Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Nov 11. doi: 10.1056/NEJMoa2307563.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown.

METHODS: In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.

RESULTS: A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001).

CONCLUSIONS: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT number, NCT03574597.).

Ratings by Clinicians (at least 3 per Specialty)
Specialty Score
Internal Medicine
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Special Interest - Obesity -- Physician
Comments from MORE raters

Endocrine rater

Although it is not surprising that a potent weight-loss medication such as semaglutide lowered CV events in persons with obesity and pre-existing CVD, this trial provides high-quality evidence to support weight loss for CV benefit. The NNT was reasonable at 66 over 3 years; however, the adverse events leading to discontinuation were high (NNH 11 over 3 years).

Family Medicine (FM)/General Practice (GP) rater

Not a surprising result. Many other studies on GLP-1 agents in persons without diabetes having similar benefits to those seen in persons with diabetes.

Family Medicine (FM)/General Practice (GP) rater

This study provides us with yet another indication for the GLP-1, semaglutide. The demand for this drug is already through the roof, primarily because of its use for weight reduction. The NNT for the composite outcome appears to be 66. The drug costs to achieve this would be substantial.

General Internal Medicine-Primary Care(US) rater

I think most primary care physicians won't know this without having read this article, but most will have suspected this finding is the case. This benefit may extend into even lower BMI groups. Now, how are we going to pay for all the GLP-1 meds since half the population have an indication for treatment?

General Internal Medicine-Primary Care(US) rater

Although the title says, "Obesity without Diabetes", two thirds of the patients had pre-diabetes (A1c >5.7%), so the benefits may be primarily through better glycemic control. It is also noteworthy that the curves comparing outcomes seem to be diverging more over time, so the benefits may be larger with longer follow-up than evaluated in the study. The biggest issue will be cost and coverage given that semaglutide currently costs about $1000 a month.

General Internal Medicine-Primary Care(US) rater

This large study of 17,000 patients, half on 2.4 mg semaglutide and half on placebo, examined the effect of this drug on death, MI, and CVA in patients with prior vascular disease manifested by MI, CVA, or PVD. It demonstrated a 20% reduction in these adverse outcomes (from 8% to 6.5%) with acceptable significant side effects.

Internal Medicine rater

This class of drugs are a game-changer in my field.

Internal Medicine rater

As a primary care physician, these results are valuable. Semaglutide 2.4 mg added to antiplatelets and lipid-lowering agents reduced a composite CV outcome, primarily driven by reduced non-fatal MI. The NNT for semaglutide is 67, with an NNH of 12 for GI adverse effects. The exclusion of SGLT2i despite 25% of patients having chronic heart failure limits the external validity of the results.

Special Interest - Obesity -- Physician rater

I think a head-to-head comparison of anti-obesity medications will make this pharmacotherapy mainstream for the disease. This trial helps us navigate a critical juncture of patient care when determining the right drug. Critical evidence shows that semaglutide is superior to placebo, as per the findings in this RCT.