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Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in Individuals With Overweight/Obesity but Without Diabetes
TAKE-HOME MESSAGE
- In this prespecified analysis of the SELECT trial involving 17,604 individuals with atherosclerotic cardiovascular disease and overweight/obesity but without diabetes, semaglutide consistently reduced the risks of major adverse cardiovascular events and composite heart failure events, irrespective of baseline glycated hemoglobin or the degree of change in glycated hemoglobin over time.
- These findings support the implementation of semaglutide to reduce cardiovascular outcomes among individuals with overweight/obesity and established cardiovascular disease, irrespective of baseline glycemia or glycemic trajectory.
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
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.
Additional Info
Disclosure statements are available on the authors' profiles:
Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT
Diabetes Care 2024 Jun 22;[EPub Ahead of Print], I Lingvay, J Deanfield, SE Kahn, PE Weeke, H Toplak, BM Scirica, L Rydén, N Rathor, J Plutzky, C Morales, AM Lincoff, M Lehrke, OK Jeppesen, G Gajos, HM Colhoun, B Cariou, D RyanFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
GLP-1 receptor agonists improve cardiovascular outcomes in people with type 2 diabetes.1 The recently published SELECT study extended the evidence for the cardiovascular benefits of semaglutide in people with overweight or obesity and established cardiovascular disease and without diabetes.2 The primary outcome of SELECT, time to first major adverse cardiovascular events (MACE), was reduced by 20% with semaglutide versus placebo. The SELECT investigators now report a prespecified analysis of the effect of subcutaneously administered semaglutide 2.4 mg once-weekly compared with placebo on cardiovascular outcomes according to HbA1c levels at baseline and change in HbA1c during the trial.3
The main finding of this analysis was that there was a consistent reduction in MACE with semaglutide across all subgroups of baseline HbA1c (interaction P value = .89). The reduction in risk of individual MACE components and a composite of cardiovascular death and worsening heart failure events was consistent regardless of baseline HbA1c or the change in Hba1c levels from baseline at week 20. There was the suggestion of heterogeneity of the effect of semaglutide on all-cause mortality with a greater effect in people with a higher HbA1c level at baseline (interaction P value = .03).
This analysis provides more granular data from SELECT to support the cardiovascular benefits of semaglutide in the absence of diabetes regardless of the level of glycemia. Should this lead to a change in practice? Based on the results of SELECT, there is now evidence to support the initiation of semaglutide in people with overweight or obesity and established cardiovascular disease and without diabetes. However, until the global supply chain issues with GLP-1 receptor agonists are resolved, their use will still be unfortunately constrained.
References
These papers1,2 are secondary publications from the SELECT trial, a cardiovascular trial considered a landmark as the first demonstration of a reduction in major adverse cardiovascular events (MACE) among individuals with established cardiovascular disease and overweight or obesity but without diabetes. However, “secondary publication” should not be used to trivialize the additional observations derived from the SELECT population as these two papers expand our knowledge of the broad effects of semaglutide in cardiometabolic disease.
SELECT enrolled 17,604 individuals from 41 countries, with 72.3% being male and the average age being 61.6 years, and randomized them to weekly semaglutide 2.4 mg subcutaneously or placebo on a background of cardiovascular risk-reduction counseling. There was no weight-loss counseling; still, weight loss continued for 65 weeks and was 8.9% greater with semaglutide, remaining stable through 4 years. Both analyses looked at three categories of HbA1c (<5.7%, 5.7% to <6.0%, and 6.0% to <6.5%), from normoglycemia to two categories of prediabetes.
Kahn et al showed that, overall, at 3 years, semaglutide increased regression to normoglycemia approximately fourfold while reducing the risk of progression to diabetes by 73% compared with placebo, with 18.5 individuals needing to be treated to prevent one case of diabetes.1 As expected, individuals in the highest HbA1c category had the greatest absolute reduction in the risk for progression to diabetes with semaglutide. Weight-loss categories and their effect on glycemia progression or regression were also studied. This paper adds to the evidence that improvements in glycemia progression or regression with semaglutide are related to both weight loss effects and the independent effects of semaglutide on glycemia, as even those who lost less than 2% of weight in the semaglutide group experienced glycemic benefits.
The paper by Lingvay et al provides several interesting observations.2 Semaglutide reduced the risk of MACE and other cardiovascular outcomes independent of baseline HbA1c category — meaning that even individuals with normoglycemia experienced the benefits of MACE risk reduction. This study also looked at the effects of different degrees of HbA1c change on MACE (< −0.3 percentage points, −0.3 to 0.3 percentage points, >0.3 percentage points). Again, semaglutide reduced the risk of MACE independent of changes in HbA1c. Even those without HbA1c improvements showed MACE risk reduction with semaglutide.
These two studies add to our expanding appreciation of the multiple effects of semaglutide. Two prior secondary papers from SELECT document the weight loss3 and nephropathy4 benefits. Taken with these two papers, the SELECT analyses support that semaglutide is a powerful medication with multiple benefits in the cardio–renal–metabolic disease spectrum. We are encouraged by these demonstrations of broad benefits and are eager for more mechanistic analyses.
References