Looking Back at Look AHEAD Through the Lens of Recent Diabetes Outcome Trials
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Look AHEAD (Action for Health in Diabetes), the largest cardiovascular disease (CVD) outcomes trial of an intensive lifestyle intervention for weight loss in diabetes mellitus, was stopped on September 14, 2012, on the basis of a futility analysis of its composite primary end point (death from cardiovascular causes, nonfatal myocardial infarction [MI], nonfatal stroke, or hospitalization for angina) and recommendations from the Data and Safety Monitoring Board.1 Its results have been widely interpreted as evidence that weight loss with lifestyle intervention does not confer CVD benefits in patients with diabetes mellitus. In contrast, recent trials of pharmacological antihyperglycemic therapies, EMPA-REG Outcome with empagliflozin (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients),2 LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) with liraglutide,3 and SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) with semaglutide,4 demonstrated both weight loss and reduced cardiovascular morbidity and mortality. Before concluding that lifestyle modification does not provide cardiovascular benefit in patients with diabetes mellitus, whereas drug therapy does, it is important to examine closely the end points, participants, and interventions in Look AHEAD in comparison with those in the pharmaceutical trials (Table).