Semaglutide reduces cardiac risks in overweight and obese individuals without diabetes

Recently, a study was published in the journal Diabetes Care in which a group of researchers assessed the cardiovascular effects of semaglutide according to baseline glycated hemoglobin (HbA1c) levels and changes in HbA1c levels in a pre-specified analysis, Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT).

Increased rates of cardiovascular events are observed during the transition from normoglycemia to diabetes, with high fasting glucose levels and dysglycemia being independent predictors of adverse outcomes. High glucose levels contribute to the development of coronary artery disease, peripheral arterial disease, stroke, and heart failure. Lowering glucose levels within the target range is important for reducing cardiovascular risk. Although lifestyle changes, metformin, and thiazolidinediones improve risk factors, they have not reduced the rate of cardiovascular events in prediabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have reduced the rate of cardiovascular events in patients with type 2 diabetes and cardiovascular disease through mechanisms including reducing inflammation and improving risk factors. Further studies are needed to understand the mechanisms and effectiveness in different glycemic populations.

The SELECT study was a multicentre, randomised, double-blind, placebo-controlled evaluation of the effects of weekly 2.4 mg semaglutide compared with placebo on cardiovascular events in people with cardiovascular disease and who were overweight or obese without diabetes. The study was approved by regulatory and ethical authorities. Participants were required to be at least 45 years old, have a body mass index (BMI) of 27 kg/m² or higher, and have established cardiovascular disease. Patients with pre-existing diabetes, high HbA1c, recent use of antidiabetic agents, severe heart failure, renal failure, recent cardiovascular events or planned revascularisation were excluded.

Participants were randomized to receive semaglutide or placebo, with the dose gradually increasing to 2.4 mg. HbA1c levels were measured at baseline, week 20, and annually, categorized according to American Diabetes Association (ADA) and International Diabetes Advisory Committee recommendations.

The study included 17,604 participants, of whom 8,803 received semaglutide and 8,801 received placebo. Participants were evenly distributed across baseline HbA1c subgroups: 33.5% had an HbA1c <5.7%, 34.6% had an HbA1c of 5.7% to <6.0%, and 31.9% had an HbA1c of 6.0% to <6.5%. Baseline characteristics were similar across treatment groups within each HbA1c subgroup. Participants with higher baseline HbA1c levels had older age, higher BMI and waist circumference, and were more likely to have chronic heart failure, hypertension, and fatty liver disease. They were also more likely to be taking lipid-lowering drugs, diuretics, and antithrombotic agents.

The mean duration of follow-up and exposure to semaglutide or placebo were comparable across HbA1c groups. Semaglutide reduced the odds of MACE (major adverse cardiovascular events), with no significant differences between HbA1c subgroups. The hazard ratios for MACE were 0.82, 0.77, and 0.81 for the lowest and highest HbA1c subgroups, respectively. Cox regression showed no trend in treatment effect by baseline HbA1c level. The reduction in cardiovascular events was consistent across all endpoints, including expanded MACE, individual MACE components, coronary revascularizations, heart failure, hospitalizations, and emergency department visits for heart failure.

The reduction in all-cause mortality was significant in the subgroup with the highest baseline HbA1c (6.0% to <6.5%), with a hazard ratio of 0.64. The percentage of cardiovascular events was highest overall in the subgroup with the highest HbA1c in both treatment groups. For example, MACE occurred in 7.7%, 7.8%, and 8.5% of placebo-treated participants and 6.4%, 6.1%, and 7.0% of semaglutide-treated participants, in the subgroups with the lowest and highest HbA1c, respectively. Although the relative reduction in events was consistent, the absolute difference was greater for those with higher baseline HbA1c.

Sensitivity analyses using the treatment-based approach showed similar, albeit stronger, results. The interaction for all-cause mortality between HbA1c subgroups was not significant in the treatment-based analysis. There was no significant interaction in the treatment effect between HbA1c change subgroups. The hazard ratios for MACE were 0.83 for improved HbA1c, 0.84 for unchanged HbA1c, and 0.55 for worsened HbA1c in the within-study analysis. In the treatment-based analysis, the hazard ratios were 0.79, 0.71, and 0.27, respectively. Overall, 54% of participants receiving semaglutide experienced a decrease in HbA1c of at least 0.3 percentage points, while 86% of participants receiving placebo did not experience a significant change in HbA1c, limiting the power of the analysis due to skewed distribution and small numbers of events in some subgroups.

In the SELECT study, semaglutide reduced the risk of cardiovascular events in overweight or obese people with pre-existing cardiovascular disease, regardless 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 translate into reductions in cardiovascular events. The benefits of semaglutide are likely related to its pleiotropic effects, such as weight loss and improvements in cardiovascular risk factors, beyond glucose reduction. These results suggest that the cardiovascular benefits of semaglutide extend across the glycemic spectrum, including people with normal HbA1c and without significant improvements in HbA1c.