Efficacy and Safety of CagriSema for Metabolic Outcomes: Systematic Review and Pairwise Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Overweight status, obesity, and diabetes represent significant socioeconomic burdens that require long-term management. METHODS: To evaluate the efficacy and safety of dual-agonist CagriSema vs semaglutide monotherapy, cagrilintide monotherapy, and placebo in adults with overweight/obese status and type 2 diabetes, we searched Embase, MEDLINE, PubMed, and the Cochrane Library up to 14 June 2026 for randomized controlled trials (RCTs). Separate pairwise meta-analyses were conducted using random effects models. RESULTS: Eight RCTs comprising 6898 participants were included. CagriSema was associated with significantly greater percentage body weight reduction compared to semaglutide [MD -6.60%; 95%CI: -8.51 to -4.68; P<0.0001; I2 =82%], cagrilintide [MD -8.15%; 95%CI: -11.40 to -4.89; P<0.0001; I2 =95%], and placebo [MD -14.30%; 95%CI: -17.41 to -11.19; P<0.0001; I2 =99%]. A greater decrease in the percentage of glycated hemoglobin was also observed for CagriSema than for semaglutide [MD -0.09%; 95%CI: -0.14 to -0.04; P=0.0004; I2 =39%], cagrilintide [MD -0.87%; 95% CI -1.48 to -0.26; p = 0.005; I2 = 97%], and placebo [MD -1.55%; 95% CI -2.14 to -0.97; p < 0.0001; I2 = 99%]. Furthermore, CagriSema achieved significantly greater reductions in absolute body weight, waist circumference and body mass index across all comparators (all p < 0.0001). CagriSema demonstrated better blood pressure control compared with cagrilintide and placebo, with effects comparable to those of semaglutide. Moreover, CagriSema significantly decreased C-reactive protein and improved lipid profiles compared with cagrilintide and placebo. CagriSema increased any adverse events and gastrointestinal adverse events compared with all comparators. Substantial statistical heterogeneity was observed in several continuous outcomes, driven by diverse baseline clinical characteristics and background therapies. CONCLUSION: Compared with current standard monotherapies and placebos, CagriSema demonstrates superior weight loss, glucose, and lipid control. Key limitations include the relatively small number of eligible trials and the current lack of long-term cardiovascular endpoints.