Overweight and obesity are independently associated with increased risk of cardiovascular events, but to date, there is a lack of evidence to prove that treating obesity itself can reduce the risk of cardiovascular outcomes.
With the emergence and increasing popularity of glucagon-like peptide 1 (GLP-1) agonists for the treatment of obesity in recent years, it might be worth investigating if these agents are able to reduce the cardiovascular risks associated with overweight and obesity, especially since they have been shown to reduce risk of major adverse cardiovascular events in patients with type 2 diabetes who are at high cardiovascular risk. Furthermore, previous trials on lifestyle and pharmacological interventions in patients with obesity or overweight have failed to show any benefit in cardiovascular outcomes. The SELECT trial aims to answer this question by investigating if Semaglutide will be superior to placebo when used in addition to standard of care in reducing the risk of major adverse cardiovascular events in obese or overweight patients without diabetes.
Patients recruited for this trial had to have a BMI of 27 or greater, with established cardiovascular disease (myocardial infarction, previous stroke or symptomatic peripheral arterial disease). Anyone with a previous diagnosis of diabetes or glycated haemoglobin of 6.5% or greater at screening was excluded. Patients in the treatment group were given subcutaneous Semaglutide once weekly, starting at 0.24mg daily and increasing the dose every 4 weeks to 0.5mg, 1.0mg, 1.7mg to the target dose of 2.4mg at 16 weeks. If patients could not tolerate the increased dose, either the dosing interval would be increased or a maintenance dose below 2.4mg would be used.
A total of 17,604 patients were recruited, with 8803 in the treatment group and 8801 in the placebo group. The majority of the patients in both groups had myocardial infarction as the only cardiovascular event. The mean baseline lipid levels and blood pressure readings were within the normal range, with most patients receiving lipid-lowering medications and platelet aggregation inhibitors. The mean follow-up period was 39.8 months,
Efficacy and Safety
The results showed that Semaglutide use was associated with a 20% risk reduction in the composite of death from cardiovascular causes, nonfatal myocardial infarction or non-fatal stroke. These benefits were also seen early after initiation. Secondary endpoints such as death from cardiovascular causes and heart failure composite (death from cardiovascular causes, hospitalization or an emergency visit due to heart failure) also occurred less frequently in the Semaglutide group, however these results were not statistically significant.
16.6% of the patients in the Semaglutide group permanently discontinued treatment due to adverse events, compared to 8.2% in the placebo group. The common adverse events leading to discontinuation were gastrointestinal disturbances such as nausea, diarrhea and vomiting and these adverse events frequently occurred during initiation or dose escalation. The incidence of serious adverse events were similar across both groups, reinforcing the safety of Semaglutide in these populations.
What this trial adds to the current evidence
The results of this trial have proven the additional benefit of cardiovascular risk reduction, in addition to weight loss effects of Semaglutide. The mechanism through which Semaglutide was able to reduce cardiovascular risks could be related to its effects of body weight and abdominal circumference, as this will help reduce glucose levels and even ectopic adipose tissue depots which may contribute to atherosclerosis and myocardial dysfunction. Reductions in excess abnormal body fat also reduce systemic proinflammatory and prothrombotic milieu associated with obesity. In addition, the use of Semaglutide has been associated with changes in multiple biomarkers of cardiovascular risk, such as blood pressure, waist circumference, glycemic control, lipid levels and C-reactive protein. With all these combined, we can hypothesise that the mechanism in which Semaglutide reduces cardiovascular outcomes is via multiple interrelated pathways. While the results of these trials are encouraging, it is still unknown if these benefits can be seen in overweight or obese patients without prior cardiovascular events, which could be a possible patient group to investigate in future. Something interesting to also explore is if these benefits can be replicated with other GLP-1 agonists as well, to determine if this is a class effect or something unique to Semaglutide.
Reference:
- Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine. 2023; doi:10.1056/nejmoa2307563
