Summary: In a prespecified analysis of the SELECT trial (17,604 adults with established cardiovascular disease and overweight or obesity, without diabetes), semaglutide produced a mean weight reduction of -10.2% versus -1.5% with placebo at 208 weeks, with the difference sustained over four years (P<0.0001). Reductions in waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) accompanied the weight change, and serious adverse events were fewer with semaglutide across every BMI category.
PICO Summary
| Element | Detail |
|---|---|
| Population | 17,604 adults aged 45 years or older with preexisting cardiovascular disease and overweight or obesity (BMI 27 kg/m² or higher), without diabetes; international multicentre double-blind randomised controlled trial (SELECT), analysed by baseline BMI category. |
| Intervention | Subcutaneous semaglutide titrated to 2.4 mg once weekly, on top of standard cardiovascular care, with weight and anthropometric outcomes assessed to 208 weeks (n approximately 8,803). |
| Comparison | Matching placebo once weekly on top of standard cardiovascular care over the same period (n approximately 8,801). |
| Outcome | At 208 weeks, mean weight change -10.2% (semaglutide) vs -1.5% (placebo); waist circumference -7.7 cm vs -1.3 cm; waist-to-height ratio -6.9% vs -1.0% (P<0.0001 for all). Weight loss continued for about 65 weeks and was sustained to 4 years. Serious adverse events (events per 100 years of observation) were lower with semaglutide in every BMI band: 43.23 vs 50.48 (BMI <30), 43.54 vs 49.66 (30 to <35), 51.07 vs 52.73 (35 to <40) and 47.06 vs 60.85 (40 or higher). Trial product discontinuation was higher with semaglutide and increased as BMI class fell. As a prespecified secondary analysis, no formal hierarchical testing or ARR/NNT was reported for these anthropometric endpoints. |
Semaglutide and long-term weight loss (SELECT)
RCT prespecified analysis · obesity, no diabetes · 208 weeks
Semaglutide 2.4 mg produced a roughly 9 percentage-point placebo-adjusted weight reduction that was sustained to four years, with fewer serious adverse events across every BMI band.
Expert Commentary
This prespecified analysis confirms that the weight effect of semaglutide 2.4 mg is large, durable and consistent across body sizes in a non-diabetic population with cardiovascular disease. A roughly 9 percentage-point placebo-adjusted weight reduction maintained to four years is among the most robust long-term obesity-pharmacotherapy datasets available, and the parallel fall in serious adverse events across BMI bands is reassuring rather than merely neutral. The verdict is that the anthropometric benefit is real and clinically meaningful. The principal limitation is interpretive: this is a secondary analysis of a trial powered for cardiovascular events, the figures were not part of the primary hierarchical testing, and the population was selected for established cardiovascular disease, so generalisation to lower-risk individuals seeking weight loss is indirect. The trial was sponsored by the manufacturer, Novo Nordisk, and several authors are company employees, which warrants the usual caution despite the double-blind design. Can I use this with my patients? Yes, for an adult with cardiovascular disease and obesity but without diabetes who is a candidate for semaglutide, this strengthens the case for sustained use and helps set realistic four-year expectations. Clinicians should still counsel on the higher discontinuation rate and weight regain on stopping. Longer pragmatic data in lower-risk groups would be welcome.
References
Ryan DH, Lingvay I, Deanfield J, Kahn SE, Barros E, Burguera B, et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med. 2024;30(7):2049-2057. doi:10.1038/s41591-024-02996-7