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

Abstract

Objective: To evaluate the cardiovascular effects of semaglutide by baseline glycated hemoglobin (HbA1c) and change in HbA1c in a prespecified analysis of Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT).

Research design and methods: In SELECT, people with overweight or obesity and atherosclerotic cardiovascular disease without diabetes were randomized to weekly semaglutide 2.4 mg or placebo. The primary end point of first major adverse cardiovascular event (MACE) (cardiovascular mortality, nonfatal myocardial infarction, or stroke) was reduced by 20% with semaglutide versus placebo. Analysis of outcomes included first MACE, its individual components, expanded MACE (cardiovascular mortality, nonfatal myocardial infarction, or stroke; coronary revascularization; or hospitalization for unstable angina), a heart failure composite (heart failure hospitalization or urgent medical visit or cardiovascular mortality), coronary revascularization, and all-cause mortality by baseline HbA1c subgroup and categories of HbA1c change (<-0.3, -0.3 to 0.3, and >0.3 percentage points) from baseline to 20 weeks using the intention-to-treat principle with Cox proportional hazards.

Results: Among 17,604 participants (mean age 61.6 years, 72.3% male), baseline HbA1c was <5.7% for 33.5%, 5.7% to <6.0% for 34.6%, and 6.0% to <6.5% for 31.9%. Cardiovascular risk reduction with semaglutide versus placebo was not shown to be different across baseline HbA1c groups and was consistent with that of the overall study for all end points, except all-cause mortality. Cardiovascular outcomes were also consistent across subgroups of HbA1c change.

Conclusions: In people with overweight or obesity and established atherosclerotic cardiovascular disease but not diabetes, semaglutide reduced cardiovascular events irrespective of baseline HbA1c or change in HbA1c. Thus, semaglutide is expected to confer cardiovascular benefits in people with established atherosclerotic cardiovascular disease who are normoglycemic at baseline and/or in those without HbA1c improvements.

Graphical abstract

Figure 1

Time to first cardiovascular event for three-point MACE (A), expanded MACE (B), all-cause mortality (C), and heart failure composite (D) in the SELECT trial by baseline HbA_1c subgroups, in-trial analysis. Data are from the in-trial period and for the full analysis set. Subgroups are defined according to a prerandomization variable (baseline HbA_1c). MACE was defined as a composite of mortality from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. Expanded MACE was defined as mortality from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; coronary revascularization; or hospitalization for unstable angina. Heart failure composite was defined as mortality from cardiovascular causes, or hospitalization or urgent medical visit for heart failure. Cumulative incidence estimates are based on time from randomization to the first occurrence of each end point. Sema, semaglutide.

Figure 2

Time to first occurrence of cardiovascular outcomes (A) and first and recurrent occurrence of cardiovascular events (B) by baseline HbA_1c, in-trial analysis. Data are from the in-trial period and for the full analysis set. Subgroups are defined according to a prerandomization variable (baseline HbA_1c). For A, data show time from randomization to the first occurrence of each end point. Hazard ratios and 95% CIs are calculated in a Cox proportional hazards model with interaction between treatment groups and the relevant HbA_1c subgroup as fixed factors. For B, data are based on a Ghosh-Lin model for recurrent events with a termination event (all-cause mortality or noncardiovascular mortality) with treatment, subgroup, and treatment-by-subgroup interactions as fixed factors. The P value is a test of no interaction effect. HbA_1c groups with values converted to mmol/mol are <5.7%, <39 mmol/mol; 5.7% to <6.0%, 39 to <42 mmol/mol; and 6.0% to <6.5%, 42 to <47 mmol/mol. CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; Sema, semaglutide.

Figure 2

Time to first occurrence of cardiovascular outcomes (A) and first and recurrent occurrence of cardiovascular events (B) by baseline HbA_1c, in-trial analysis. Data are from the in-trial period and for the full analysis set. Subgroups are defined according to a prerandomization variable (baseline HbA_1c). For A, data show time from randomization to the first occurrence of each end point. Hazard ratios and 95% CIs are calculated in a Cox proportional hazards model with interaction between treatment groups and the relevant HbA_1c subgroup as fixed factors. For B, data are based on a Ghosh-Lin model for recurrent events with a termination event (all-cause mortality or noncardiovascular mortality) with treatment, subgroup, and treatment-by-subgroup interactions as fixed factors. The P value is a test of no interaction effect. HbA_1c groups with values converted to mmol/mol are <5.7%, <39 mmol/mol; 5.7% to <6.0%, 39 to <42 mmol/mol; and 6.0% to <6.5%, 42 to <47 mmol/mol. CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; Sema, semaglutide.

Figure 3

Time to occurrence of cardiovascular outcomes after 20 weeks by change in HbA_1c from baseline to week 20, in-trial analysis. Data are from the in-trial period and for the full analysis set. Subgroups are defined according to a postrandomization variable (change in HbA_1c from baseline to 20 weeks of treatment). Only individuals who reached the week 20 visit are included in this analysis. Hazard ratios and 95% CIs are calculated in a Cox proportional hazards model with interaction between treatment groups and the relevant HbA_1c subgroup as fixed factors. The P value is a test of no interaction effect. HbA_1c groups with values converted to mmol/mol are <5.7%, <39 mmol/mol; 5.7% to <6.0%, 39 to <42 mmol/mol; and 6.0% to <6.5%, 42 to <47 mmol/mol. CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; Sema, semaglutide.