This 40-week, open-label, phase 3b RCT (COMBINE 4) compared once-weekly IcoSema (basal insulin icodec + semaglutide) vs. once-daily insulin glargine U100 in 485 insulin-naive adults with type 2 diabetes (HbA1c ≥8.0%) inadequately controlled on oral glucose-lowering medications across 97 sites in 9 countries.
IcoSema was superior on both primary and secondary endpoints: HbA1c dropped 3.32 vs. 2.44 percentage points (ETD −0.88 pp; p<0.001), bodyweight fell 0.79 kg vs. rose 3.81 kg (ETD −4.61 kg; p<0.001), and clinically significant or severe hypoglycaemia was lower with IcoSema (0.29 vs. 0.59 episodes/person-year; rate ratio 0.56; p=0.04). Gastrointestinal adverse events were more common with IcoSema.
Open-label design may introduce bias in patient-reported outcomes. No active GLP-1 receptor agonist comparator arm was included, limiting head-to-head context against other combination approaches. The 40-week duration does not capture long-term cardiovascular or renal outcomes.
For insulin-naive patients with type 2 diabetes poorly controlled on oral agents, once-weekly IcoSema offers greater HbA1c reduction, weight loss rather than gain, and fewer hypoglycaemic events compared with once-daily glargine U100. Clinicians should counsel patients to expect GI side effects, consistent with GLP-1 receptor agonist use.
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