What the ACCORD, ADVANCE trials reveal about diabetes treatment

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A change in diabetic treatment remains unclear. Source: Epsilon Group  

Near-normal glycemic control does not reduce cardiovascular events within a median of 3.5 to 5 years, based on the ACCORD and ADVANCE trials, published in the June 12 issue of the New England Journal of Medicine. However, the ACCORD trial was halted in February due to an unexpected increase in mortality rate, while the ADVANCE results confirmed the predicted reductions in new-onset microalbuminuria and nephropathy.

Both the ADVANCE (Action in Diabetes and Vascular Disease) and the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trials were presented this week at the American Diabetes Association meeting in San Francisco.

In the ACCORD trial, 10,251 randomized patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1 percent were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6 percent) or standard therapy (targeting a level from 7 to 7.9 percent). Of the patients, 38 percent were women and 35 percent had had a previous cardiovascular (CV) event. The primary outcome was a composite of nonfatal MI, nonfatal stroke or death from CV causes.

The finding of higher mortality in the intensive-therapy group led the National Heart, Lung and Blood Institute to discontinue intensive therapy after a mean of 3.5 years of follow-up in the ACCORD trial.

Nineteen of the 41 unexpected excess deaths from CV causes in ACCORD “may plausibly be related to or may have been precipitated by hypoglycemia and misclassified as having a CV cause. Combination therapies, such as a sulfonylurea with insulin, are known to be associated with an increased risk for hypoglycemia and appear to have been used routinely in this study,” said Robert G. Dluhy, MD, and Graham T. McMahon, MD, who wrote the accompanying editorial to both studies in the NEJM.

“If hypoglycemia was indeed a contributing cause of death in the ACCORD trial, future studies of cardiovascular risk reduction should focus on targeting near-normal glycemic levels with the use of strategies and therapies associated with a lower risk of hypoglycemia,” the editorial authors noted.

The ACCORD results showed that at one year, stable median glycated hemoglobin levels of 6.4 and 7.5 percent were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group. At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group. The authors noted that the difference in mortality emerged one to two years after randomization.

The ACCORD authors concluded that the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. They also noted that their findings have “identified a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes mellitus and high glycated hemoglobin levels.”

While the goals of both the ACCORD and ADVANCE trials were similar, the trials “differed substantially,” according to Dluhy and McMahon.

For example, the majority of patients in both studies received drugs from a variety of classes, with or without insulin.

In the ACCORD study, “there were no restrictions on glucose-lowering treatments to reach glycemic targets, whereas in the ADVANCE study, all patients in the intensive-control group were required to receive the sulfonylurea gliclazide (modified release) at initiation. Thiazolidinedione treatment was infrequent during the ADVANCE trial (less than 20 percent of participants), whereas rosiglitazone was used in 90 percent of the intensive-therapy group and in 58 percent of the standard-therapy group during the ACCORD trial,” Dluhy and McMahon wrote.

The ADVANCE researchers randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide plus other drugs as required to achieve a glycated hemoglobin value of 6.5 percent or less. The researchers said their primary end points were composites of major macrovascular events (death from CV causes, nonfatal MI or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy),