Once-weekly IcoSema versus once-daily insulin glargine U100 in type 2 diabetes management (COMBINE 4): an open-label, multicentre, treat-to-target, randomised, phase 3b trial
Primary result · Mean change in HbA1cResult — go to the resultEstimated treatment difference −0.88 percentage points 95% CI −1.12 to −0.63Authors' conclusion
Once-weekly IcoSema demonstrated superior HbA1c reduction and bodyweight change, with lower rates of clinically significant or severe hypoglycaemia, versus glargine U100
Study context
- Population
- Adults (≥18 years) with T2D (HbA1c ≥8.0%) receiving oral glucose-lowering medications, 97 sites in nine countries; median age 58 years, 59% malerandomised 1:1
- Participants
- 485 adults
- Comparison
- Once-weekly IcoSema vs once-daily glargine U100
- IcoSeman = 243
- Glargine U100n = 242reference
- Primary endpoint
- Change in HbA1c from baseline
- Follow-up
- Week 40
Methodological detailsopen-label, multicentre, treat-to-target, phase 3b, 1:1 randomisation without stratification, 40-week trial; titration target 3.9-5.0 mmol/L (70-90 mg/dL)
- Open-label
- Multicentre
- Treat-to-target
- Phase 3b
- 1:1 randomisation without stratification
- 40-week trial; titration target 3.9-5.0 mmol/L (70-90 mg/dL)
Primary result
Mean change in HbA1c · baseline to week 40
Estimated treatment difference
−0.88 percentage points
95% CI −1.12 to −0.63
P < 0.001
Change by group
IcoSema
−3.32
mean · percentage points
Glargine U100
−2.44
mean · percentage points
IcoSemavs glargine U100
estimated treatment difference −0.88 percentage points (95% CI −1.12 to −0.63); P < 0.001
As reported in the abstract
Further findings
Baseline HbA1c
Mean, kg
| Outcome | IcoSema | Glargine U100 | Estimated treatment difference (kg) (95% CI) | P value | |
|---|---|---|---|---|---|
| Mean change in bodyweight (secondary confirmatory endpoint) · baseline to week 40Superiority confirmed | −0.79 | 3.81 | −4.61 (−5.46 to −3.75) | P < 0.001 | |
| −10−505Difference, kg (linear scale) |
Safety
| Outcome | IcoSema | Glargine U100 | Estimated rate ratio (95% CI) | P value | |
|---|---|---|---|---|---|
| Combined clinically significant (blood glucose <3.0 mmol/L [<54 mg/dL]) or severe hypoglycaemiaEpisodes per person-year of exposure | 0.29 | 0.59 | 0.56 (0.32–0.97) | P = 0.04 | |
| 0.20.5125Estimated rate ratio (log scale) |
Adverse events · weeks 0-45
- Gastrointestinal disorders were the most frequently reported adverse events with IcoSema
Original publication
Once-weekly IcoSema versus once-daily insulin glargine U100 in type 2 diabetes management (COMBINE 4): an open-label, multicentre, treat-to-target, randomised, phase 3b trial. Lancet Diabetes Endocrinol. Published 13 August 2026. doi:10.
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