ACCORD and ADVANCE Trials

The ACCORD and ADVANCE Trials: Implications for Patients with Type 2 Diabetes
Interventions that produced improvements in microvascular measures did not produce improvements in patient-important outcomes.

In patients with diabetes, high glycated hemoglobin (HbA1c) levels are associated with elevated risks for cardiovascular events and death. Some, but not all, studies have shown that lowering HbA1c levels reduces cardiovascular risk, and these data have been used to support current guidelines that recommend a target HbA1c level of 7.0%. To further investigate the effect of tight glucose control on cardiovascular outcomes in high-risk patients with type 2 diabetes, two studies were conducted: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

In the ACCORD trial, 10,251 type 2 diabetic patients (mean age, 62; 38% women) were randomized to receive intensive glucose-lowering therapy (target HbA1c, <6.0%) or standard therapy (target HbA1c, 7.0%–7.9%). The primary outcome was a composite of nonfatal MI, nonfatal stroke, and cardiovascular-related death. The glucose-control arm of the 2x2 factorial design study was discontinued after 3.5 years of follow-up because of a greater number of deaths among patients receiving intensive therapy than among those receiving standard therapy (257 vs. 203; hazard ratio [HR], 1.22; P=0.04) (JW Cardiol Feb 13 2008).

Within 4 months after randomization, median HbA1c levels decreased more in the intensive-therapy group (from 8.1% to 6.7%) than in the standard-therapy group (from 8.1% to 7.5%); at 1 year, median HbA1c levels had stabilized (at 6.4% and 7.5%, respectively). Thiazolidinediones were used by 92% of patients in the intensive-therapy group versus 58% of those in the standard-therapy group; the use of other glucose-lowering treatments was also more common in the intensive-therapy group. The primary outcome occurred in 6.9% of patients in the intensive-therapy group and in 7.2% of those in the standard-therapy group (HR, 0.90; P=0.16), but hypoglycemia was more common among intensive-therapy patients (10.5% vs. 3.5%; P<0.001). The higher mortality rate associated with intensive therapy could not be explained by severe hypoglycemia, differences in drug use, or weight change. Microvascular events were not reported.

In the ADVANCE trial, 11,140 type 2 diabetic patients (mean age, 66; 43% women) were randomized to intensive therapy (target HbA1c, <6.5%) or standard therapy (target HbA1c defined by local guidelines). The primary outcomes, redefined during the study, were a composite of major macrovascular events (nonfatal MI, nonfatal stroke, or cardiovascular-related death) as well as separate and joint assessments of major microvascular events (nephropathy and retinopathy).

Mean HbA1c levels at study’s end (median follow-up, 5.0 years) decreased more in the intensive-therapy group (7.5% to 6.5%) than in the standard-therapy group (7.5% to 7.3%). Again, both thiazolidinediones and other treatments were used by a higher proportion of intensive-therapy patients than standard-therapy patients (17% vs. 11%). Macrovascular events occurred at a lower rate in patients receiving intensive therapy (10.0% vs. 10.6%; HR, 0.94; P=0.3), as did microvascular events (9.4% vs. 10.9%; HR, 0.86; P=0.01). Mortality was slightly lower in the intensive-therapy group (8.9% vs. 9.6%; HR, 0.93; P=0.3). Severe hypoglycemia was more common among intensive-therapy patients (2.7% vs. 1.5%; HR, 1.86; P<0.001).

Comment:
These two studies, involving different strategies with different patterns of medication use, fail to support the hypothesis that tight glucose control in patients with type 2 diabetes will reduce their risk for macrovascular complications. Moreover, the strategies were associated with an increased risk for hypoglycemia in both studies and with higher mortality in ACCORD. The lower risk for microvascular complications in ADVANCE (this outcome was not reported in ACCORD) was the only favorable finding. The bottom line is that these studies will cause a reexamination of guidelines and performance measures and are further evidence that knowing the effect of a strategy on a surrogate outcome, such as a risk factor, does not always tell you the effect on patients.

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Harlan M. Krumholz, MD, SM
Published in Journal Watch Cardiology June 6, 2008

Citation(s):

1. Patel A et al. for the ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008 Jun 6; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0802987).
2. Gerstein HC et al. for the Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008 Jun 6; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0802743).