Evidence of the Month

Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.

Eberhard Standl Munich Diabetes Research Group/Diabetes Research Institute Munich, Germany	Click here to download PowerPoint slides of this commentary.
	Click here for the programme evaluation and post-test.

Background
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was designed as a large-scale and long-term trial to directly assess the impact of glycaemic, lipid, and blood pressure control on reducing cardiovascular-related morbidity and mortality in individuals with Type 2 diabetes. The study was undertaken in response to epidemiological research and limited trials that had pointed to but had not definitively established a relationship between intensive glycaemic control and a reduction in the risk of macrovascular complications in individuals with Type 2 diabetes. Due to safety concerns the intensive glycaemic control treatment arm of the study was stopped 17 months early after a mean follow-up of 3.5 years.

Methods and Key Results
Inclusion criteria for this North American study included middle-aged or older individuals with Type 2 diabetes, an HbA_1c ≥7.5 %, and established cardiovascular disease or multiple cardiovascular risk factors. A total of 10,251 participants were randomized to intensive glucose control (target HbA_1c, <6.0 %) or standard glucose control (target HbA_1c, 7.0 % to 7.9 %). Subsets of participants were also randomized to blood pressure or lipid interventions. The primary outcome was a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular-related death.

Participants had a mean age of 62.2 years and a median HbA_1c of 8.1 %. Stable HbA_1c levels of 6.4 % and 7.5% were attained at 1 year in the intensive therapy group and the standard therapy group, respectively, and maintained throughout follow-up. A between-group comparison of the primary composite outcome was non-significant. The primary outcome occurred in 352 individuals in the intensive therapy group and 371 individuals in the standard therapy group (HR, 0.90; 95 CI, 0.78 to 1.04; P=0.16). However, significant differences were evident in the rates of individual cardiovascular events. In the intensive therapy group, the rate of cardiovascular-related death was higher (2.6% vs. 1.8%; HR, 1.35; 95% CI, 1.04 to 1.76; P=0.02), as was the rate of death from any cause (5.0% vs. 4.0%; HR, 1.22; 95% CI, 1.01 to 1.46; P=0.04). The rate of non-fatal myocardial infarction was lower in the intensive therapy group (3.6% vs. 4.6%; HR, 0.76; 95% CI, 0.62 to 0.92; P=0.004), and there was no significant difference between the intensive and standard therapy groups in the rate of non-fatal stroke (1.3% vs. 1.2%; HR, 1.06; 95% CI, 0.75 to 1.50; P=0.74). Those in the intensive therapy group had a significantly higher incidence of hypoglycaemia, weight gain, and fluid retention.

Clinical Implications
Adequately powered to assess the relationship between glycaemic control and cardiovascular risk in Type 2 diabetes, the ACCORD trial found that an intensive glycaemic control regimen targeting an HbA_1c level <6.0 % significantly increased the risk of death from any cause. Compared with the standard therapy group, the group receiving intensive therapy had a 22% relative increase in mortality and an absolute increase of 1%. Differences in mortality appeared 1 to 2 years following randomization. The reason for the higher mortality rate was not determined, although the study did not find that either hypoglycaemia or any single or combination of anti-diabetic drugs played a role. The significant decrease in myocardial infarctions contributed to a non-significant decrease in the primary outcome after about 3 years, perhaps indicating that any gain from intensive glucose lowering may take several years to appear, but this benefit carries with it an increased risk of death. On January 8, 2008, an independent data and monitoring committee decided that the increased risk of death from any cause with the intensive therapy outweighed any benefits and asked that the intensive therapy be stopped for safety reasons. Individuals receiving intensive glucose therapy were switched to standard glucose therapy. The blood pressure lowering and lipid lowering arms of the trial are being continued.