hypothesis was so entrenched that when the National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases proposed the study in the 1990s, they explained that it would be ethical. Even though most people assumed that lower blood sugar was better, no one had rigorously tested the idea. So the study would ask if very low blood sugar levels in people with Type 2 diabetes — the form that affects 95 percent of people with the disease — would protect against heart disease and save lives.

Some said that the study, even if ethical, would be impossible. They doubted that participants — whose average age was 62, who had had diabetes for about 10 years, who had higher than average blood sugar levels, and who also had heart disease or had other conditions, like high blood pressure and high cholesterol, that placed them at additional risk of heart disease — would ever achieve such low blood sugar levels.

Study patients were randomly assigned to one of three types of treatments: one comparing intensity of blood sugar control; another comparing intensity of cholesterol control; and the third comparing intensity of blood pressure control. The cholesterol and blood pressure parts of the study are continuing.

Dr. John Buse, the vice-chairman of the study’s steering committee and the president of medicine and science at the American Diabetes Association, described what was required to get blood sugar levels low, as measured by a protein, hemoglobin A1C, which was supposed to be at 6 percent or less.

“Many were taking four or five shots of insulin a day,” he said. “Some were using insulin pumps. Some were monitoring their blood sugar seven or eight times a day.”

They also took pills to lower their blood sugar, in addition to the pills they took for other medical conditions and to lower their blood pressure and cholesterol. They also came to a medical clinic every two months and had frequent telephone conversations with clinic staff.

Those assigned to the less stringent blood sugar control, an A1C level of 7.0 to 7.9 percent, had an easier time of it. They measured their blood sugar once or twice a day, went to the clinic every four months and took fewer drugs or lower doses.

So it was quite a surprise when the patients who had worked so hard to get their blood sugar low had a significantly higher death rate, the study investigators said.

The researchers asked whether there were any drugs or drug combinations that might have been to blame. They found none, said Dr. Denise G. Simons-Morton, a project officer for the study at the National Heart, Lung and Blood Institute. Even the drug Avandia, suspected of increasing the risk of heart attacks in diabetes, did not appear to contribute to the increased death rate.

Nor was there an unusual cause of death in the intensively treated group, Dr. Simons-Morton said. Most of the deaths in both groups were from heart attacks, she added.

For now, the reasons for the higher death rate are up for speculation. Clearly, people without diabetes are different from people who have diabetes and get their blood sugar low.

It might be that patients suffered unintended consequences from taking so many drugs, which might interact in unexpected ways, said Dr. Steven E. Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

Or it may be that participants reduced their blood sugar too fast, Dr. Hirsch said. Years ago, researchers discovered that lowering blood sugar very quickly in diabetes could actually worsen blood vessel disease in the eyes, he said. But reducing levels more slowly protected those blood vessels.

And there are troubling questions about what the study means for people who are younger and who do not have cardiovascular disease. Should they forgo the low blood sugar targets?

No one knows.

Other medical experts say that they will be discussing and debating the results for some time.

“It is a great study and very well run,” Dr. Dove said. “And it certainly had the right principles behind it.”

But maybe, he said, “there may be some scientific principles that don’t hold water in a diabetic population.”