Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists and Co-agonists for Weight Loss Among Adults Without Diabetes : An Updated Systematic Review.
Orforglipron resulted in a placebo-subtracted weight loss of -12.4% in adults without diabetes, but gastrointestinal side effects were common.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This systematic review evaluated the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and co-agonists for weight management in adults without diabetes. A total of 38 randomized controlled trials (RCTs) involving 25,816 participants were included, with orforglipron showing a placebo-subtracted weight loss of -12.4%. The study highlights a range of weight loss outcomes for various GLP-1 RAs and co-agonists.
Abstract
Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for weight management. Purpose To update our prior systematic review evaluating the efficacy and safety of GLP-1 RAs and co-agonists among adults with overweight or obesity without diabetes. Data sources MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from 5 October 2024 through 25 March 2026. Study selection Randomized controlled trials ([RCTs] treatment duration ≥16 weeks). Data extraction Two reviewers independently extracted data. Data synthesis Thirty-eight RCTs (n = 25 816) were included, adding 14 new trials (n = 11 000) to the prior review. Among commercially available therapies, placebo-subtracted weight loss reached up to -5.8% (95% CI, -8.0% to -3.6%) for liraglutide, -14.8% (CI, -16.2% to -13.4%) for subcutaneous semaglutide, -14.3% (CI, -17.2% to -11.4%) for oral semaglutide, -12.4% (CI, -15.1% to -9.7%) for orforglipron, and -19.0% (CI, -21.6% to -16.4%) for tirzepatide. Numerically greater placebo-subtracted reductions were seen with emerging multiagonists, including -23.9% (CI, -29.3% to -18.5%) with amycretin and -22.1% (CI, -24.9% to -19.3%) with retatrutide. Gastrointestinal adverse events (AEs) remained common (GLP-1 RA vs. placebo: 76.0% vs. 40.1%). Discontinuation due to AEs was generally low (10.7% vs. 3.4%) but numerically higher with some oral agents. Serious AEs (6.5% vs. 5.2%) and deaths (0.1% vs. 0.0%) were rare, with no new safety signals identified. Head-to-head data showed greater weight loss with semaglutide and JNJ-64565111 than liraglutide and greater weight loss with tirzepatide and cagrilintide-semaglutide (CagriSema; Novo Nordisk) than semaglutide. Limitations Heterogeneity precluded quantitative synthesis. Safety outcomes were inconsistently reported. Conclusion Glucagon-like peptide-1 receptor agonists demonstrate substantial weight loss in adults without diabetes, with an expanding range of therapeutic options, including oral and multiagonist therapies. Primary funding source None. (PROSPERO: CRD42024505558).
Background
This paper addresses the efficacy and safety of GLP-1 receptor agonists in weight management for adults without diabetes. Prior studies have shown varying degrees of weight loss with these agents, but comprehensive updates are necessary to evaluate emerging therapies. The significance of this review lies in its systematic approach to consolidating data from multiple RCTs to inform clinical practice.
Methods
The study included 38 randomized controlled trials (RCTs) with a total of 25,816 participants, focusing on treatments lasting 16 weeks or longer. Data were extracted independently by two reviewers, and the review aimed to synthesize findings regarding weight loss efficacy and safety profiles. The review included both established and emerging GLP-1 RAs and co-agonists.
Results
The primary endpoint showed a placebo-subtracted weight loss of -12.4% for orforglipron (95% CI, -15.1% to -9.7%). Other GLP-1 RAs demonstrated varying weight loss, with liraglutide at -5.8%, subcutaneous semaglutide at -14.8%, oral semaglutide at -14.3%, and tirzepatide at -19.0%. Gastrointestinal adverse events were common, occurring in 76.0% of participants receiving GLP-1 RAs, compared to 40.1% in the placebo group.
Interpretation
The findings indicate that orforglipron and other GLP-1 RAs can lead to significant weight loss in adults without diabetes, although the clinical significance of the weight loss varies. While the results are statistically significant, the clinical relevance should be assessed in the context of individual patient needs and potential adverse effects. Limitations such as heterogeneity and inconsistent reporting of safety outcomes may affect the robustness of the conclusions.
Key findings
- -12.4% placebo-subtracted weight loss for orforglipron (95% CI, -15.1% to -9.7%)
- -5.8% for liraglutide (95% CI, -8.0% to -3.6%)
- -14.8% for subcutaneous semaglutide (95% CI, -16.2% to -13.4%)
- -14.3% for oral semaglutide (95% CI, -17.2% to -11.4%)
- -19.0% for tirzepatide (95% CI, -21.6% to -16.4%)
- Gastrointestinal adverse events occurred in 76.0% of participants receiving GLP-1 RAs vs. 40.1% with placebo
Limitations
- Heterogeneity precluded quantitative synthesis
- Safety outcomes were inconsistently reported
- No new safety signals identified
- Short treatment duration may limit long-term applicability