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.

Ji L, Benamar M, Mohan V, Pletsch-Borba L, Porcellati F, Wang N, Watada H, Rea RR

The lancet. Diabetes & endocrinology13 Aug 2026Cited by 1 (Europe PMC)

PMID42594928DOI10.1016/s2213-8587(26)00136-1PepBankPUB-42594928

Publisher page PubMedAsk about this study

Summary

The text of this summary is not shown here, because the article license does not allow reuse. Read it at the source (opens in a new tab)

Text rights: Publisher copyright. Results still quote short attributed sentences.

Results from this study4

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone4

In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Semaglutide.

01HumanNot a test of Semaglutide aloneRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes on oral glucose-lowering medications, once-weekly IcoSema (insulin icodec plus semaglutide) lowered HbA1c more than once-daily insulin glargine U100 at week 40.
In plain wordsIn adults with type 2 diabetes, the once-weekly IcoSema combination lowered HbA1c more than daily insulin glargine.
Peptide
Semaglutide
Outcome
DecreaseHbA1c change from baseline to week 40
Study
n = 485
Comparator
Insulin glargine U100
Analysis
Primary
Outcome group
Glycemic control · Metabolic and weight
Source sentences
Summary
For HbA_1c, from baseline (9·57% for IcoSema and 9·50% for glargine U100), mean change to week 40 was greater with IcoSema versus glargine U100 (-3·32 vs -2·44 percentage points; estimated treatment difference [ETD] -0·88 percentage points [95% CI -1·12 to -0·63]), confirming superiority of IcoSema (p<0·001).
1 context sentence(design, population, supporting numbers)
Summary · context
Adults (aged ≥18 years) with type 2 diabetes (HbA_1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Report a problemFND-4259492801
02HumanNot a test of Semaglutide aloneRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes on oral glucose-lowering medications, bodyweight fell with once-weekly IcoSema and rose with insulin glargine U100 over 40 weeks.
In plain wordsIn adults with type 2 diabetes, weight fell with the IcoSema combination and rose with daily insulin glargine.
Peptide
Semaglutide
Outcome
DecreaseBodyweight change from baseline to week 40
Study
n = 485
Comparator
Insulin glargine U100
Analysis
Secondary
Outcome group
Body weight · Metabolic and weight
Source sentences
Summary
From baseline to week 40, mean bodyweight decreased with IcoSema and increased with glargine U100 (-0·79 vs 3·81 kg; ETD -4·61 kg [95% CI -5·46 to -3·75]), confirming superiority of IcoSema (p<0·001).
1 context sentence(design, population, supporting numbers)
Summary · context
Adults (aged ≥18 years) with type 2 diabetes (HbA_1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Report a problemFND-4259492802
03HumanNot a test of Semaglutide aloneRandomized controlled trialSafety outcome
In adults with type 2 diabetes on oral glucose-lowering medications, the rate of clinically significant or severe hypoglycaemia was lower with IcoSema than with insulin glargine U100.
In plain wordsIn adults with type 2 diabetes, the IcoSema combination caused fewer serious low blood sugar episodes than daily insulin glargine.
Peptide
Semaglutide
Outcome
DecreaseClinically significant or severe hypoglycaemia rate
Study
n: not reported in source
Comparator
Insulin glargine U100
Outcome group
Glycemic control · Metabolic and weight
Source sentences
Summary
Rate of combined clinically significant (blood glucose <3·0 mmol/L [<54 mg/dL], confirmed with a blood glucose meter) or severe hypoglycaemia (severe cognitive impairment requiring external assistance for recovery) was statistically significantly lower with IcoSema versus glargine U100 (0·29 vs 0·59…
1 context sentence(design, population, supporting numbers)
Summary · context
Adults (aged ≥18 years) with type 2 diabetes (HbA_1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Report a problemFND-4259492803
04HumanNot a test of Semaglutide aloneRandomized controlled trialSafety outcome
In adults with type 2 diabetes, gastrointestinal disorders were the most frequently reported adverse events with IcoSema.
In plain wordsIn adults with type 2 diabetes, stomach and gut problems were the most common side effects reported with the IcoSema combination.
Peptide
Semaglutide
Outcome
Not applicableGastrointestinal adverse events
Study
n: not reported in source
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Source sentences
Summary
Gastrointestinal disorders were the most frequently reported adverse events with IcoSema.
1 context sentence(design, population, supporting numbers)
Summary · context
Adults (aged ≥18 years) with type 2 diabetes (HbA_1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Report a problemFND-4259492804

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3NCT06269107

A Research Study to See How Well New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Levels in People With Type 2 Diabetes (T2D), Compared to Daily Insulin Glargine (COMBINE 4)

Novo Nordisk A/Sn = 48515 Feb 2024 to 8 Jul 2025

Type 2 Diabetes

Trial page ClinicalTrials.govUpdated 5 Jun 2026

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

PepBank is a research reference. Talk to a doctor before you use any peptide.