The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial 1–5 was designed primarily to address, in patients with type 2 diabetes at high risk of cardiovascular events, whether intensive glucose control would result in a lower risk of atherosclerotic disease events or death than would standard treatment.
It was widely expected that intensive treatment would confer either modest benefit or, at worst, no benefit. However, the glucose-lowering arm of the trial was terminated early because of a higher mortality rate in the intensively treated group. (The ACCORD trial has two other arms, which concern blood pressure and lipid-lowering, and these are continuing.)
In earlier trials in type 2 diabetes, concerns had been raised about an increased risk of cardiovascular events and possibly death associated with glucose-lowering drugs, hypoglycemia itself, or both, and these were well known when ACCORD was convened. ACCORD was very carefully designed and included careful adjudication of each cardiovascular event and death, including whether hypoglycemia might have been a proximate cause of some sudden deaths. 5
Therefore, the surprising result of the higher mortality rate with intensive glycemic control in ACCORD will be fodder for discussion in many arenas over the next several years, and it poses some challenges for physicians and patients in determining treatment goals, as well as for organizations that write clinical practice guidelines (and perhaps organizations involved in pay-for-performance based on these guidelines).
Still, I believe that the ACCORD results should not substantially change our approach to treatment goals in type 2 diabetes, although hemoglobin A 1c targets below 6% may not have much added value for cardiovascular risk reduction. The low overall mortality rate in all the arms of the ACCORD trial emphasizes the importance of lifestyle modification, lipid and blood pressure therapy, and encouragement of aspirin use in all patients with type 2 diabetes.
This article reflects my views as a practicing diabetologist and clinical trialist (I was an investigator in the ACCORD trial) with a long-standing interest in clinical trials and in how the results influence clinical practice. The views I express herein may not reflect the views of other ACCORD investigators, the National Heart, Lung, and Blood Institute (NHLBI), the ACCORD trial coordinating center at Wake Forest University, or its data safety and monitoring board.
RISK OF CORONARY DISEASE INCREASES WITH GLUCOSE
Many observational studies 6–10 have shown that the risk of cardiovascular disease, especially coronary heart disease, is two to five times higher in people with diabetes mellitus than in people without diabetes. The risk appears to be continuous, so the higher one’s glucose or hemoglobin A 1c, the higher the risk. 6 This risk even extends to glucose values well below the threshold values currently used to diagnose diabetes mellitus. 6 Since there is no glucose threshold for coronary heart disease, the term dysglycemia (rather than hyperglycemia) has been proposed to note the relationship between glucose and coronary heart disease. (The glucose threshold for microvascular complications of diabetes, such as retinopathy and nephropathy, appears to be between 110 and 126 mg/dL).