NHLBI recommends early termination of the intensive blood sugar lowering strategy in the ACCORD trial

February 7, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [mailto:vkunadian@perfuse.org]

The National Heart, Lung and Blood Institute {NHLBI} has issued a press release today regarding the early termination of the intensive blood sugar lowering arm due to an increase in the number of deaths in this group compared to the standard less-intensive treatment arm in the ACCORD trial.

Diabetes mellitus is a major adverse risk factor for the development of cardiovascular disease. Specifically diabetic patients have diffuse multivessel coronary artery disease and microvascular dysfunction resulting in significant cardiovascular (CV) morbidity and mortality. There are over 20 million Americans who have diabetes mellitus and over a quarter of a million patients die as a result of this with more than half of the deaths related to cardiovascular causes.

The ACtion to COntrol Risk in Diabetes (ACCORD) trial was designed to determine the impact of intensive glycemic control on major adverse cardiovascular events among patients with type II diabetes mellitus in 77 clinical sites in the United States and Canada. This study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and by the National Institute of Health (NIH}. Many pharmaceutical companies are providing medications for the trial.

According to the February 6 NHLBI press release regarding the trial modification, a total of 10,251 patients aged 40-82 years have been enrolled in the ACCORD trial so far. There were 5,128 patients in the intensive treatment group and 5,123 patients in the standard less-intensive treatment group. Intensive glycemic control was achieved using the FDA approved hypoglycemic agents including metformin, rosiglitazone, sulphonyureas, exenatide, acarbose and insulin. Patients in this treatment group were to achieve a target HbA1C level of <6.0% compared to a target HbA1C level of 7-7.9% in the standard less-intensive treatment group. The primary endpoint of this trial consisted of major adverse cardiovascular events including non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. The primary result of this trial was anticipated to be available in 2010 with a mean follow-up of 5.6 years.

However, 18 months prior to the planned completion of this trial (in June 2009), the intensive glycemic treatment has been terminated today due to an increase in mortality in this group. In total, 257/5128 (5.01%) patients have died in the intensive treatment group compared to 203/5123 (3.96%) patients in the standard less-intensive treatment group. Half of the patients in the intensive and standard treatment groups achieved an HbA1C levels less than 6.5% and 7.5% respectively.

After carefully reviewing the data, the study’s Data Safety Monitoring Board decided to terminate this arm of the study. In the NHLBI press release, Dr. Elizabeth G. Nabel M.D., Director of NHLBI, stated, “Though we have stopped this part of the trial, we will continue to care for these participants, who now will receive the less-intensive standard treatment. In addition, we will continue to monitor the health of all participants, seek the underlying causes for this finding, and carry on with other important research within ACCORD.” These areas of reasearch on the effect on major CV events include: (1) a combination therapy of good glycemic control and good lipid control with fibrates and statins compared to statins alone among 5,518 patients and (2) using a combination therapy of good glycemic control and systolic blood pressure <120 mmHg compared to a systolic blood pressure <140 mm Hg alone among 4,733 patients in the study.

The press release also notes that after extensive evaluation of the ACCORD trial data, the investigators did not find a link to the cause of death among these patients (including an analysis consisting of rosiglitazone therapy).

Further information on the ACCORD trial could be obtained on the web pages of NHLBI. http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2551 http://www.nhlbi.nih.gov/health/prof/heart/other/accord/