The Action in Diabetes and Vascular Disease: Pretarax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial was designed to investigate the effects of intensive glucose control on macro and microvascular complications in patients with type 2 diabetes. For that purpose, 11,140 patients with type 2 diabetes with mean glycated hemoglobin levels of 7.5% were randomized to either standard glucose control therapy or intensive glucose control therapy (gliclazide plus other glucose-lowering drugs). After a median follow-up of 5 years, the intensive therapy group achieved glycated hemoglobin levels of 6.5% compared to 7.3% in patients treated with the standard approach. Compared to the standard therapy group, the hazard ratio for future major micro or macrovascular events was 0.90 (95% CI, 0.82-0.98, p=0.01) and 0.86 (95% CI, 0.77-0.97, p=0.01) for major microvascular events only. There was no evidence for a reduction in major macrovascular events. The authors also found no evidence supporting the idea that the type of glucose-lowering therapy would influence macro or microvascular outcomes or death from any cause. Although severe hypoglycemia appeared to be scarce, patients in the intensive therapy group had increased risk of hypoglycemia [hazard ratio=1.86 (95% CI, 1.42-2.40, p<0.001)]. The authors concluded that the major benefit of the ADVANCE trial was the 20% reduction in renal complications, which underlines the importance of intensive therapy to prevent microvascular complications. Two editorials accompanied the publication of the ACCORD and ADVANCE trials in the latest issue of the New England Journal of Medicine. The first editorial, written by Dluhy and McMahon, highlighted the difference between the baseline characteristics of the study participants in both trials as well as the differences between medical treatments at study completion, an observation likely to have affected the outcomes of the trials. Based on the results of those trials, they suggested that the most appropriate target for glycated hemoglobin levels should remain 7% and that it could be lower if the intervention is focused on primary prevention of cardiovascular disease. They concluded their editorial by suggesting that clinicians who really care about their patients with type 2 diabetes should focus on lifestyle modification therapy such as smoking cessation as well as improving physical activity levels and dietary habits. As for pharmacotherapy, blood pressure control, aspirin, and statin use should not be neglected. The other editorial by Dr. William T. Cefalu also mentioned noticeable differences between the two trials. He also raised the following question: “Did the rate of decline in glycated haemoglobin contribute to the differences in reported cardiovascular outcomes between the two studies?” Moreover, as the potential benefits of achieving glycated hemoglobin levels below 7% in most patients with type 2 diabetes at low cardiovascular disease risk are currently unknown, Cefalu suggested that other clinical trials should be conducted in order to answer those specific scientific and clinical questions. Similar to the other editorial, he also mentioned that the target of 7% for glycated hemoglobin levels is the most appropriate target in this high-risk population.
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