ADA 2008: ACCORD trial reveals increased risk of death

June 8, 2008

An intense glucose-lowering strategy in high-risk patients with type 2 diabetes was associated with an excess of mortality in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, the U.S. counterpart to the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) study.

This in contrast with ADVANCE, vis-a-vis intensive glucose control in high-risk patients with type 2 diabetes

An intense glucose-lowering strategy in high-risk patients with type 2 diabetes was associated with an excess of mortality in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, the U.S. counterpart to the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) study.

ADVANCE was conducted in 20 countries from Asia, Australia, Europe, and North America. In that trial, intensive glycemic control significantly reduced the risk of kidney disease in type 2 diabetes and had no effect on overall mortality or cardiovascular disease (CVD) events.

ACCORD was sponsored by the National Heart, Lung, and Blood Institute. This trial was terminated prematurely because an interim safety review identified an increase in death in the intensively treated group (hemoglobin [Hb] A1c goal < 6%) compared with standard glycemic control (HbA1c goal of 7.0 to 7.9%).

ACCORD included 10,251 high-risk middle-aged or older adults (mean age: 62 years) with type 2 diabetes from the United States and Canada. The participants were considered at high risk by virtue of a prior myocardial infarction (MI) or stroke (35%) or subclinical CVD or major cardiovascular risk factors (at least two of the following: elevated low-density lipoprotein cholesterol, a low level of high-density lipoprotein cholesterol, hypertension, an elevated body mass index, or cigarette smoking). The achieved HbA1c levels in the two treatment strategies were 6.4% in those randomized to the intensive strategy and 7.5% in the subjects randomized to standard glycemic control.

Patients assigned to the intensive strategy had clinic visits every 2 months and were required to monitor their blood glucose levels two to four times daily. Patients assigned to standard control had clinic visits every 4 months and were required to do self-monitoring only once a day.

Fifty-two percent of patients in the intensively treated group required treatment with insulin plus three oral agents to achieve their glycemic target, compared with 16% in the standard group. Choice of therapy was at the discretion of the treating physician.

During 3.5 years of follow-up (planned follow-up was 5 years), 257 (5.1%) patients in the intensive group died, compared with 203 (4.0%) in the standard control group, representing a 22% increase (p = 0.04) in the group randomized to the intensive strategy. There was no subgroup identified among intensively treated patients that was more likely to die in response to intensive therapy.

The primary outcome of the trial, ie, the first occurrence of a major fatal or nonfatal cardiovascular event, was achieved by 10% fewer patients assigned to the intensive strategy, but this difference failed to achieve statistical significance (p = 0.16).

Intensive therapy was associated with a 35% increase (p = 0.02) in cardiovascular death and a 24% reduction (p = 0.004) in nonfatal MI. There was no difference between the two strategies in the occurrence of nonfatal stroke or heart failure.