Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial

Lingvay, I; Benamar, M; Chen, L; Fu, A; Jódar, E; Nishida, T; Riveline, JP; Yabe, D; Zueger, T; Réa, R

doi:10.1007/s00125-024-06348-5

Type 2 & other diabetes

Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial

DiabetologiaPublished 17 Jan 2025Randomised controlled trial

An erratum to this article was published (Diabetologia, Jul 2025 ↗)

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Authors' conclusion

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 HbA1c reduction, 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.

Study context

Population: Adults with T2D (HbA1c 53.0–85.8 mmol/mol [7.0–10.0%]) inadequately managed with GLP-1 RA therapy, with or without oral glucose-lowering medications; 121 sites in 13 countries/regionsrandomised 1:1
Participants: 683 adults

Comparison: Once-weekly IcoSema vs once-weekly semaglutide 1.0 mg
IcoSeman = 342
Semaglutide 1.0 mgn = 341reference
Primary endpoint: Change in HbA1c from baseline
Follow-up: Week 52

Methodological detailsmulticentre, open-label, parallel group, Phase IIIa, superiority

Multicentre
Open-label
Parallel group
Phase IIIa
Superiority

Primary result

As reported in the abstract

Change in HbA1c · baseline to week 52

IcoSema

−14.7

mean · mmol/mol

Semaglutide 1.0 mg

−9.88

mean · mmol/mol

IcoSema vs Semaglutide 1.0 mgEstimated treatment difference, mmol/mol (95% CI)P value

Superiority confirmed

−4.85(−6.13 to −3.57)

P < 0.0001

IcoSema vs Semaglutide 1.0 mgEstimated treatment difference, %-points (95% CI)

Change in HbA1c

−0.44(−0.56 to −0.33)

Secondary outcomes

Estimated mean, mmol/l

Outcome	IcoSema	Semaglutide 1.0 mg	← Lower with IcoSema ←→ Higher with IcoSema →	Estimated treatment difference (mmol) (95% CI)	P value
Change in FPG · baseline to week 52	−2.48	−1.43	−2−101	−1.05 (−1.36 to −0.75)	P < 0.0001
			−2−101Difference, mmol (linear scale)

Mean, kg

Outcome	IcoSema	Semaglutide 1.0 mg	← Lower with IcoSema ←→ Higher with IcoSema →	Estimated treatment difference (kg) (95% CI)	P value
Change in body weight · baseline to week 52	+0.84	−3.70	−50510	4.54 (3.84–5.23)	P < 0.0001
			−50510Difference, kg (linear scale)

Safety

Outcome	IcoSema	Semaglutide 1.0 mg	← Lower with IcoSema ←→ Higher with IcoSema →	Estimated rate ratio (95% CI)	P value
Combined clinically significant (level 2) or severe (level 3) hypoglycaemia · baseline to week 57Episodes per person-year of exposure	0.042	0.036	0.20.5125	1.20 (0.53–2.69)	P = 0.66
			0.20.5125Estimated rate ratio (log scale)

Gastrointestinal adverse events

IcoSema31.4%

Semaglutide 1.0 mg34.4%

Gastrointestinal adverse events

Proportion with GI adverse events similar between groups

Original publication

Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial. Diabetologia. Published 17 January 2025. doi:10.1007/s00125-024-06348-5

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