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ACCORD Results Show Increased Mortality With Aggressive Diabetes Treatment

BETHESDA, Md -- June 9, 2008 -- Intensively targeting blood sugar to near-normal levels in adults with type 2 diabetes at very high risk for heart attack and stroke does not significantly reduce the risk of major cardiovascular events and actually increases the risk of death. Researchers from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) 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. 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 2 cardiovascular disease risk factors in addition to diabetes.

The first published results of the ACCORD trial of over 10,000 participants appear online in the New England Journal of Medicine today and will be in the June 12 print edition. The results are being presented at the American Diabetes Association (ADA) 68th Scientific Sessions in San Francisco on June 10.

Conducted at 77 sites nationwide and in Canada, ACCORD randomly assigned 10,251 participants aged between 40 and 79 years to standard or intensive blood sugar treatment goals. Therapy in both groups included patient education and counselling, and treatment with any of the major classes of US Food and Drug Administration-approved diabetes medications, as prescribed by their study clinician: metformin, thiazolidinediones (TZDs, primarily rosiglitazone), insulins, sulfonylureas, exenatide, and acarbose. Combinations of medications could be used as needed to reach the treatment goals.

Haemoglobin (Hb) A1C levels were used to monitor participants' blood sugar. The standard strategy group aimed to lower blood sugar levels to an Hb A1C of 7% to 7.9% -- a target similar to what is achieved, on average, by individuals treated for type 2 diabetes in the United States. The intensive strategy group had an Hb 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 Hb A1C level of 7.5% or higher. At study enrollment, one-half of the participants had an Hb A1C level over 8.1%.

Half of the participants in the standard strategy group achieved an Hb A1C less than 7.5%, and half of the intensive strategy group achieved an Hb 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 with 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.

To meet their more aggressive targets, participants in the intensive group used more medications, were more likely to use combinations of medications, and changed medications and/or doses of medications more frequently than those in the standard group. For example, 52% of participants in the intensive strategy group were on 3 oral medications plus insulin compared with 16% of participants in the standard strategy group. The intensive strategy was associated with more adverse side effects from medications, hypoglycaemia events, weight gain, and fluid retention.

The researchers also studied whether participants' characteristics at enrolment had an impact on their outcomes. They compared persons with and without existing cardiovascular disease, women and men, those aged older and younger than 65 years, those with Hb A1C levels lower and higher than 8%, and white and non-white participants. Death rates were consistently higher in the intensive strategy group regardless of baseline characteristics. However, compared with participants in the standard group, those in the intensive group who began the study with no history of heart attack or stroke, or with lower blood sugar levels had fewer combined cardiovascular events, such as fatal and nonfatal heart attacks or strokes, during the study.

"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," noted lead author Hertzel C. Gerstein, MD, MSc, Division of Endocrinology & Metabolism and Diabetes Care and Research Program at McMaster University and Hamilton Health Sciences, Hamilton, Ontario. "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."

ACCORD's ongoing studies of the effects of aggressively lowering blood pressure and treating multiple blood lipids in high-risk patients with diabetes are expected to continue through June 2009. Future analyses from ACCORD will determine the effects of the intensive blood sugar strategy on microvascular diseases, cognition, quality of life, and other outcomes in the study participants.


SOURCE: National Institutes of Health

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