Intensive glycemic control to prevent vascular events: contrasting ADVANCE and ACCORD results published

9 June 2008

MedWire News: Results of two important diabetes trials show differing results for the effects of intensive blood glucose control on cardiovascular complications in Type 2 diabetes.

The ACCORD and ADVANCE trials were presented at the ongoing American Diabetes Association annual scientific sessions and their results simultaneously published in an advance online publication by the New England Journal of Medicine.

TheACCORD (Action to Control Cardiovascular Risk in Diabetes) trial included 10,521 patients with Type 2 diabetes who were treated to a target glycated hemoglobin level of below 6.0% (intensive therapy) or between 7.0% and 7.9% (standard therapy).

As previously reported by MedWire News, the intensive therapy part of the trial was stopped early owing to higher mortality in the intensive therapy arm after 3.5 years of follow-up.

At 1 year, patients achieved stable median glycated hemogolobin levels of 6.4% and 7.5% in the intensive and standard therapy arms, respectively. During the 3.5-year follow-up there was a nonsignificant 10% reduction in the relative risk for the composite primary outcome of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes among those assigned to intensive therapy compared with the standard therapy group.

However, 5% of the intensive therapy patients died compared with 4% of the standard therapy group, representing a significant 20% increased relative risk for all-cause mortality.

The ACCORD investigators emphasized that they were unable to identify any subgroup at particular risk for death as a result of intensive therapy, having analyzed the data according to various factors including the treatment strategy used.

The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial was designed to test the impact of intensive glucose control on both macro- and microvascular complications of diabetes.

The study included 11,140 Type 2 diabetic patients who were randomly assigned to receive intensive therapy involving initial gliclazide to a target glycated hemoglobin level of 6.5% or less or to standard glucose control therapy.

At the end of follow-up, which lasted a median 5 years, mean glycated hemoglobin levels were 6.5% in the intensive group and 7.3% in the standard-control group.

The investigators report that the intensive therapy group had a significantly lower incidence of the primary endpoint of combined major macro- and microvascular events compared with the standard therapy group, at 18.2% versus 20.0%, equating to a 10% lower relative risk (p=0.01). This was due to a significant reduction in major microvascular events with intensive therapy (9.4% vs 10.9%, hazard ratio [HR]=0.86; p=0.01), which in turn was primarily due to a reduction in nephropathy (4.1% vs 5.2%, HR=0.79; p=0.006).

However, major macrovascular events or death from cardiovascular causes were not reduced with intensive therapy compared with standard therapy, at HRs of 0.94 and 0.88, respectively.

In contrast to ACCORD, there was no evidence in ADVANCE of an increase in deaths from any cause with intensive versus standard therapy, at a HR of 0.93.

Although uncommon, severe hypoglycemia occurred more frequently with intensivethan standard therapy, at 2.7% versus 1.5% (HR=1.86, p<0.001).

In one of three related editorials, Harlan Krumholz (Yale University, New Haven, Connecticut, USA) and Thomas Lee (Partners Healthcare System, Boston, Massachusetts, USA) discussed the implications of the contrasting ACCORD and ADVANCE results in terms of different treatment strategies and use of surrogate endpoints.

They wrote: "The risk-benefit ratio of interventions designed to modify risk factors can vary depending on the type and number of medications and other approaches that are concurrently incorporated. In particular, some medications may have beneficial or harmful effects beyond their effect on a risk factor."

Furthermore, they noted: "We are now beginning to appreciate that a strategy's effect on a risk factor may not predict its effect on patient outcomes."

N Engl J Med 2008; Advance online publication