The SELECT trial of semaglutide in patients with overweight or obesity without diabetes: establishing a new pathway to secondary prevention of cardiovascular disease
Year: 2023
Type: article
Abstract: Overweight or obesity has been independently associated with increased cardiovascular risk, yet interventional trials of lifestyle or pharmacologic management strategies for overweight or obesity have uniformly failed to demonstrate a reduction in cardiovascular events.1 Agonists of the glucagon-like peptide-1 receptor (GLP-1RAs) affect a broad range of metabolic pathways associated with glucose metabolism, energy homeostasis, and inflammation2 and have shown efficacy in improving glycaemic control and reducing the incidence of major cardiovascular events among patients with type 2 diabetes.3 While these agents reduce bodyweight in people with or without diabetes, it was unknown whether they would improve cardiovascular outcomes outside the type 2 diabetes setting. The large-scale multicentre SELECT trial evaluated whether treatment with semaglutide, a potent long-acting GLP-1RA, would reduce the risk of major cardiovascular events among patients with overweight or obesity who did not have diabetes.4 A total of 17 604 patients with pre-existing cardiovascular disease and body mass index (BMI) of 27 kg/m2 or greater, but without diabetes, were randomized to once-weekly subcutaneous semaglutide 2.4 mg or matching placebo superimposed upon the evidence-based standard of care for underlying cardiovascular disease and associated risk factors. Over a mean of 39.8 months, semaglutide reduced the risk of a first event of the composite cardiovascular endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 20% (hazard ratio, 0.80; 95% confidence interval, 0.72–0.90; P < 0.001). The difference in cardiovascular disease incidence between semaglutide and placebo arms emerged very early after initiation of treatment, and the effects of semaglutide were concordant across cardiovascular endpoints and patient subgroups. There was no increase in rates of serious safety events with semaglutide. Mechanisms of cardiovascular benefit with semaglutide remain speculative but likely involve multiple pathways relating to physiologic effects of reduction in metabolically dysfunctional body fat, improvements in glycaemia and other cardiovascular risk factors, reductions in inflammation, and perhaps direct pharmacologic effects on vascular and platelet function.2 Irrespective of the mediators of benefit, the SELECT trial establishes overweight or obesity as a modifiable risk factor for cardiovascular disease. With a growing global epidemic of overweight and obesity affecting the cardiovascular disease burden, SELECT brings good news. SELECT suggests that the use of semaglutide in those with overweight or obesity should take its place alongside other standard evidence-based practices such as pharmacologic treatment of hypertension, diabetes, and dyslipidaemia for secondary atherosclerotic cardiovascular disease prevention. The SELECT trial was funded by Novo Nordisk. Conflict of interest: A.M.L. declares having received honoraria from Novo Nordisk, Eli Lilly, Akebia, Ardelyx, Becton Dickson, Endologix, Fibrogen, GlaxoSmithkline, Medtronic, Neovasc, Provention Bio, ReCor, Brainstorm Cell, Alnylam, and Intarcia for consulting activities and research funding to his institution from AbbVie, Esperion, Astra Zeneca, CSL Behring, Novartis, and Eli Lilly. D.H.R. declares having received consulting honoraria from Altimmune, Amgen, Biohaven, Boeringer Intelheim, Calibrate, Carmot Therapeutics, CinRx, Eli Lilly, Epitomee, Gila Therapeutics, Ifa Celtic, Novo Nordisk, Pfizer, Rhythm, Scientific Intake, Wondr Health, and Zealand; she declares she received stock options from Calibrate, Epitomee, Scientific Intake, and Xeno Bioscience. As this is a PharmaPulse article, no new data were generated or analysed in support of this research.
Authors: A Michael Lincoff, Donna H Ryan
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: Novo Nordisk
OpenAlex ID: W4389514280