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Semaglutide reduced cardiovascular events by 20% in adults with obesity or who are overweight, without diabetes mellitus, study results have shown.
The SELECT trial, results of which were published in the New England Journal of Medicine on 11 November 2023, included 17,604 patients who were overweight or had obesity and were aged over 45 years or older with pre-existing cardiovascular disease. Patients were assigned to receive 2.4mg of semaglutide or placebo weekly for a mean duration of 34 months.
Semaglutide is a glucagon-like peptide (GLP-1) receptor agonist, traditionally used for treatment of type 2 diabetes mellitus. In March 2023, NICE recommended use of semaglutide for weight management, alongside a reduced-calorie diet and increased physical activity through specialist NHS weight management services, for a maximum of two years.
The two-year prescribing limit led to some reservation among healthcare professionals owing to the relapsing nature of obesity.
In the study, researchers found that primary cardiovascular end points — cardiovascular deaths, non-fatal heart attack and non-fatal stroke — occurred in 569 patients (6.5%) in the semaglutide group, compared with 701 patients (8.0%) in the placebo group (hazard ratio 0.80; P<0.001).
Adverse events leading to discontinuation of the trial drug occurred in 1,461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001).
Commenting on the study, Paul Wright, lead cardiac pharmacist at Barts Health NHS Trust, said: “We have seen cardiovascular benefits [of semaglutide] outside of their benefits in diabetes.
“In addition to benefits of weight loss, this trial with longer follow up demonstrates reductions in cardiovascular events.
“A review of the cost effectiveness should be undertaken by NICE to review the previous direction to cap the duration at two years,” Wright added.
On 15 November 2023, a spokesperson for NICE told The Pharmaceutical Journal: “The patient population for this trial falls outside of the remit for our appraisal of semaglutide for managing overweight and obesity.
“We would have to consider it as a new topic and I believe the company would have to apply for an extension to their marketing authorisation,” they added.
On 15 November 2023, a spokesperson for Novo Nordisk, which manufactures semaglutide, told The Pharmaceutical Journal: “Novo Nordisk has filed for a label update of Wegovy® [semaglutide] in the UK, United States and EU to include an indication of reducing the risk of major adverse cardiovascular events (cardiovascular death, non-fatal heart attack or non-fatal stroke) in people with an initial BMI [body mass index] of 27 kg/m2 or greater and established cardiovascular disease.
“A decision is expected in 2024. We can’t provide further information about the duration of treatment at the moment,” they added.
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News of the recently published study on the effect of semaglutide on cardiovascular outcomes in people aged ≥45 years with cardiovascular disease (but not diabetes) and a BMI ≥27 kg/m2 has been widely reported in the medical and general media. The report in the PJ provides a brief overview of the trial results and presents the data on the primary composite outcome and the risk of discontinuing the trial because of adverse effects.
Unfortunately, the headline accompanying many of the news stories (including the one in the PJ) promotes the relative risk reduction in the primary composite endpoint of 20% rather than the more helpful absolute risk reduction of 1.5% .(1) To put this figure in context, 67 people would need to be treated for 34 months to prevent one primary endpoint event (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). For the individual components of the composite endpoint, the 95% confidence interval for the hazard ratio (HR) was less than 1 for only one of the three outcomes and the secondary endpoint of death from cardiovascular causes was not statistically significant:
Nonfatal myocardial infarction 2.7% vs 3.7% (HR 0.72, 95% CI 0.61 to 0.85)
Death from cardiovascular causes 2.5% vs 3.0% ( HR 0.85, 95% CI 0.71 to 1.01; p=0.07)
Nonfatal stroke 1.7% vs 1.9% (HR 0.93, 95% CI 0.74 to 1.15)
The data on adverse events leading to "permanent discontinuation of trial product" suggest that one person would discontinue treatment for every 12 people treated with semaglutide.
In October, DTB published an article (https://dtb.bmj.com/content/early/2023/10/25/dtb.2023.000007) in which Professor Joel Lexchin and Professor Barabara Mintzes explore the the evidence for semaglutide, discuss the hype surrounding the drug and highlight the need to tackle the other determinants of obesity. (2) They emphasise the importance of addressing the complex factors that contribute to the development of obesity rather than relying on medication as a damage limitation exercise.
It is important that we report the results from clinical trials in a balanced manner that allows readers to assess absolute risk reductions, relative risk reductions, numbers-needed-to-treat and numbers-needed-to-harm. We need to move beyond headlines that rely on data from company press releases.
1. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023. doi:10.1056/NEJMoa2307563. [Epub ahead of print 11 November 2023].
2. Lexchin J, Mintzes B. Semaglutide: a new drug for the treatment of obesity. Drug Ther Bull. 2023. doi:10.1136/dtb.2023.000007 [Epub ahead of print 25 October 2023].