CagriSema 2.4/2.4 mg versus CagriSema 1.0/1.0 mg in adults with type 2 diabetes: a dose-comparison systematic review and meta-analysis of randomized controlled trials

Background: Once-weekly cagrilintide-semaglutide (CagriSema) has been evaluated at two maintenance doses, 2.4/2.4 mg and 1.0/1.0 mg, in type 2 diabetes (T2DM), but they have not been directly compared. We compared their efficacy and safety. Methods: We searched PubMed, Embase, and Cochrane CENTRAL for randomized controlled trials (RCTs) comparing both doses. Contrasts derived from arm-level estimates were pooled using random-effects models. Primary outcomes were interpreted against prespecified minimally important differences (MIDs) of 3 percentage points (pp) for body weight and 0.3 pp (3.3 mmol/mol) for glycated hemoglobin (HbA1c). Results: Three trials (1,506 participants) were included. CagriSema 2.4/2.4 mg produced a greater reduction in body weight (mean difference [MD] -2.07 pp; 95% confidence interval [CI] -2.91 to -1.24), with the entire CI below the MID, and higher proportions achieving reductions of ≥10% (64.9% vs. 55.1%) and ≥15% (41.9% vs. 30.9%). The difference in HbA1c was not statistically significant (MD -0.16 pp [-1.7 mmol/mol]; 95% CI -0.43 to 0.10 [-4.7 to 1.1 mmol/mol]). The higher dose increased gastrointestinal disorders (64.8% vs. 53.2%; risk ratio 1.22; 95% CI 1.12 to 1.32), without differences in serious adverse events or adverse events leading to treatment discontinuation. Certainty of evidence was high for body weight and moderate for HbA1c. Conclusions: CagriSema 2.4/2.4 mg provided additional weight loss smaller than the MID, no clear HbA1c benefit, and more gastrointestinal adverse events than 1.0/1.0 mg, supporting individualized dose selection.