Novel Amylin‐Based Therapies for Weight Management in Adults With Overweight or Obesity Without Diabetes: A Network Meta‐Analysis

BACKGROUND: Long-acting amylin-based therapies (ABTs) are emerging anti-obesity agents; we sought to compare their effects on weight and anthropometric outcomes in adults with overweight/obesity without diabetes, evaluate gastrointestinal (GI) safety, and rank agents and doses within a network meta-analysis (NMA) framework. METHODS: We conducted a frequentist random-effects NMA of randomized controlled trials comparing novel ABTs with placebo or active comparators in R. Primary outcome was the percent change in body weight from baseline. Secondary outcomes included absolute weight changes, anthropometric measures, and overall and specific GI adverse events (AEs). Treatments (including dose strata) were compared with placebo within a single network and ranked using P scores. RESULTS: Six trials (N = 4642; 12-68 weeks) were included. Compared with placebo, high dose (HiD) subcutaneous amycretin produced the largest reduction in percent body weight (mean difference -23.95%; P score 1.00), followed by HiD eloralintide (-18.01%; P score 0.89) and HiD CagriSema (-17.18%; P score 0.85), all exceeding semaglutide 2.4 mg (-11.45%) and liraglutide 3.0 mg (-6.4%). Almost similar patterns were observed for absolute weight, body mass index, waist circumference and categorical weight-loss thresholds. GI AEs, nausea, vomiting and constipation were more common with HiD ABTs, especially oral amycretin and CagriSema, while diarrhoea mainly increased with semaglutide 2.4 mg. Only HiD CagriSema increased AE-related discontinuation. CONCLUSIONS: Novel ABTs, such as HiD amycretin, CagriSema and eloralintide, may induce substantial short- to medium-term weight loss but may also increase GI AEs; given sparse, low-certainty data, these findings are preliminary and require confirmation in larger trials. TRIAL REGISTRATION: The meta-analysis was registered in PROSPERO (CRD420261340457). The review protocol summary can be accessed at the PROSPERO website (https://www.crd.york.ac.uk/PROSPERO/view/CRD420261340457).