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), assessed both jointly and separately.

After a median five-year follow-up, the ADVANCE researchers found that the mean glycated hemoglobin level was lower in the intensive-control group (6.5 percent) than in the standard-control group (7.3 percent). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1 vs. 20 percent with standard control), as well as that of major microvascular events (9.4 vs. 10.9 percent), primarily because of a reduction in the incidence of nephropathy (4.1 vs. 5.2 percent), with no significant effect on retinopathy.

The ADVANCE results revealed no significant effects of the type of glucose control on major macrovascular events death from cardiovascular causes or death from any cause. The authors noted that severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7 vs. 1.5 percent in the standard-control group).

Among the other differences, Dluhy and McMahon noted that thiazolidinediones “were widely prescribed during the ACCORD trial (92 percent in the intensive-therapy group vs. 58 percent in the standard-therapy group, with rosiglitazone used almost exclusively) but were administered more sparingly in the ADVANCE trial (17 percent in the intensive-control group vs. 11 percent in the standard-control group).”

Dluhy and McMahon said that with secondary analyses is necessary “to investigate whether particular combinations of medicines, glucose patterns or coexisting risk factors can predict an increased mortality in patients with diabetes.”

However, the editorial authors noted that while “improved glucose control can clearly protect against the development of microvascular complications, the absence of a reduction in macrovascular events implicates an additive effect of nonglycemic risk factors that often accompany diabetes, such as hypertension, hyperlipidemia and hypercoagulability.”

The results of the ACCORD and ADVANCE studies should be interpreted in the context of comprehensive care of patients with diabetes: “There is clear evidence that aspirin, a statin and the targeted lowering of blood pressure are each associated with substantial reductions in cardiovascular risk in patients with diabetes; there may be even greater benefit when these reductions are achieved together,” Dluhy and McMahon concluded.

For specific treatment, they recommended the “most appropriate target for glycated hemoglobin should remain 7 percent, though lower individualized targets may be appropriate when the focus is primary prevention of macrovascular disease.”

“Neither the ADVANCE trial nor the ACCORD trial undermines the importance of meeting the current guidelines for care, and they should not be interpreted as diminishing the importance of glycemic control. The lower-than-anticipated rate of cardiovascular events seen in the intensive-treatment group and the standard-treatment group in these studies is an affirmation of the success of modern therapeutics, even when incompletely implemented,” Dluhy and McMahon concluded.