Summary: In this prespecified 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 reduced all-cause death versus placebo (HR 0.81; 95% CI 0.71-0.93) over a mean 3.3 years. The cardiovascular death difference did not reach significance (HR 0.85; 95% CI 0.71-1.01), while the non-cardiovascular benefit (HR 0.77; 95% CI 0.62-0.95) was driven largely by fewer infectious and COVID-19-related deaths.
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). Mortality was a secondary analysis with prospectively adjudicated causes of death. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for a mean of 3.3 years (n is approximately 8,803). |
| Comparison | Matching placebo on a background of standard care (n is approximately 8,801). |
| Outcome | Of 833 total deaths, 485 (58%) were cardiovascular and 348 (42%) were non-cardiovascular. All-cause death: HR 0.81 (95% CI 0.71-0.93), favouring semaglutide. 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, the most common non-cardiovascular cause, was lower with semaglutide (62 vs 87; HR 0.71; 95% CI 0.51-0.98). Incident COVID-19 was not reduced; however, among those who developed COVID-19, fewer treated participants 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). Absolute risk reduction and NNT were not reported. |
Semaglutide and Mortality (SELECT)
RCT secondary analysis · obesity + CVD, no diabetes · 3.3 yrs
Semaglutide 2.4 mg significantly reduced all-cause death versus placebo; the cardiovascular death reduction alone was not significant, and much of the non-cardiovascular benefit came from fewer infectious and COVID-19-related deaths. As a secondary endpoint, these findings are supportive rather than confirmatory.
Expert Commentary
This secondary analysis of a large, double-blind randomised trial offers a credible signal that semaglutide 2.4 mg lowers all-cause mortality in patients with obesity and cardiovascular disease, an outcome few therapies have achieved in this group. The verdict is cautiously positive: the all-cause death benefit was statistically significant and biologically coherent, yet the cardiovascular death reduction alone did not reach significance, and much of the overall mortality advantage was carried by fewer non-cardiovascular deaths, chiefly infectious and COVID-19-related, during a pandemic window. The dominant limitation is that mortality was a secondary endpoint analysed post hoc; the trial was powered for major adverse cardiovascular events, not for adjudicated cause-specific death, so these subcategory hazard ratios are hypothesis-generating rather than confirmatory. Two further caveats temper enthusiasm: the trial was sponsored by the manufacturer, with several authors employed by it, and the COVID-19 mortality effect may partly reflect the unusual pandemic context rather than a durable, reproducible mechanism. Can I use this with my patients? Yes, for a patient who already meets SELECT criteria, namely overweight or obesity with established cardiovascular disease and no diabetes, this reinforces the case for semaglutide, though the mortality claim should be framed as supportive rather than proven. Confirmation of cause-specific mortality effects in dedicated analyses 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