BACKGROUND: Patients with overweight and obesity are at increased risk of death from multiple causes, including cardiovascular (CV) death, with few therapies proven to reduce the risk.
OBJECTIVES: This study sought to assess the effect of semaglutide 2.4 mg on all-cause death, CV death, and non-CV death, including subcategories of death and death from coronavirus disease-2019 (COVID-19).
METHODS: The SELECT (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity) trial randomized 17,604 participants =45 years of age with a body mass index =27 kg/m2 with established CV disease but without diabetes to once-weekly subcutaneous semaglutide 2.4 mg or placebo; the mean trial duration was 3.3 years. Adjudicated causes of all deaths, COVID-19 cases, and associated deaths were captured prospectively.
RESULTS: Of 833 deaths, 485 (58%) were CV deaths, and 348 (42%) were non-CV deaths. Participants assigned to semaglutide vs placebo had lower rates of all-cause death (HR: 0.81; 95% CI: 0.71-0.93), CV death (HR: 0.85; 95% CI: 0.71-1.01), and non-CV death (HR: 0.77; 95% CI: 0.62-0.95). The most common causes of CV death with semaglutide vs placebo were sudden cardiac death (98 vs 109; HR: 0.89; 95% CI: 0.68-1.17) and undetermined death (77 vs 90; HR: 0.85; 95% CI: 0.63-1.15). Infection was the most common cause of non-CV death and occurred at a lower rate in the semaglutide vs the placebo group (62 vs 87; HR: 0.71; 95% CI: 0.51-0.98). Semaglutide did not reduce incident COVID-19; however, among participants who developed COVID-19, fewer participants treated with semaglutide had COVID-19-related serious adverse events (232 vs 277; P = 0.04) or died of COVID-19 (43 vs 65; HR: 0.66; 95% CI: 0.44-0.96). High rates of infectious deaths occurred during the COVID-19 pandemic, with less infectious death in the semaglutide arm, and resulted in fewer participants in the placebo group being at risk for CV death.
CONCLUSIONS: Compared to placebo, patients treated with semaglutide 2.4 mg had lower rates of all-cause death, driven similarly by CV and non-CV death. The lower rate of non-CV death with semaglutide was predominantly because of fewer infectious deaths. These findings highlight the effect of semaglutide on mortality across a broad population of patients with CV disease and obesity. (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity [SELECT]; NCT03574597).
| Discipline Area | Score |
|---|---|
| Special Interest - Obesity -- Physician |  |
| Endocrine |  |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
| Internal Medicine | |
| Cardiology |  |
These results show remarkable benefits of GLP-1 agonists in reducing morbidity and morality compared with placebo, especially CV mortality and infection-related mortality. The remarkable benefits of obesity treatment with semaglutide are well proven beyond doubt by several RCTs and systematic reviews, and this new evidence on the mortality benefit sheds more light on our knowledge base. However, these results do not clearly mention whether the benefits observed have any direct or indirect correlation to the degree of weight loss. I hope post-hoc analyses and subgroup analyses of these data give a clearer picture of the same. With the emergence of newer evidence, clinicians are expected to use these new classes of antiobesity agents especially the latest addition in the market, Tirzepatide more widely and judiciously bearing in mind the treatment costs. However, if used in appropriately selected patients, these drugs can be cost effective as they might induce diabetes remission
A small effect size.
There is no Table 1 to assess the patients studied: age, sex, race, BMI class, etc. Also, the results are not presented relevant to these groups, so unable to decide which patients may benefit. Also, need to note which patients were included and excluded to know who may benefit. No information on the number of patients who withdrew and why or the wt loss associated with the treatment. The trial was industry sponsored and they were involved in all aspects of the study. Undetermined deaths were attributed to CV disease, although we don't know which category, and that may have affected the results. Despite the title and abstract, CV deaths and all subgroups of this other than sudden death were not affected by the treatment (CI crosses 1). These curves were starting to diverge toward the end of the trial, so perhaps a longer duration may have reached significance. They acknowledge that Covid infections and deaths may have affected the results, so that makes all results suspect.
Clear and important benefits in this high-risk population. I'd like to see what the non-ASCVD benefits are in individuals with obesity without known vascular disease. Important information.
Very important new data.
Really interesting to look at all the potential benefits of reducing obesity, or explore another hypothesis re mechanism of infection benefit.
Semaglutide wins again. It's great that the study was coincident with the pandemic.
Although we may quibble about whether obesity is a risk-factor for death in adults diagnosed with COVID-19, I think most are in agreement that obesity is a risk factor for hospitalization with COVID-19. It is probably the case that the highest levels of obesity increases the risk for mortality. It is astounding that semaglutide for obesity not only reduced all-cause mortality (randomized comparison), but also reduced death and adverse complications in those hospitalized with COVID-19 (technically a subgroup comparison that no longer benefits from randomization - an observational analysis). It's unclear exactly how this benefit works. It could be for biomechanical reasons related to weight loss, although I do wonder about the inflammatory impact of obesity. This is yet another world-changing result from the semaglutide obesity trials that deserves to be broadcast widely, with the only caveat being the COVID-related findings are technically "observational" / subgroup.