For Safety, NHLBI Changes Intensive Blood Sugar Treatment Strategy in Clinical Trial of Diabetes and Cardiovascular Disease
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has stopped one treatment within a large, ongoing North American clinical trial of diabetes and cardiovascular disease 18 months early due to safety concerns after review of available data, although the study will continue.
In this trial of adults with type 2 diabetes at especially high risk for heart attack and stroke, the medical strategy to intensively lower blood glucose (sugar) below current recommendations increased the risk of death compared with a less-intensive standard treatment strategy. Study participants receiving intensive blood glucose lowering treatment will now receive the less-intensive standard treatment.
The ACCORD (Action to Control Cardiovascular Risk in Diabetes) study enrolled 10,251 participants. Of these, 257 in the intensive treatment group have died, compared with 203 within the standard treatment group. This is a difference of 54 deaths, or 3 per 1,000 participants each year, over an average of almost four years of treatment. The death rates in both groups were lower than seen in similar populations in other studies.
"A thorough review of the data shows that the medical treatment strategy of intensively reducing blood sugar below current clinical guidelines causes harm in these especially high-risk patients with type 2 diabetes," said Elizabeth G. Nabel, M.D., director, NHLBI. "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."
In stopping this part of the trial, Nabel accepted the recommendation of the 10-member Data and Safety Monitoring Board (DSMB) — an independent advisory group of experts in diabetes, cardiovascular disease, epidemiology, patient care, biostatistics, medical ethics, and clinical trial design that has been monitoring ACCORD since it began. A specific charge of any DSMB is to monitor participant safety.
ACCORD participants will continue to receive blood sugar treatment from their study clinicians until the planned trial conclusion in June 2009. Those participants in the intensive treatment group will now be treated to the same A1C goals as those already in the standard treatment group.
The intensive treatment group had a target blood sugar goal, measured by hemoglobin A1C, of less than 6 percent. This is similar to blood sugar levels in adults without diabetes. The standard treatment group aimed for a target similar to what is achieved, on average, by those with diabetes in the United States (A1C of 7 to 7.9 percent) and lower than at study entry.
"The ACCORD findings are important, but will not change therapy for most patients with type 2 diabetes. Few patients with high cardiovascular risk like those studied in ACCORD are treated to blood sugar levels as low as those tested in this study, " said Judith Fradkin, M.D., director, Division of Diabetes, Endocrinology, and Metabolic Diseases at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "People with diabetes should never adjust their treatment plan or goals without consulting their health care providers."
In ACCORD, intensive treatment group participants achieved, on average, A1C values lower than standard treatment group participants. Half of the participants in the intensive treatment group achieved an A1C of less than 6.4 percent, and half of the participants in the standard treatment group achieved an A1C of less than 7.5 percent. The average blood sugar levels for both groups were lower than when they entered the study.
The ACCORD trial was designed to determine whether intensively lowering blood sugar would reduce the risk of cardiovascular events such as heart attack, stroke, or death from cardiovascular disease, specifically in people with type 2 diabetes who are at particularly high risk for a cardiovascular event. Prior studies suggested that reducing blood sugar to levels found in non-diabetic adults may reduce the rate of cardiovascular diseases among those with diabetes. However, a randomized clinical trial was needed to determine whether that hypothesis is accurate.
Conducted at 77 sites nationwide and in Canada, the trial includes adults between the ages of 40 and 82 at enrollment who, in addition to type 2 diabetes, also have two or more other risk factors for heart disease or had been diagnosed with heart disease before entering the study. Thus, participants were included in the ACCORD trial because they were at especially high risk — more risk than is associated with diabetes alone — for having a heart attack, stroke, or of dying from cardiovascular disease. Participants, who on average had diabetes for 10 years at enrollment, were randomly assigned to either standard (5,123 participants) or intensive (5,128) blood sugar treatment goals. They were also enrolled in one of two other ACCORD randomized clinical trials examining effects of treatments for blood pressure or blood lipids; those study components will continue. Participants had been followed for 2 years to 7 years at the time the intensive blood sugar control treatment was stopped.
These results from ACCORD do not apply to patients with type 1 (juvenile) diabetes, according to Fradkin. It is also unclear whether the results apply to patients with recently diagnosed type 2 diabetes or those whose cardiovascular risk is lower than the participants studied in ACCORD.
Most participants in the intensive treatment group achieved their lower blood sugar goals with combinations of Food and Drug Administration-approved diabetes medications. For both the intensive and standard treatment groups, study clinicians could use all major classes of diabetes medications available: metformin, thiazolidinediones (TZDs, primarily rosiglitazone), insulins, sulfonylureas, exanatide, and acarbose.