CagriSema versus Semaglutide 2.4 mg monotherapy for weight management in adults with overweight or obesity, with or without type 2 diabetes: a systematic review, meta-analysis, and trial sequential analysis

INTRODUCTION: Semaglutide 2.4 mg is the reference pharmacotherapy for weight management, yet many patients do not reach ambitious weight-loss targets. CagriSema, a fixed-dose combination of cagrilintide and semaglutide, may offer additional benefit through complementary mechanisms. We quantified its incremental efficacy and safety against semaglutide 2.4 mg monotherapy in adults with overweight or obesity, with and without type 2 diabetes. METHODS: This PRISMA 2020-compliant review (PROSPERO CRD420261380458) searched PubMed, Embase, Cochrane CENTRAL, ScienceDirect, ClinicalTrials.gov and WHO ICTRP to 30 June 2026 for randomised controlled trials comparing CagriSema with semaglutide 2.4 mg or placebo. Effects were pooled within two prespecified comparator strata using random-effects models with restricted maximum likelihood estimation of τ² and a Hartung-Knapp-Sidik-Jonkman small-sample adjustment, with prediction intervals, leave-one-out and phase-3a-restricted sensitivity analyses, trial sequential analysis. RESULTS: Five trials (4,746 unique participants) were included. Versus semaglutide 2.4 mg, CagriSema produced greater weight loss (mean difference -6.89 percentage points, 95% CI -8.70 to -5.06; I² = 33%; prediction interval -8.91 to -4.86), a greater absolute reduction in body weight (-7.16 kg, 95% CI -9.15 to -5.17) and in body-mass index (-2.41 kg/m², 95% CI -2.83 to -1.99), and roughly twice the likelihood of reaching a 20% reduction (RR 2.10, 95% CI 1.78 to 2.47). Waist circumference fell further (-4.07 cm, 95% CI -5.10 to -3.04). No incremental glycaemic benefit was detected, with intervals for glycated haemoglobin (-0.07, 95% CI -0.14 to 0.01) and fasting plasma glucose lying entirely within prespecified minimal important differences. Injection-site reactions were more frequent (RR 3.14, 95% CI 1.42 to 6.96); gastrointestinal adverse events were not significantly increased under the primary model (RR 1.09, 95% CI 0.97 to 1.21). CONCLUSION: CagriSema produces clinically meaningful additional weight loss and modest improvements in surrogate cardiometabolic measures compared with semaglutide 2.4 mg alone, at the cost of more frequent injection-site reactions and, at most, modestly more frequent gastrointestinal events. The evidence is insufficient to determine whether serious adverse events or neoplasms differ between treatments, and long-term durability, cardiovascular outcomes and body composition remain undetermined. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420261380458.