The COMBINE 3 trial was a 52-week open-label randomized, treat-to-target, multi-center trial that was carried out in 109 outpatient clinics and hospitals in 14 countries. It was designed to assess the non-inferiority of IcoSema compared to traditional BBT and to investigate if IcoSema would provide extra clinical benefits. Adults older than 18 years with type 2 diabetes not well controlled on daily basal insulin (HbA1c 7.0–10.0% or 53.0–85.8 mmol/mol) taking 20–80 units of daily insulin were included. Participants were allocated at random to receive once-weekly IcoSema or BBT, which included daily insulin glargine and two to four daily insulin aspart injections.
Results
• Of 844 people screened from November 2021 through September 2022, 679 were recruited (mean age 59.6 years; 59% male).
By week 52, both treatment groups had significant HbA1c reductions:
• IcoSema group: −1.47 percentage points (SE 0.05; equivalent to −16.0 mmol/mol)
• BBT group: −1.40 percentage points (SE 0.06; −15.3 mmol/mol)
• The estimated treatment difference was −0.06 percentage points (95% CI −0.22 to 0.09), establishing non-inferiority of IcoSema (p<0.0001).
Superiority was evident with other outcomes, in particular:
• Weight Loss: IcoSema resulted in a mean bodyweight loss of −6.72 kg (95% CI −7.58 to −5.86; p<0.0001) versus BBT
• Insulin Dose: Weekly total insulin dose was lower with IcoSema (ETD −270 units; 95% CI −303 to −236; p<0.0001)
• Hypoglycemia Rates: The incidence of clinically significant or severe hypoglycemic events was 0.21 per person-year with IcoSema compared with 2.23 using BBT (rate ratio 0.12; 95% CI 0.08 to 0.17; p<0.0001)
Safety analyses revealed contrasting adverse event profiles for the two regimens:
• In the IcoSema group, gastrointestinal disorders were the most frequent adverse events, occurring in 44% of participants (148 out of 340 individuals, with 443 events reported).
• By comparison, BBT participants had infections and infestations more often, at 35% (116 out of 328 participants with 193 events).
Weekly IcoSema showed non-inferior glycemic control and better outcomes in body weight reduction, reduction in insulin dose, and rate of hypoglycemia compared to basal-bolus treatment. The trial favors IcoSema as a viable, more convenient, and safer alternative for treating adults with type 2 diabetes needing intensification over basal insulin.
Reference:
Billings, L. K., Andreozzi, F., Frederiksen, M., Gourdy, P., Gowda, A., Ji, L., Pletsch-Borba, L., Suzuki, R., Unnikrishnan, A. G., & Vianna, A. G. D. (2025). Once-weekly IcoSema versus multiple daily insulin injections in type 2 diabetes management (COMBINE 3): an open-label, multicentre, treat-to-target, non-inferiority, randomised, phase 3a trial. The Lancet. Diabetes & Endocrinology, 13(7), 556–567. https://doi.org/10.1016/S2213-8587(25)00052-X
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