Researchers in the US said they abruptly halted part of a major federal study of more than 10,000 middle-aged and older people with type 2 diabetes. The reason was that a treatment that most experts have long believed would save lives, lowering blood sugar to near normal levels, instead increased the risk of death.
For decades, researchers have thought that if people with diabetes could lower their blood sugar to normal levels, they would no longer have a high risk of dying from heart disease. The results of the new study showed just the opposite, and call into question how the disease should be managed.
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There were 54 additional deaths among study participants who were randomly assigned to get their blood sugar levels to nearly normal as compared to those whose levels were controlled, but less rigidly. The patients had been in the study for an average of four years when the investigators called a halt to the intensive blood sugar lowering and told all the patients to follow the less intense regimen.
The results do not mean that blood sugar is meaningless. And, in fact, lowered blood sugar can protect patients against kidney disease, blindness and amputations. But, the findings inject an element of uncertainty into what has been dogma in the diabetes field—that the lower the blood sugar, the better, and that normal blood sugar levels will save 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.
Diabetes researchers said they had to ask whether they had missed some crucial biological principle.
“This study raises fundamental questions about the primary hypothesis in diabetes,” said Dr Irl Hirsch, a diabetes researcher at the University of Washington.
And, Hirsch said, it will be hard to explain the news to patients. Many just won’t believe it, he predicted. He has patients who have spent years and enormous effort 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 oestrogen,” Hirsch said. “Telling these patients to get their blood sugar up will be very difficult.”
He adds that major organizations such as the American Diabetes Association and the American Association of Clinical Endocrinologists, will be in a quandary. Their guidelines call for blood sugar targets that are as close as possible to normal levels.
Insurance companies also have pushed for low blood sugar levels, paying doctors extra if their diabetic patients got their blood levels as nearly as low as those of people without diabetes.
In fact, so entrenched was the low blood sugar hypothesis 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 late 1990s, they had to defend it against critics who said it would be unethical. Lower blood sugar was clearly better, critics said, so how could they ask some people to relax their guard?
But no one had ever rigorously tested the idea that very low blood sugar levels in people with type 2 diabetes, the form that affects 95% of people with the disease, would protect against heart disease and save lives.
Some thought the study, even if it was ethical, would be impossible. They doubted that study 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 other conditions such as high blood pressure and high cholesterol levels, that placed them at additional heart disease risk—would be able to achieve normal blood sugar levels to begin with.
“This was a clinical study to try and do something that’s never been done before,” said Dr John Buse, the vice-chairman of the study’s steering committee and the president of medicine and science at the American Diabetes Association.
The study tested three types of treatments simultaneously intense as compared to less intense blood sugar control, intense as compared to less intense cholesterol control, and intense as compared to less intense blood pressure control. Patients were randomly assigned to each of the three types of treatment. The cholesterol and blood pressure parts of the study are continuing.
Buse described what was required to get blood sugar levels low, as measured by a protein, haemoglobin A1C, which was supposed to be at a level of 6% 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, one or two several times a day, in addition to the pills they took for other medical conditions and to lower their blood pressure and cholesterol. The subjects also came to a medical clinic every two months and had frequent telephone conversations with clinic staff.
“It was just intense, what these people were doing,” Buse said.
Those assigned to the less stringent blood sugar control level, an A1C level of 7-7.9%, had an easier time of it. They measured their blood sugar once or twice a day, went to the clinic every four months, took fewer drugs or lower doses, and were not as concerned if their blood sugar sometimes rose a bit. “It was a different amount of work,” Buse said.
So, it was quite a surprise when those patients who had worked so hard to get their blood sugar low had a significantly higher death rate, the study investigators said.
The researchers pored over the data, asking whether there were any drugs or drug combinations that might have been to blame. But they found none, said Dr Denise Simons-Morton, a project officer for the study at the National Heart, Lung and Blood Institute. Even Avandia, recently suspected of increasing the risk of heart attacks in diabetes patients, did not appear to be contributing to the increased death rate.
The researchers also asked whether there might be a specific cause of death in the intensively treated group. Once again, Simons-Morton said they found nothing. Most of the deaths in both groups were from heart attacks, she added.
“Clearly, we did not anticipate the findings,” said Dr Elizabeth Nabel, director of the National Heart, Lung and Blood Institute.
For now, the reasons for the higher death rate are just speculation. Clearly, people without diabetes are physically different from those who have diabetes and get their blood sugar low.
It might be that the patients were suffering unintended consequences from taking so many drugs, which might interact in unexpected ways, said Dr Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic.
“Drugs have complex effects,” Nissen said. “They have effects on the target you are treating, and they have other effects.”
Or it may be that the participants reduced their blood sugar too fast, Hirsch said. Years ago, researchers discovered that lowering blood sugar very quickly in diabetics 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 patients 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 what these results mean for some time to come. “It is a great study and very well run,” Dove said. “And it certainly had the right principles behind it, based on the literature to date.”
But maybe, he said, “there may be some scientific principles that don’t hold water in a diabetic population.”
©2008/the New York Times