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Clinical question
In adults with obesity or overweight and no diabetes, how much weight loss and cardiovascular benefit do once-weekly GLP-1-based medications provide compared with placebo, and what are their harms?
Search
PubMed and CINAHL were searched for randomized controlled trials using the terms semaglutide, tirzepatide, obesity and weight loss. Three large, double-blind, placebo-controlled phase 3 trials published in the New England Journal of Medicine were selected.
The trials
| Trial | Participants | Intervention | Main results |
|---|---|---|---|
| STEP 1 (Wilding et al., 2021) | 1,961 adults with BMI ≥30, or ≥27 with a weight-related condition, without diabetes | Semaglutide 2.4 mg weekly or placebo, plus lifestyle intervention, for 68 weeks | Mean weight change −14.9% vs. −2.4%; 86.4% vs. 31.5% lost at least 5% of body weight |
| SURMOUNT-1 (Jastreboff et al., 2022) | 2,539 adults with the same BMI criteria, without diabetes | Tirzepatide 5, 10 or 15 mg weekly or placebo for 72 weeks | Mean weight change −15.0%, −19.5% and −20.9% by dose vs. −3.1% with placebo |
| SELECT (Lincoff et al., 2023) | 17,604 adults aged 45 or older with cardiovascular disease and BMI ≥27, without diabetes | Semaglutide 2.4 mg weekly or placebo; mean follow-up 39.8 months | Cardiovascular death, nonfatal heart attack or nonfatal stroke in 6.5% vs. 8.0% (hazard ratio 0.80) |
Synthesis
Weight loss. Both drugs produced large weight losses compared with placebo. Tirzepatide, which acts on both GIP and GLP-1 receptors, produced the largest mean losses at higher doses, but no head-to-head comparison was included, so the trials can't show that one drug is better.
Cardiovascular outcomes. SELECT is the only trial here designed to test hard outcomes. It showed a 20% relative reduction in major cardiovascular events with semaglutide in people with established cardiovascular disease. That supports benefit beyond weight loss for this group, but it doesn't show the same benefit in people without heart disease.
Harms. Gastrointestinal effects (nausea, diarrhea, vomiting and constipation) were the most common adverse events in all three trials, usually mild to moderate and mostly during dose escalation. More participants stopped semaglutide than placebo because of adverse events (16.6% vs. 8.2% in SELECT).
Quality and limitations
All three trials were large, randomized and double-blind, which places them at a high level of evidence. All were funded by the manufacturers. Follow-up was 68 to 72 weeks in the weight-loss trials, so long-term effects and what happens after stopping are less certain. Participants were mostly selected for trials and may not reflect every patient in practice.
Implications for advanced practice
The evidence supports offering these medications, with lifestyle support, to eligible adults with obesity, and especially considering semaglutide for patients with established cardiovascular disease. The advanced practice nurse should explain expected benefits and side effects, start low and titrate slowly to reduce gastrointestinal effects, and discuss cost and long-term use before starting.
References
Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., & Stefanski, A. (2022). Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 387(3), 205–216. https://doi.org/10.1056/NEJMoa2206038
Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., Deanfield, J., Emerson, S. S., Esbjerg, S., Hardt-Lindberg, S., Hovingh, G. K., Kahn, S. E., Kushner, R. F., Lingvay, I., Oral, T. K., Michelsen, M. M., Plutzky, J., Tornøe, C. W., & Ryan, D. H. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine, 389(24), 2221–2232. https://doi.org/10.1056/NEJMoa2307563
Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., Wharton, S., Yokote, K., Zeuthen, N., & Kushner, R. F. (2021). Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine, 384(11), 989–1002. https://doi.org/10.1056/NEJMoa2032183
