In a recent study published in the journal Diabetes Care, a group of researchers evaluated 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).
Study: Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT. Image Credit: Douglas Cliff / Shutterstock
Background
The prevalence of cardiovascular events increases from normoglycemia to diabetes, with elevated fasting glucose and dysglycemia as independent predictors of adverse outcomes. High glucose levels contribute to coronary artery disease, peripheral artery disease, stroke, and heart failure. Lowering glucose within a target range is crucial for cardiovascular risk reduction. While lifestyle changes, metformin, and thiazolidinediones improve risk factors, they have not reduced cardiovascular events in prediabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have reduced cardiovascular events in type 2 diabetes patients with cardiovascular disease through mechanisms like reduced inflammation and improved risk factors. Further research is needed to understand the mechanisms and efficacy across different glycemic populations.
About the study
The present SELECT trial was a multicenter, randomized, double-blind, placebo-controlled study assessing the effect of weekly 2.4 mg semaglutide versus placebo on cardiovascular events in individuals with cardiovascular disease and overweight or obesity without diabetes. Approved by regulatory and ethics authorities, the trial required participants to be at least 45 years old with a body mass index (BMI) of 27 kg/m² or higher and established cardiovascular disease. Exclusions included prior diabetes, high HbA1c, recent glucose-lowering medication use, severe heart failure, renal disease, recent cardiovascular events, or planned revascularization.
Participants were randomized to semaglutide or placebo, with dose escalation to 2.4 mg. Completion rates were high, with 97.1% for semaglutide and 96.8% for placebo. Cardiovascular care standards were maintained, and healthy lifestyle counseling was provided. HbA1c was measured at baseline, week 20, and annually, categorized per American Diabetes Association (ADA) and International Expert Committee guidelines.
Endpoints included major adverse cardiovascular events (MACE), expanded MACE, individual MACE components, all-cause mortality, and heart failure outcomes. Statistical analyses utilized Cox proportional hazards models for time-to-event endpoints, considering baseline HbA1c and HbA1c changes.
Study results
In the trial, 17,604 participants were randomized, with 8,803 receiving semaglutide and 8,801 placebo. Participants were evenly distributed across baseline HbA1c subgroups: 33.5% had HbA1c <5.7%, 34.6% had HbA1c between 5.7% and <6.0%, and 31.9% had HbA1c between 6.0% and <6.5%. Baseline characteristics were similar across treatment groups within each HbA1c subgroup. Participants with higher baseline HbA1c were older, had higher BMI and waist circumference, and were more likely to have chronic heart failure, hypertension, and fatty liver disease. They were also more frequently treated with lipid-lowering medications, diuretics, and antithrombotic agents.
The mean follow-up duration and exposure to semaglutide or placebo were consistent across HbA1c groups. Semaglutide reduced the likelihood of MACE, with no significant differences across HbA1c subgroups. The hazard ratios for MACE were 0.82, 0.77, and 0.81 for the lowest to highest HbA1c subgroups, respectively. Cox regression analysis showed no trend in treatment effect with respect to baseline HbA1c. The reduction in cardiovascular events was consistent across all endpoints, including expanded MACE, individual MACE components, coronary revascularizations, heart failure composite, heart failure hospitalizations, and urgent care visits for heart failure.
All-cause mortality reduction was significant in the highest baseline HbA1c subgroup (6.0% to <6.5%), with a hazard ratio of 0.64. The proportion of cardiovascular events was generally highest in the highest HbA1c subgroup in both treatment groups. For instance, MACE occurred in 7.7%, 7.8%, and 8.5% of placebo participants and 6.4%, 6.1%, and 7.0% of semaglutide participants across the lowest to highest HbA1c subgroups. Although relative event reduction was consistent, the absolute difference was greater for those with higher baseline HbA1c. When accounting for competing events, no interaction across baseline HbA1c subgroups was found in recurrent cardiovascular events.
Sensitivity analysis using an on-treatment approach yielded similar, albeit more robust, findings. The interaction for all-cause mortality across HbA1c subgroups was not significant in the on-treatment analysis. There was no significant interaction in treatment effect across subgroups of HbA1c change. Hazard ratios for MACE were 0.83 for improved HbA1c, 0.84 for unchanged HbA1c, and 0.55 for worsened HbA1c in the in-trial analysis. In the on-treatment analysis, hazard ratios were 0.79, 0.71, and 0.27, respectively. Overall, 54% of semaglutide participants had a reduction in HbA1c of at least 0.3 percentage points, while 86% of placebo participants had no significant HbA1c change, limiting the power of the analysis due to uneven distribution and the small number of events in some subgroups.
Conclusions
To summarize, in the SELECT trial, semaglutide reduced cardiovascular event risk in people who were overweight or obese and had preexisting cardiovascular disease independent of baseline HbA1c. Event rates were lower in normoglycemic participants, but the relative risk reduction was consistent across HbA1c groups. Changes in HbA1c did not impact cardiovascular event reduction. The benefits of semaglutide are likely due to its pleiotropic effects beyond glucose-lowering, such as weight reduction and improved cardiovascular risk factors. These findings suggest semaglutide's cardiovascular benefits extend across the glycemic spectrum, including those with normal HbA1c and without significant HbA1c improvements.
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