Groups collaborate with guidance on A1c levels

Just how low can A1c safely go in people with type 2 diabetes?

Researchers who pushed for very low blood glucose levels uncovered some surprising results recently, and three medical associations teamed up to provide clinical clarity.

Certain patients are more likely to be harmed than helped if physicians push for A1c levels much below 7%, according to a statement drafted by the American College of Cardiology, the American Diabetes Assn. and the American Heart Assn.

The Centers for Disease Control and Prevention estimates about 24 million Americans are affected by diabetes. As a result, most primary care physicians increasingly are caring for patients with this condition. And, while this new document did not advance any big treatment changes, some fine-tuning may be in order.

For instance, maintaining A1c levels at or below 7% should remain the goal for most people with diabetes. Numerous studies have found that this level reduces the risk of microvascular complications such as eye, kidney and nerve disease, according to the joint statement.

However, for patients with long-standing diabetes who are at heightened risk for cardiovascular disease, an A1c level of 7%, or a little above, is a good place to stop. Don't try to go lower, said Jay Skyler, MD, who headed the group that wrote the joint statement. With such a patient "you quit and you wouldn't push super hard." Dr. Skyler is a professor of medicine, pediatrics and psychology in the Division of Endocrinology, Diabetes and Metabolism at the University of Miami School of Medicine.

Several of the statement's authors, including Dr. Skyler, received research support from pharmaceutical companies or served as consultants and advisers. The statement was published online Dec. 17, 2008, by each of the associations.

Study results raised questions

The analysis was triggered by seemingly conflicting findings in major diabetes studies released last year. The ACCORD -- Action to Control Cardiovascular Risk in Diabetes -- trial was halted because patients subjected to aggressive lowering of A1c levels to less than 6% were more likely to die. The trial was designed to test conventional wisdom that the lower the A1c level, the better the chance of preventing heart attacks, which are the leading killers of people with diabetes.

Barely a week later, though, an analysis of data from the ADVANCE trial -- Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation -- were released with a different take-home message. Researchers found no evidence of increased deaths among participants who received aggressive treatment to lower their blood glucose levels.

A third trial, the Veterans Affairs Diabetes Trial, had results similar to ADVANCE. In addition, neither of these two studies found evidence of cardiovascular benefits.

"Given the confusion created by these conflicting results, we thought it imperative to review our recommendations for all people with diabetes," said Dr. Skyler. "What we conclude is that for most people with diabetes, there's no need to change treatment goals in light of these findings and many reasons to continue to strive for good glycemic control. But for some people with type 2 diabetes, depending on their history and current medical condition, it may be wise to make adjustments."

Daniel Einhorn, MD, vice president of the American Assn. of Clinical Endocrinologists, who had no role in the guidelines, agreed that "for some patients it may not be beneficial or it may be dangerous to go to very, very tight control."

A theme from recent studies is that glucose control is complicated, said Dr. Einhorn. "You can show benefit from blood pressure control within a year. You can show benefit of lipid control within two to three years. But showing benefit from glucose control may take a decade or more."

Although AACE has not changed its recommended A1c goal of 6.5% or lower, "now we add the qualifier that if you have more established cardiovascular disease or are at risk for hypoglycemia, a higher target might be suggested," said Dr. Einhorn.

Steven Nissen, MD, chair of the cardiovascular medicine department at the Cleveland Clinic, also advises against pushing patients lower than 7%. "If they have A1c levels of 7, leave them at 7," said Dr. Nissen, who had no role in the guidelines. He added that lowering A1c levels from 8% to 7% provides more benefit than going from 7% to 6%.

The closer patients get to A1c levels of 6% the more likely they are to experience hypoglycemia and other adverse effects, said Dr. Nissen. "Moderate control, which has always been recommended, makes a certain amount of sense."

As for why patients participating in the ACCORD trial died, hypoglycemia is mentioned most frequently. The authors of the statement reason: "Death from a hypoglycemic event may be mistakenly ascribed to coronary artery disease, since there may not have been a blood glucose measurement and since there are no anatomical features of hypoglycemia detected postmortem."

The jury also remains out on whether very low glucose levels protect patients' cardiovascular health. Study results have not shown that to be the case.

Dr. Nissen said clear evidence has never been found to support the belief that lowering A1c levels reduces cardiovascular risk. He believes the drugs used to lower glucose rates may play a role in the increased risk and proposed last year that the Food and Drug Administration adopt more rigorous standards for testing new drugs.

The agency now requires the manufacturers of new drugs and biologics for type 2 diabetes to show evidence their drugs do not pose increased heart risks. Until now the FDA had required manufacturers to show only that their drugs reduce blood glucose levels.