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 (HbA53.0-85.8 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 HbAfrom 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; <3.0 mmol/l) or severe (level 3; associated with severe cognitive impairment requiring external assistance for recovery) hypoglycaemia (baseline to week 57).
RESULTS: Overall, 683 participants were randomised using a Randomisation and Trial Supply Management system to IcoSema (n=342) or semaglutide 1.0 mg (n=341). Mean ± SD baseline characteristics were as follows: HbA64.0±8.2 mmol/mol (8.0±0.7%); diabetes duration 12.6±6.9 years; and BMI 31.1±4.7 kg/m. From baseline to week 52, mean change in HbAwas -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 (p<0.0001). The estimated mean change in fasting plasma glucose from baseline to week 52 was statistically significantly reduced with IcoSema vs semaglutide (-2.48 mmol/l vs -1.43 mmol/l, respectively; ETD -1.05 [95% CI -1.36, -0.75] mmol; p<0.0001). Mean change in body weight from baseline to week 52 was statistically significantly different between groups: +0.84 kg for IcoSema vs -3.70 kg for semaglutide (ETD 4.54 kg [95% CI 3.84, 5.23]; p<0.0001). There was no statistically significant difference in the rate of combined clinically significant or severe hypoglycaemia between IcoSema and semaglutide (0.042 vs 0.036 episodes per person-year of exposure; estimated rate ratio 1.20 [95% CI 0.53, 2.69]; p=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 HbAreduction, 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.