IcoSema is a once-weekly, fixed-ratio injection that combines insulin icodec, a weekly basal insulin, with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist. It is intended to control fasting and post-meal glucose in a single weekly injection whilst limiting the weight gain and hypoglycaemia that accompany insulin therapy. Its pivotal trials each used a different comparison treatment, and the only previous pairwise synthesis pooled them into single estimates carrying extreme statistical heterogeneity. We therefore re-synthesised the randomised evidence using a comparator-specific approach. Eight sources (PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), ClinicalTrials.gov, and citation searching) were searched from inception to September 5, 2026, for randomised controlled trials of IcoSema in adults with type 2 diabetes. Two reviewers independently screened records, extracted data, and applied Cochrane Risk of Bias 2. Covariate-adjusted treatment differences were combined by random-effects inverse-variance meta-analysis, stratified by comparator class, with an exploratory all-comparator pool retained for comparison only and certainty rated with GRADE. Four phase 3 trials (3,138 participants) were eligible: COMBINE 1, 2, 3 and 4. Against basal insulin alone (COMBINE 1 and 4; two trials, 1,776 participants), IcoSema lowered HbA1c by 0.74 percentage points (95% confidence interval (CI) -0.95 to -0.53; I² = 63%), reduced body weight by 5.15 kg (95% CI -6.10 to -4.19; I² = 70%), and reduced clinically significant or severe hypoglycaemia (rate ratio 0.35, 95% CI 0.14 to 0.87; I² = 84%). Against semaglutide alone (COMBINE 2; single trial), IcoSema lowered HbA1c by a further 0.44 percentage points (95% CI -0.56 to -0.33), but body weight was 4.54 kg higher (95% CI 3.84 to 5.23), with no significant difference in hypoglycaemia. Against daily basal-bolus insulin (COMBINE 3; single trial), IcoSema met non-inferiority for HbA1c (-0.06 percentage points, 95% CI -0.22 to 0.09), reduced body weight by 6.72 kg (95% CI -7.58 to -5.86), and reduced hypoglycaemia (rate ratio 0.12, 95% CI 0.08 to 0.17). Exploratory pooling across all comparators produced estimates with I² of 92%-99.5% that should not be read as an overall treatment effect. The effects of IcoSema on glycaemia, weight, and hypoglycaemia differ in size, and for body weight in direction, according to the regimen it is compared with; comparator-specific estimates, not a single pooled figure, should inform interpretation.
