Newer GLP-1 agents yield substantial weight loss in nondiabetic adults
1. In this updated systematic review, glucagon-like peptide-1 receptor agonists and co-agonists produced substantial weight loss in adults without diabetes, with greater reductions observed with newer agents.
2. Newer agents also produced consistent reductions in body mass index and waist circumference, although their effects on blood pressure were variable.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become a mainstay of obesity management, with randomized controlled trials (RCTs) of novel agents continuing to emerge. Updating a previous systematic review, this study assessed the efficacy and safety of GLP-1 RAs and co-agonists for weight management in adults without diabetes. Higher doses of subcutaneous and oral semaglutide were associated with greater weight loss, while tirzepatide continued to produce substantial reductions across trials. Liraglutide was associated with more modest effects. Several premarket therapies, including agents targeting both GLP-1 and amylin pathways, also produced substantial weight loss. Newly evaluated GLP-1 RAs demonstrated dose-dependent reductions in body mass index and waist circumference consistent with those of previously studied agents, although effects on blood pressure were more variable. Gastrointestinal adverse events were common but generally mild to moderate and associated with dose escalation. Treatment discontinuation due to adverse events was generally uncommon, although rates appeared higher with newer oral nonpeptide agents. In head-to-head trials, tirzepatide and CagriSema produced greater weight loss than semaglutide. Generalizability was limited by heterogeneity in trial designs, dosing regimens, and study populations, including the enrollment of mixed populations with and without type 2 diabetes. Overall, these findings reinforce the substantial weight-loss efficacy of GLP-1 RAs and co-agonists in adults without diabetes, with the largest reductions observed with newer agents.
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In-Depth [systematic review and meta-analysis]: This systematic review updated the researchers’ previous review by incorporating new randomized controlled trials (RCTs) evaluating the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and co-agonists. MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for RCTs published between October 2024 and March 2026 that evaluated these agents for weight management in adults with overweight or obesity without diabetes. Trials involving narrowly defined populations were excluded. The primary outcome was relative change in total body weight. Secondary outcomes included changes in absolute weight, body mass index (BMI), waist circumference, and blood pressure (BP); safety outcomes included adverse events (AEs), treatment discontinuation, serious AEs, and death. Fourteen new RCTs involving approximately 11,000 participants were identified. Overall, 38 RCTs comprising 25,816 participants evaluated 17 agents, five of which were commercially available. Most participants were female (66.1%), and mean BMI ranged from 30.0 to 40.9 kg/m². Among the new trials, eight had a low overall risk of bias. Higher-dose subcutaneous semaglutide produced greater weight loss than the standard dose (-14.8% vs -11.7% at 72 weeks). Weight loss reached 19.0% with tirzepatide but was more modest with liraglutide, at up to 5.8%. Several premarket agents also demonstrated substantial effects, including Amycretin (23.9% at 36 weeks), CagriSema (17.3% at 68 weeks), and mazdutide (20.9% at 20 weeks). Reductions in BMI and waist circumference were generally dose-dependent, whereas BP effects were less consistent. In head-to-head comparisons, tirzepatide and CagriSema produced greater weight loss than semaglutide, with estimated treatment differences of -6.5% and -5.5%, respectively. AEs were common with both active treatment and placebo (87.7% vs 79.6%), while gastrointestinal AEs occurred more frequently with active treatment (76.0% vs 40.1%). Treatment discontinuation due to AEs remained relatively uncommon overall (10.4% vs 3.4%) but was more frequent with newer oral nonpeptide agents. Overall, GLP-1 RAs and co-agonists, particularly newer agents, produced substantial weight loss in adults without diabetes.
Image: PD
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