Multiagonists Outpace Older GLP-1 Drugs for Weight Loss

An updated systematic review has reaffirmed that glucagon-like peptide-1 (GLP-1) receptor agonists and coagonists produce substantial, clinically meaningful weight loss in adults with overweight or obesity who do not have diabetes, while documenting a rapidly expanding menu of oral, extended-interval, and multipathway agents since the same research team's prior analysis.¹ The review was published in Annals of Internal Medicine.

38 Trials, More Than 25,000 Participants

The researchers identified 14 new randomized controlled trials published between October 2024 and March 2026, adding roughly 11,000 participants to their 2025 review. The final analysis spanned 38 trials and 25,816 participants, evaluating 17 GLP-1–based agents, up from 13 in the earlier review. Among commercially available therapies, placebo-subtracted weight loss at the highest doses studied reached −14.8% for subcutaneous semaglutide (7.2 mg), −14.3% for oral semaglutide (50 mg), −12.4% for orforglipron, and −19.0% for tirzepatide, compared with −5.8% for liraglutide.

Emerging premarket multiagonists numerically exceeded those figures. Amycretin, a dual GLP-1/amylin agonist, reached −23.9%. Retatrutide, a triple agonist targeting GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon, posted a similar −22.1%. Reductions in body mass index and waist circumference generally tracked weight loss, though blood pressure effects varied more across agents.

Head-to-Head Data Favor Dual and Multiagonist Regimens

Three new active-comparator trials strengthened the case that multipathway agents outperform GLP-1 monotherapy. In SURMOUNT-5 (NCT05822830), tirzepatide produced significantly greater weight loss than semaglutide at 72 weeks.² In REDEFINE-1 (NCT05567796) and REDEFINE-5 (NCT05813925), cagrilintide-semaglutide (CagriSema) likewise outperformed semaglutide alone.¹ The authors noted, however, that cagrilintide-semaglutide offered only a slight blood pressure edge over semaglutide.

The review's evidence base now includes oral small-molecule GLP-1 agonists beyond orforglipron and oral semaglutide. Two candidates evaluated in newly identified trials, danuglipron and lotiglipron, showed dose-dependent weight loss but were associated with numerically higher discontinuation rates than the therapies now available to patients. Both have since had their clinical development discontinued over safety findings: liver enzyme elevations tied to lotiglipron and a potential case of drug-induced liver injury linked to danuglipron.

The commercially available oral options fared differently. When orforglipron won FDA approval, the ATTAIN program supporting that decision showed roughly 12% mean weight loss at the highest dose over 72 weeks, alongside improvements in several cardiometabolic markers.³

Safety Signals Remain Consistent With Prior Reviews

Gastrointestinal adverse events were common with active treatment versus placebo (76.0% vs 40.1%), while serious adverse events (6.5% vs 5.2%) and deaths (0.1% vs 0.0%) were rare, with no new safety signals identified.¹ The authors flagged persistent limitations: heterogeneity in trial design precluded formal meta-analysis, follow-up capped out at 2 years across the review, and none of the included trials prospectively assessed sarcopenia despite estimates that lean mass accounts for 25% to 40% of total weight loss with these agents.

For payers and health systems, the review underscores that the GLP-1 treatment landscape is diversifying beyond injectable monotherapy just as oral options reach the market, a shift tracked through both the orforglipron and oral semaglutide approvals.³ With multiple dual and triple agonists in later-stage development, the authors say individualized treatment selection and longer-term comparative safety data will become increasingly important for coverage and formulary decisions.¹

References

1. Moiz A, Filion KB, Samuels AE, et al. Efficacy and safety of glucagon-like peptide-1 receptor agonists and co-agonists for weight loss among adults without diabetes: an updated systematic review. Ann Intern Med. Published online August 31, 2026. doi:10.7326/ANNALS-25-05519
2. Santoro C. Tirzepatide outperforms semaglutide in weight loss trial. AJMC^®. December 5, 2024. Accessed August 31, 2026. https://www.ajmc.com/view/tirzepatide-outperforms-semaglutide-in-weight-loss-trial
3. Hohmann E. FDA approves Lilly's oral GLP-1 orforglipron for obesity. AJMC. April 1, 2026. Accessed August 31, 2026. https://www.ajmc.com/view/fda-approves-lilly-s-oral-glp-1-orforglipron-for-obesity