Summary: In a pre-specified secondary analysis of the SELECT trial (17,604 adults with overweight or obesity and established cardiovascular disease, without diabetes), once-weekly semaglutide 2.4 mg lowered all-cause death (HR 0.81; 95% CI 0.71-0.93) and non-cardiovascular death (HR 0.77; 95% CI 0.62-0.95). Cardiovascular death was not significantly reduced (HR 0.85; 95% CI 0.71-1.01), and the non-cardiovascular benefit was driven largely by fewer infectious deaths during the COVID-19 pandemic.
PICO Summary
| Element | Detail |
|---|---|
| Population | 17,604 adults aged 45 years or older with body mass index 27 kg/m2 or higher and established cardiovascular disease, without diabetes; multicentre, multinational double-blind randomised controlled trial; mean follow-up 3.3 years. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg (n = 8,803). |
| Comparison | Matching once-weekly subcutaneous placebo (n = 8,801). |
| Outcome | Of 833 deaths, 485 (58%) were cardiovascular and 348 (42%) non-cardiovascular. All-cause death: HR 0.81 (95% CI 0.71-0.93). Cardiovascular death: HR 0.85 (95% CI 0.71-1.01), not statistically significant. Non-cardiovascular death: HR 0.77 (95% CI 0.62-0.95). Infectious death (most common non-cardiovascular cause): 62 vs 87; HR 0.71 (95% CI 0.51-0.98). Incident COVID-19 was not reduced; 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 0.44-0.96). Absolute differences and numbers needed to treat were not reported for these endpoints. |
SELECT: Semaglutide and Mortality
RCT secondary analysis · obesity + CVD, no diabetes · 3.3 years
Once-weekly semaglutide 2.4 mg reduced all-cause and non-cardiovascular death in adults with obesity and cardiovascular disease without diabetes. Cardiovascular death was not significantly reduced, and the non-cardiovascular benefit was driven largely by fewer infectious deaths during the COVID-19 pandemic.
Expert Commentary
This secondary analysis adds a mortality signal to the SELECT cardiovascular outcomes programme, and the all-cause death reduction is the headline a clinician should weigh. The finding is biologically plausible and internally consistent, yet several cautions are warranted. Mortality was a secondary endpoint and the cause-of-death subcategories, including the COVID-19 outcomes, are exploratory and hypothesis-generating rather than confirmatory; they should not be read as proof that semaglutide treats or prevents infection. The single most important limitation is confounding by the pandemic itself: much of the non-cardiovascular benefit reflects fewer infectious deaths during a defined COVID-19 window, so the result may not generalise to non-pandemic conditions. Notably, cardiovascular death was not significantly reduced, and incident COVID-19 was unchanged. The trial was industry funded, with several manufacturer-affiliated co-authors, which warrants the usual scrutiny, though the double-blind randomised design and adjudicated deaths are genuine strengths. Can I use this with my patients? For an adult with obesity and established cardiovascular disease but no diabetes, this strengthens the existing case for semaglutide 2.4 mg, but the COVID-specific claims remain exploratory and should not drive prescribing. Confirmatory, pre-specified mortality analyses outside a pandemic context would be welcome.
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. J Am Coll Cardiol. 2024;84(17):1632-1642. doi:10.1016/j.jacc.2024.08.007