[NPInfo] Dibetes/Groundbreaking info

[David Mittman]


February 7, 2008
Diabetes Study Partially Halted After Deaths
By GINA KOLATA
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.”


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