A Medical Device Daily
Intensively targeting blood sugar to near-normal levels in adults with Type 2 diabetes at especially high risk for heart attack and stroke does not significantly reduce the risk of major cardiovascular events, such as fatal or nonfatal heart attacks or stroke, but increases risk of death, compared to standard treatment.
Researchers from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) clinical trial compared a medical strategy aimed at near-normal blood sugar levels — below current recommendations — to a strategy to reach more standard blood sugar levels. Supported by the National Institutes of Health, the study evaluated the effects of intensively targeting blood sugar control among adults with established diabetes, high blood sugar levels, and pre-existing heart disease or at least two cardiovascular disease risk factors in addition to diabetes.
The first published results of the ACCORD trial of more than 10,000 participants appear in the New England Journal of Medicine (NEJM). The results were presented at the American Diabetes Association's (Alexandria, Virginia) 68th annual Scientific Sessions in San Francisco on June 10.
In February, the NIH's National Heart, Lung and Blood Institute (NHLBI) stopped the intensive blood sugar strategy after an average of 3.5 years of treatment, instead of the planned 5.6 years, due to safety concerns.
The intensive strategy group had a 22% higher risk of death — or 54 more deaths — compared to the standard group. The increased risk began emerging within 1 to 2 years after the strategy began to aggressively lower the participants' blood sugar levels. All participants now follow a medical strategy to reach the standard blood sugar levels while other components of the study continue.
"ACCORD is providing important evidence to help guide treatment recommendations for adults with established Type 2 diabetes who have had a heart attack or stroke or who have two or more risk factors for cardiovascular disease in addition to diabetes," said NHLBI Director Elizabeth Nabel, MD. "For these individuals, intensively lowering blood sugar to near-normal levels appears to be too risky."
The researchers caution that the results might not apply to patients who are at lower risk of cardiovascular disease than the ACCORD participants or to patients with more recently diagnosed type 2 diabetes. On average, ACCORD participants had been diagnosed with diabetes for 10 years at enrollment.
ACCORD's ongoing studies of the effects of aggressively lowering blood pressure and treating multiple blood lipids (cholesterol and triglycerides) in high-risk diabetic patients are expected to continue through June 2009.
"Adults with Type 2 diabetes are two to four times more likely than adults without diabetes to die from heart disease, so identifying the safest and most effective ways to help them lower their risk of heart disease, stroke, and death is critical," Nabel said.
An estimated 21 million Americans have diabetes and 284,000 die from it each year. Nearly 65% of deaths in persons with diabetes are from cardiovascular causes.
Conducted at 77 sites nationwide and in Canada, ACCORD randomly assigned 10,251 participants between the ages 40 and 79 (average age 62) to standard or intensive blood sugar treatment goals. Therapy in both groups included patient education and counseling, and treatment with any of the major classes of FDA-approved diabetes medications, as prescribed by their study clinician: metformin, thiazolidinediones (TZDs, primarily rosiglitazone), insulins, sulfonylureas, exanatide, and acarbose. Combinations of medications could be used as needed to reach the treatment goals.
Hemoglobin A1C levels, a standard measure of average blood sugar levels over the preceding two to three months, were used to monitor participants' blood sugar. The standard strategy group (5,123 participants) aimed to lower blood sugar levels to an A1C of 7% to 7.9% — a target similar to what is achieved, on average, by individuals treated for Type 2 diabetes in the U.S. The intensive strategy group (5,128 participants) had an A1C blood sugar target of less than 6% — similar to that found in adults without diabetes. To join the study, participants needed to have an A1C level of 7.5% or higher; at study enrollment, one-half of the participants had an A1C level over 8.1%.
Half of the participants in the standard strategy group achieved an A1C less than 7.5%, and half of the intensive strategy group achieved an A1C less than 6.4%. On average, participants in both groups achieved these levels within the first year of the study and maintained them throughout the study.
After an average of 3.5 years, 257 people in the intensive strategy group died, compared to 203 participants in the standard strategy group. This difference of 54 deaths resulted in a 22% increased death rate in the intensive group. Causes of death were similar in each group, with about half from cardiovascular conditions, such as heart attack, sudden cardiac death, stroke, or heart failure. However, the intensive group had 41 more cardiovascular deaths than the standard group, resulting in a 35% higher cardiovascular death rate.
"Despite detailed analyses, we have been unable to identify the precise cause of the increased risk of death in the intensive blood sugar strategy group," said lead author Hertzel Gerstein, MD. "Our analyses to date suggest that no specific medication or combination of medications is responsible. We believe that some unidentified combination of factors tied to the overall medical strategy is likely at play."
Gerstein holds the Population Health Research Institute Chair in Diabetes and is director of the Division of Endocrinology & Metabolism and Diabetes Care and Research Program at McMaster University and Hamilton Health Sciences (both Hamilton, Ontario).
The increased risk of death from the intensive strategy surprised researchers and other experts because earlier studies had shown that blood sugar at near-normal levels was associated with lower cardiovascular disease risk in people with Type 2 diabetes. However, these were observational studies, rather than randomized clinical trials, as they did not test treatments to reduce blood sugar. In addition, intensive blood sugar control has been shown in clinical trials to reduce microvascular complications from diabetes — including eye, kidney, and nervous system diseases — in people with Type 1 or Type 2 diabetes, and to lower cardiovascular disease risk in people with type 1 diabetes. However, the levels tested in other studies were not at as low as the level targeted in the ACCORD intensive treatment group.
The ADA clinical guidelines recommend that most people with Type 2 diabetes reach and maintain an A1C of less than 7%.