Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

To the Editor: In reporting the results of the Trial to Evaluate Cardiovascular and Other Longterm Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6), Marso et al. (Nov.10 issue) 1 describe a lower rate of cardiovascular events among patients with type 2 diabetes mellitus who received the glucagon-like peptide 1 (GLP-1) analogue semaglutide than among patients who received placebo.Their results are consistent with those in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, 2 which assessed the effects of another GLP-1 analogue, liraglutide.In SUSTAIN-6, the use of insulin at trial entry was similar between the two groups.However, during the LEADER trial, the use of insulin was approximately two times higher in the placebo group than in the liraglutide group, and during SUSTAIN-6, the use of insulin was approximately three times higher in the placebo group than in the semaglutide group.The significantly greater use of insulin in the placebo groups in these two trials may, at least in part, explain the increase in the risk of death from any cause as well as the increase in the risks of heart failure, cardiovascular events, renal failure, and hypoglycemia in these two groups.Hazard ratios for these events associated with increased use of insulin range from 1.23 to 4.57, as shown in two cohort studies in primary care. 3,4Thus, we wonder whether the greater use of insulin in the placebo groups than in the liraglutide and semaglutide groups during these trials may have amplified the beneficial effects of liraglutide and semaglutide.