Cardiometabolic outcomes of once-weekly IcoSema in adults with type 2 diabetes: systematic review and meta-analysis of the COMBINE trials.

BACKGROUND: Patients with type 2 diabetes face a high residual risk of atherosclerotic cardiovascular disease (ASCVD) despite advances in therapy. Once-weekly IcoSema, a fixed-ratio combination of basal insulin icodec and semaglutide, offers the potential to simultaneously address glycemic control, weight, and multiple cardiometabolic risk factors with a single weekly injection. METHODS: We conducted a PRISMA-compliant systematic review and random-effects meta-analysis of randomized trials from the COMBINE program. Data from COMBINE 1 (active comparator: once-weekly insulin icodec) and COMBINE 3 (active comparator: basal-bolus insulin therapy) (N = 1,970) were pooled comparing IcoSema with insulin-based intensification strategies in patients inadequately controlled on basal insulin. COMBINE 2 was excluded because its semaglutide monotherapy comparator addresses a fundamentally different clinical question (escalation from GLP-1 RA monotherapy). The primary focus was on changes in body weight, Systolic blood pressure and HbA1c; key secondary outcomes included changes in lipid profile relevant to ASCVD risk. Certainty of evidence was assessed using GRADE. RESULTS: IcoSema showed no statistically significant difference in HbA1c reduction compared with control (pooled MD -0.37%, 95% CI -0.95 to 0.21; P = 0.21; I²=98%) but shows highly significant body weight reduction (pooled MD -6.10 kg, 95% CI -7.21 to -5.00; P < 0.00001). It significantly lowered systolic blood pressure (MD -2.45 mmHg, 95% CI -3.52 to -1.38; P < 0.00001), total cholesterol (ETR 0.97, 95% CI 0.95-0.98; P = 0.0001), LDL-C (ETR 0.94, 95% CI 0.90-0.98; P = 0.005), triglycerides (ETR 0.94, 95% CI 0.91-0.97; P = 0.0006), and VLDL-C (ETR 0.94). An exploratory, hypothetical ASCVD risk modeling analysis based on these surrogate-marker changes is presented in the Supplementary Appendix and is intended as an illustration only. CONCLUSIONS: Once-weekly IcoSema delivers meaningful improvements in weight, blood pressure, and atherogenic lipids, all key modifiable drivers of ASCVD in adults with type 2 diabetes. These surrogate benefits, combined with reduced injection burden and low risk of hypoglycemia, suggest potential for enhanced ASCVD prevention and improved long-term adherence. Results should be interpreted as hypothesis-generating only because only two trials met the inclusion criteria. Dedicated cardiovascular outcome trials are essential to validate these surrogate-marker benefits and to confirm whether they translate into a reduction in cardiovascular events.