COMBINE 3
Trial question
Is once-weekly combination therapy with basal insulin icodec and semaglutide (IcoSema) noninferior to basal bolus therapy in patients with T2DM?
Study design
Multi-center
Open label
RCT
Population
Characteristics of study participants
41.0% female
59.0% male
N = 679
679 patients (280 female, 399 male).
Inclusion criteria: adult patients with T2DM receiving daily basal insulin.
Key exclusion criteria: anticipated initiation or change in concomitant medication known to affect weight or glucose metabolism; any episodes of diabetic ketoacidosis within 90 days; pancreatitis within 180 days; NYHA Class IV HF; recurrent severe hypoglycemic episodes within the last year; uncontrolled and potentially unstable diabetic retinopathy or maculopathy; pregnancy or lactation.
Interventions
N=340 basal insulin icodec plus semaglutide (IcoSema) (once-weekly subcutaneous injection on the same day every week for 52 weeks).
N=339 basal bolus therapy only (once-daily subcutaneous insulin glargine U100 with 2-4 daily insulin aspart injections for 52 weeks).
Primary outcome
Mean reduction in hemoglobin A1c at week 52
1.47%
1.4%
1.5 %
1.1 %
0.7 %
0.4 %
0.0 %
Basal insulin icodec plus semaglutide
(IcoSema)
Basal bolus therapy
only
Difference not exceeding
non-inferiority
margin ✓
Difference not exceeding non-inferiority margin in mean reduction in HbA1c at week 52 (1.47% vs. 1.4%; MD 0.06, 95% CI -0.09 to 0.22).
Secondary outcomes
Significant decrease in overall rate of clinically significant or severe hypoglycemia at week 57 (0.21 episodes / p-y of exposure vs. 2.23 episodes / p-y of exposure; RR 0.12, 95% CI 0.08 to 0.17).
Safety outcomes
No significant difference in adverse events.
Conclusion
In adult patients with T2DM receiving daily basal insulin, basal insulin icodec plus semaglutide (IcoSema) was noninferior to basal bolus therapy only with respect to mean reduction in HbA1c at week 52.
Reference
Liana K Billings, Francesco Andreozzi, Marie Frederiksen et al. 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. Lancet Diabetes Endocrinol. 2025 Jun 4:S2213-8587(25)00052-X. Online ahead of print.
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