Summary: In this secondary mortality analysis of the SELECT randomised controlled trial (17,604 adults with overweight or obesity and established cardiovascular disease but without diabetes), once-weekly semaglutide 2.4 mg was associated with lower all-cause death than placebo over a mean of 3.3 years (hazard ratio 0.81; 95% CI 0.71 to 0.93). The reduction was distributed across cardiovascular and non-cardiovascular causes, with the non-cardiovascular signal driven mainly by fewer infectious deaths during the COVID-19 pandemic.
PICO Summary
| Element | Detail |
|---|---|
| Population | 17,604 adults aged 45 years or older with a body mass index of 27 kg/m2 or higher and established cardiovascular disease but without diabetes; multinational, double-blind randomised controlled trial (SELECT; NCT03574597). Analysis based on 833 adjudicated deaths. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg over a mean trial duration of 3.3 years. |
| Comparison | Matching placebo, with identical monitoring and follow-up. |
| Outcome | All-cause death was lower with semaglutide (HR 0.81; 95% CI 0.71 to 0.93). Cardiovascular death was not significantly reduced (HR 0.85; 95% CI 0.71 to 1.01). Non-cardiovascular death was lower (HR 0.77; 95% CI 0.62 to 0.95), driven mainly by fewer infectious deaths (62 vs 87; HR 0.71; 95% CI 0.51 to 0.98). Semaglutide did not lower the incidence of COVID-19, but among those who developed COVID-19, fewer had COVID-19-related serious adverse events (232 vs 277; p = 0.04) and fewer died of COVID-19 (43 vs 65; HR 0.66; 95% CI 0.44 to 0.96). Absolute risk reductions and numbers needed to treat were not reported for these subcategory endpoints. |
Semaglutide and mortality in SELECT
RCT secondary analysis · obesity + CVD, no diabetes · 3.3 y
Semaglutide 2.4 mg was associated with lower all-cause mortality than placebo, shared across cardiovascular and non-cardiovascular causes. Mortality was a secondary, exploratory endpoint and cardiovascular death alone was not significantly reduced.
Expert Commentary
This prespecified secondary analysis of SELECT reports that semaglutide 2.4 mg was associated with a lower rate of all-cause death in patients with obesity and cardiovascular disease but without diabetes, with the benefit shared between cardiovascular and non-cardiovascular causes. The headline all-cause finding is supported by a confidence interval that excludes unity. The verdict, however, should be read with restraint. SELECT was not powered for mortality as a primary endpoint, and cause-specific outcomes are exploratory rather than confirmatory. The most weighed limitation is that the non-cardiovascular benefit was driven largely by fewer infectious deaths during the COVID-19 pandemic, a period-specific and partly chance-susceptible signal that should not be assumed to be a generalisable class effect, particularly as semaglutide did not reduce the incidence of COVID-19 itself. Cardiovascular death alone did not reach statistical significance. The trial was funded by the manufacturer, Novo Nordisk, and several authors are company employees, which warrants the usual caution even within a double-blind design. Can I use this with my patients? For a patient with obesity and established cardiovascular disease but no diabetes who is already a candidate for semaglutide, this analysis adds reassurance on mortality but should not by itself drive prescribing. Future independent and longer-term data are needed to confirm whether the infection-related mortality signal persists outside a pandemic context.
References
Scirica BM, Lincoff AM, Lingvay I, et al. The Effect of Semaglutide on Mortality and COVID-19-Related Deaths: An Analysis From the SELECT Trial. Journal of the American College of Cardiology. 2024;84(17):1632-1642. doi:10.1016/j.jacc.2024.08.007