Summary: In adults with type 2 diabetes inadequately managed on GLP-1 receptor agonist therapy (n=683), once-weekly IcoSema (basal insulin icodec plus semaglutide) was superior to once-weekly semaglutide 1.0 mg for HbA1c reduction at 52 weeks (estimated treatment difference -0.44 percentage points, 95% CI -0.56 to -0.33; p<0.0001). However, body weight increased by 0.84 kg with IcoSema versus a 3.70 kg reduction with semaglutide (difference +4.54 kg favouring semaglutide; p<0.0001), with comparable rates of significant or severe hypoglycaemia and gastrointestinal adverse events.
PICO Summary
| Element | Detail |
|---|---|
| Population | 683 adults with type 2 diabetes inadequately managed on GLP-1 RA therapy (with or without oral glucose-lowering drugs); baseline HbA1c 8.0%, diabetes duration 12.6 years, BMI 31.1 kg/m2. 52-week, multicentre, open-label, parallel-group, Phase IIIa randomised trial across 121 sites in 13 countries/regions. |
| Intervention | Once-weekly IcoSema, a fixed combination of basal insulin icodec and semaglutide (n=342). |
| Comparison | Once-weekly semaglutide 1.0 mg (n=341). |
| Outcome | HbA1c change at week 52: -1.35% (IcoSema) vs -0.90% (semaglutide); ETD -0.44 percentage points (95% CI -0.56 to -0.33), p<0.0001 (superiority confirmed). Fasting plasma glucose: ETD -1.05 mmol/l (95% CI -1.36 to -0.75), p<0.0001 favouring IcoSema. Body weight: +0.84 kg vs -3.70 kg; ETD +4.54 kg (95% CI 3.84 to 5.23), p<0.0001 favouring semaglutide. Clinically significant or severe hypoglycaemia: 0.042 vs 0.036 episodes per person-year; rate ratio 1.20 (95% CI 0.53 to 2.69), p=0.66 (no significant difference). Gastrointestinal adverse events: 31.4% vs 34.4%. |
IcoSema vs semaglutide (COMBINE 2)
RCT · type 2 diabetes · 52 weeks
Adding insulin icodec to semaglutide cut HbA1c by a further 0.44 percentage points at 52 weeks, but at the cost of 4.54 kg more body weight versus semaglutide alone.
Expert Commentary
This Phase IIIa trial establishes that adding basal insulin icodec to semaglutide produces a modest but statistically robust glycaemic advantage over semaglutide alone in patients no longer controlled on GLP-1 receptor agonist therapy. The HbA1c benefit, an estimated 0.44 percentage points, was achieved without an increase in clinically significant or severe hypoglycaemia, which is reassuring for an insulin-containing regimen. The finding that should temper enthusiasm is body weight: where semaglutide produced a 3.70 kg reduction, IcoSema was associated with a 0.84 kg gain, a 4.54 kg between-group difference that is clinically meaningful in a population with a mean BMI of 31 kg/m2. The trade-off therefore is glucose lowering against weight, and the choice will depend on which matters more for the individual. The principal limitation is the open-label design, which can bias subjective endpoints and management decisions, compounded by funding and conduct by the manufacturer of both agents. Can I use this with my patients? Not yet, because IcoSema is not an approved therapy; the data are most relevant to a patient prioritising glycaemic control over weight once a GLP-1 receptor agonist alone is insufficient. Confirmation of cardiovascular and longer-term safety, ideally in blinded designs, should precede any change in practice.
References
Lingvay I, Benamar M, Chen L, et al. Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial. Diabetologia. 2025;68(4):739-751. doi:10.1007/s00125-024-06348-5