Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes

Study Questions:

What are the 5-year outcomes of intensive glucose lowering on mortality and key cardiovascular events?

Methods:

The investigators randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7-7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7-7.9% for all participants, who were followed until the planned end of the trial.

Results:

Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (p = 0.13), but had more deaths from any cause (primarily cardiovascular) (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.02-1.44) and fewer nonfatal myocardial infarctions (HR, 0.79; 95% CI, 0.66-0.95). These trends persisted during the entire follow-up period (HR for death, 1.19; 95% CI, 1.03-1.38; and HR for nonfatal myocardial infarction, 0.82; 95% CI, 0.70-0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups.

Conclusions:

The authors concluded that as compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions, but increased 5-year mortality.

Perspective:

The results of the ACCORD trial show that in persons who have a high risk of cardiovascular disease and suboptimally controlled long-standing diabetes, with good blood pressure and lipid control, an intensive therapeutic approach targeting normal glycated hemoglobin levels with the use of multiple medications is associated with higher mortality than is a standard approach targeting higher glycated hemoglobin levels. The higher risk of death from any cause and from cardiovascular causes in the intensive-therapy group would imply that a therapeutic approach that targets glycated hemoglobin levels below 6% should not be generally recommended in this population. Further analyses should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality.

Keywords: Hemoglobin A, Glycosylated, Myocardial Infarction, Follow-Up Studies, Blood Glucose, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors, Glucose


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