Once-Weekly Semaglutide-Insulin Combo Matches Daily Basal-Bolus in Type 2 Diabetes Control: Study
According to a Phase 3 trial published in The Lancet Diabetes & Endocrinology, a once-weekly combination of semaglutide and insulin icodec was noninferior to traditional daily basal-bolus therapy in lowering A1C levels in patients with type 2 diabetes not adequately controlled with daily basal insulin. The combination also led to greater weight loss, lower total weekly insulin requirements, and fewer hypoglycemic events. The study was published by Prof Liana K. Billings and fellow researchers.
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
