Setting: 77 clinical centers in the U.S. and Canada.
Synopsis: 10,251 diabetic patients with established cardiovascular disease or additional cardiovascular risk factors, and median glycated hemoglobin level of 8.1%, received either intensive therapy (targeting glycated hemoglobin level <6.0%) or standard therapy (targeting level from 7.0% to 7.9%). The primary outcome was a composite of non-fatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes.
Data indicated intensive therapy did decrease the rate of non-fatal myocardial infarctions, however, it did not significantly reduce the primary composite of major cardiovascular events. Moreover, intensive therapy resulted in a significant increase in death from cardiovascular causes, as well as a relative increase of 22% of death from any cause, during follow up of three and a half years. Due to this finding, the intensive therapy regimen was discontinued 17 months before the scheduled end of the study.
Analysis of the data has not identified a cause for the unexpected increased mortality in the intensive therapy group, and has not shown any medication or combination of medications to be responsible.
Bottom Line: Intensive glucose-lowering therapy in diabetic patients at high risk for cardiovascular events increased mortality and did not significantly reduce major cardiovascular events.
Citation: Action to control cardiovascular risk in diabetes study group. Effects of intensive glucose lowering in type-2 diabetes. N Engl J Med. 2008;358:2545-2559.
Clinical Question: Does intensive glucose-lowering therapy decrease major macrovascular and microvascular events in high-risk diabetic patients?
Background: Prospective studies show a direct association between elevated glycated hemoglobin levels in diabetics and increased risk of vascular events. However, definitive evidence from randomized trials about the role of intensive glucose control in preventing vascular disease in diabetics is lacking.
Study Design: Multicenter randomized controlled trial led by the ADVANCE Collaborative Group.
Setting: 215 clinical centers in 20 countries from Asia, Australia, Europe, and North America.
Synopsis: 11,140 diabetic patients received either standard glucose therapy or intensive glucose therapy using gliclazide, as well as other drugs, to reach a targeted glycated hemoglobin of 6.5% or less. The primary outcome was a composite of major macrovascular and microvascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, death from cardiovascular causes, nephropathy, and retinopathy.
Intensive glucose-lowering therapy, as compared to standard therapy, resulted in a 21% relative reduction of new or worsening nephropathy. There was no significant effect on the rate of MI, strokes, death from cardiovascular causes, or retinopathy. Furthermore, intensive glucose control was associated with an increased risk of severe hypoglycemia and increased rate of hospitalization. In contrast to the ACCORD study, intensive therapy did not result in an increase in mortality.
Bottom Line: While targeting normal glycated hemoglobin levels with a gliclazide-based regimen reduced the rate of nephropathy, this strategy did not have an effect on preventing major macrovascular events.
Citation: ADVANCE collaborative group. Intensive blood glucose control and vascular outcomes in patients with type-2 diabetes. N Eng J Med. 2008;358:2560-2572.