Semaglutide and Cardiovascular Outcomes by Baseline and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT

OBJECTIVE To evaluate the cardiovascular (CV) effects of semaglutide by baseline and change in HbA1c in a prespecified analysis of SELECT. RESEARCH DESIGN AND METHODS In SELECT, people with overweight/obesity and atherosclerotic CV disease (ASCVD) without diabetes were randomized to weekly semaglutide 2.4 mg or placebo. The primary endpoint of first MACE (CV mortality, non-fatal myocardial infarction [MI], or stroke) was reduced by 20% with semaglutide versus placebo. First MACE, its individual components, expanded MACE (CV mortality, non-fatal MI or stroke, coronary revascularization, or hospitalization for unstable angina), a heart failure (HF) composite (HF hospitalization or urgent medical visit, or CV mortality), coronary revascularization, and all-cause mortality were analyzed by baseline HbA1c subgroup and categories of HbA1c change (<−0.3, −0.3 to 0.3, >0.3 %-points) from baseline to 20 weeks using the intention-to-treat principle using Cox proportional hazards. RESULTS Among 17,604 participants (mean age 61.6 years, 72.3% male), 33.5% had baseline HbA1c of <5.7%, 34.6% had 5.7-<6.0%, and 31.9% had 6.0-<6.5%. The CV risk reduction with semaglutide versus placebo was not shown to be different across baseline HbA1c groups and was consistent with the overall study for all endpoints, except all-cause mortality. CV outcomes were also consistent across subgroups of HbA1c change. CONCLUSIONS In people with overweight or obesity and established ASCVD but not diabetes, semaglutide reduced CV events irrespective of baseline or change in HbA1c. Thus, semaglutide is expected to confer CV benefits in people with established ASCVD who are normoglycemic at baseline and/or in those without HbA1c improvements.