Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial

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Abstract
Aims/hypothesis: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. Methods: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA1c 53.0–85.8 mmol/mol [7.0–10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; n=342) or semaglutide 1.0 mg (n=341). Mean ± SD baseline characteristics were as follows: HbA1c 64.0±8.2 mmol/mol (8.0±0.7%); diabetes duration 12.6±6.9 years; and BMI 31.1±4.7 kg/m2. From baseline to week 52, mean change in HbA1c was −14.7 mmol/mol (−1.35%-points) in the IcoSema group and −9.88 mmol/mol (−0.90%-points) in the semaglutide group; the estimated treatment difference (ETD) was –4.85 (95% CI −6.13, −3.57) mmol/mol (−0.44 [95% CI −0.56, −0.33]%-points), confirming superiority of IcoSema to semaglutide (pppp=0.66). The proportion of participants experiencing gastrointestinal adverse events was similar between treatment groups (IcoSema 31.4%; semaglutide 34.4%). Conclusions/interpretation: In people living with type 2 diabetes inadequately managed with GLP-1 RA therapy, with or without additional oral glucose-lowering medications, switching to once-weekly IcoSema in comparison with once-weekly semaglutide 1.0 mg demonstrated superiority in HbA1c reduction, similar rates of clinically significant or severe hypoglycaemia, and similar frequency of gastrointestinal adverse events. However, weight change from baseline to week 52 was statistically significantly in favour of semaglutide 1.0 mg. Trial registration: ClinicalTrials.gov NCT05259033 Funding: This trial was funded by Novo Nordisk Graphical
Funding Information
  • Novo Nordisk A/S

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