From Our 2008 Archives

2 Diabetes Studies Give Mixed Message

Intense Blood Sugar Control Cuts Eye and Kidney Complications, but Not Heart Complications

By Kathleen Doheny
WebMD Health News

Reviewed By Louise Chang, MD

June 6, 2008 — Intense control of blood glucose levels in type 2 diabetes helps reduce the risk of kidney and eye complications, but not cardiovascular risks such as heart attacks and strokes, researchers said at a news briefing during the annual meeting of the American Diabetes Association in San Francisco.

In one of the two studies highlighted at the briefing, patients who reduced their hemoglobin A1c levels even lower than what is routinely recommended actually had a higher rate of death from cardiovascular problems. But the researchers point out that these were sicker patients than many with type 2 diabetes.

Hemoglobin A1c is a measure representing average blood glucose control for the previous three months. The American Diabetes Association recommends A1c levels of less than 7%. People without diabetes have an A1c of about 5%.

The bottom line for patients hoping to avoid all the diabetes-related complications? Lowering blood glucose levels does help reduce kidney and eye complications from diabetes, but paying attention to blood pressure and cholesterol levels is crucial to reduce the heart attack and stroke-related risks that accompany a diagnosis of type 2 diabetes, researchers from both studies say.

"You can safely reduce glucose A1c to about 6.5% by using the sort of gradual, gentle approach that we used," says Stephen MacMahon, PhD, an investigator of one study, called ADVANCE (Action in Diabetes and Vascular Disease). "It won't improve cardiovascular risks, but it will improve kidney risks."

"If you want to manage cardiovascular risks, focusing on blood pressure and lipids is likely where the money is," says John B. Buse, MD, PhD, president of medicine and science for the American Diabetes Association, who also participated in the briefing.

The studies, along with two editorials and a perspective, are published online in the New EnglandJournal of Medicine.

Both studies looked at the value of lowering blood glucose levels in those with type 2 diabetes more intensely that what is routinely recommended.

Study Details: ADVANCE

In the ADVANCE study, researcher Anushka Patel, MBBS, and colleagues followed more than 11,000 participants, assigning them to a standard group or to an intense control group with a goal of getting their A1c to 6.5%.

The average age of participants was 66, and about a third had already had a stroke or heart attack; the rest were at high risk for cardiovascular problems because of high cholesterol or other risk factors.

After five years, the intense group average A1c was 6.5% and the standard group, 7.3%, Patel says.

"The major effect shown in this is a 21% reduction in risk for kidney disease," Patel tells WebMD. "That was major."

While there was no significant reduction in heart attack, stroke, or death from cardiovascular disease with the intense group, they found "no evidence of increased risk of death [from cardiovascular disease] in the intensely controlled," Patel says.

"This is important because in the ACCORD study, they said those controlled at 6.5% had a significant increased risk of cardiovascular death and they don't know why," Patel says. That arm of the ACCORD study ended in February when the increased risk of death became apparent.

Study Details: ACCORD

In the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes), researchers followed more than 10,000 participants with type 2 diabetes, focusing on whether intense control of blood glucose could reduce the risk of cardiovascular disease.

The target A1c in the intervention group was less than 6% and 7% to 7.9% in the standard group.

When it was found that the intense treatment group had a 22% higher relative risk of death than the standard treatment group, the intense treatment arm was terminated.

The increased death rate remains a puzzle, says Hertzel Gerstein, MD, a principal investigator of the ACCORD study. Since the arm was terminated, he says, many analyses have been done. "At this point in time, none of these analyses have identified any one reason why this occurred," he says.

ACCORD patients were at high risk, the researchers note: 35% had had a stroke or heart attack before entering the trial, and the rest had risk factors such as high blood pressure.

Second Opinions

The new study results from ADVANCE suggest that many of those with type 2 diabetes shouldn't worry about the previous result showing an increased risk of cardiovascular death with intense control, says Spyros Mezitis, MD, an endocrinologist at Lenox Hill Hospital and assistant professor of clinical medicine, New York Presbyterian-Cornell Medical Center, New York. "We shouldn't be much worried about the ACCORD results," he says.

He reviewed the ADVANCE study for WebMD but was not involved in it.

"The major result shown in this study is the 21% reduction in risk for kidney disease," he says. "That was major." Also major, he adds: "No evidence of increased risk of death in the intensive control group."

The ACCORD and ADVANCE studies were made up of different participants, he points out. "It is a different study," he says of the ACCORD study. Blood sugars were worse initially for patients in that study. "You are comparing apples and oranges."

Many unanswered questions remain, experts who reviewed the study for WebMD concur. ''The question that will probably not be answered by the data we have from the ACCORD trial is whether the problem is with the goal itself of an A1c of 6.4% or ... how you use the insulin to achieve that goal?" says Andrew Drexler, MD, director of the Gonda Diabetes Center at the University of California Los Angeles.

"Some patients appear to be only on long-acting insulin, others on short- and long-acting," Drexler says. "Which of those two strategies were used could potentially explain the difference in outcome, but that data does not appear to exist."

"Early and aggressive blood glucose control remains the optimum treatment approach for people with type 2 diabetes," says James Underberg, MD, clinical assistant professor of medicine at New York University Medical School, who also reviewed study results for WebMD. The ACCORD trial, he says, "was conducted in a select patient population, which is just not reflective of the majority of the millions of Americans with type 2 diabetes."

SOURCES: Anushka Patel, MBBS, SM, PhD, study director, ADVANCE trial and director, cardiovascular division, The George Institute for International Health, University of Sydney, Sydney, Australia. Spyros Mezitis, MD, endocrinologist, Lenox Hill Hospital; assistant professor of clinical medicine, New York Presbyterian-Cornell Medical Center, New York City. Hertzel Gerstein, MD, principal investigator, ACCORD Canadian Investigator and chair of the Glycemia Working Group; professor, McMaster University and Hamilton Health Sciences, Ontario, Canada. Andrew Drexler, MD, director, University of California Los Angeles Gonda Diabetes Center. Stephen MacMahon, PhD, co-principal investigator, ADVANCE; principal director, The George Institute for International Health; professor of cardiovascular medicine and epidemiology, University of Sydney, Australia. John B. Buse, MD, PhD, president of medicine and science, American Diabetes Association, Alexandria, Va. James Underberg, MD, clinical assistant professor of medicine, New York University Medical School. American Diabetes Association 68th annual Scientific Sessions, San Francisco, June 6, 2008. ACCORD Study Group, The New England Journal of Medicine, online June 6, 2008; vol 358: pp 2545-2559. ADVANCE Collaborative Group, The New England Journal of Medicine, online June 6, 2006; vol 358: pp 2560-2572. Dluhy, R. The New England Journal of Medicine, online June 6, 2006; vol 358: pp 2630-2633. Cefalul, W. The New England Journal of Medicine, online June 6, 2006; vol 358: pp 2633-2635. Krumholz, H. The New England Journal of Medicine, online June 6, 2006; vol 358: pp 2537-2539.

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