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.

Billings LK, Andreozzi F, Frederiksen M, Gourdy P, Gowda A, Ji L, Pletsch-Borba L, Suzuki R, Unnikrishnan AG, Vianna AGD

The lancet. Diabetes & endocrinology4 Jun 2025Cited by 19 (Europe PMC)

PMID40482670DOI10.1016/s2213-8587(25)00052-xPepBankPUB-40482670

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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 study5

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

Studies that did not test the peptide alone5

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 daily basal insulin, once-weekly IcoSema (icodec plus semaglutide) was non-inferior to basal-bolus therapy for HbA1c change at week 52 (estimated difference -0·06 percentage points).
In plain wordsIn adults with type 2 diabetes, a weekly insulin-plus-semaglutide product lowered HbA1c about as much as daily multiple insulin injections.
Peptide
Semaglutide
Outcome
No significant changeHbA1c change from baseline to week 52
Study
n = 679
Comparator
Basal-bolus therapy (insulin glargine U100 plus insulin aspart)
Analysis
Primary
Outcome group
Glycemic control · Metabolic and weight
Measurements
HbA1c change
−1.47 percentage points
IcoSema
HbA1c change
−1.4 percentage points
BBT
Estimated treatment difference
−0.06 percentage points
IcoSema versus BBT
Source sentences
Summary
At week 52, estimated mean change in HbA_1c was -1·47 percentage points (SE 0·05; -16·0 mmol/mol [0·6]) with IcoSema and -1·40 percentage points (0·06; -15·3 mmol/mol [0·7]) with BBT, confirming non-inferiority of IcoSema versus BBT (estimated treatment difference [ETD] -0·06 percentage po…
2 context sentences(design, population, supporting numbers)
Summary · context
We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin.
Summary · context
COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries.
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-4048267001
02HumanNot a test of Semaglutide aloneRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes on daily basal insulin, once-weekly IcoSema (icodec plus semaglutide) reduced bodyweight more than basal-bolus therapy at week 52 (estimated difference -6·72 kg).
In plain wordsIn adults with type 2 diabetes, a weekly insulin-plus-semaglutide product led to lower body weight than daily multiple insulin injections.
Peptide
Semaglutide
Outcome
DecreaseBodyweight change from baseline to week 52
Study
n = 679
Comparator
Basal-bolus therapy (insulin glargine U100 plus insulin aspart)
Analysis
Secondary
Outcome group
Body weight · Metabolic and weight
Measurements
Estimated treatment difference in bodyweight
−6.72 kg
IcoSema versus BBT
Source sentences
Summary
Superiority was confirmed for IcoSema versus BBT for change in bodyweight from baseline to week 52 (ETD -6·72 kg [95% CI -7·58 to -5·86]; p<0·0001
2 context sentences(design, population, supporting numbers)
Summary · context
We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin.
Summary · context
COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries.
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-4048267002
03HumanNot a test of Semaglutide aloneRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes on daily basal insulin, once-weekly IcoSema (icodec plus semaglutide) needed a lower weekly total insulin dose than basal-bolus therapy during weeks 50-52 (estimated difference -270 U).
In plain wordsIn adults with type 2 diabetes, a weekly insulin-plus-semaglutide product needed less total insulin than daily multiple insulin injections.
Peptide
Semaglutide
Outcome
DecreaseWeekly total insulin dose during weeks 50-52
Study
n = 679
Comparator
Basal-bolus therapy (insulin glargine U100 plus insulin aspart)
Analysis
Secondary
Outcome group
Glycemic control · Metabolic and weight
Measurements
Estimated treatment difference in weekly insulin dose
−270 U
IcoSema versus BBT
Source sentences
Summary
weekly total insulin dose during weeks 50-52 (ETD -270 U [-303 to -236]; p<0·0001
2 context sentences(design, population, supporting numbers)
Summary · context
We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin.
Summary · context
COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries.
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-4048267003
04HumanNot a test of Semaglutide aloneRandomized controlled trialSafety outcome
In adults with type 2 diabetes on daily basal insulin, once-weekly IcoSema (icodec plus semaglutide) had a lower rate of clinically significant or severe hypoglycaemia than basal-bolus therapy (0·21 vs 2·23 episodes per person-year).
In plain wordsIn adults with type 2 diabetes, a weekly insulin-plus-semaglutide product caused fewer low blood sugar events than daily multiple insulin injections.
Peptide
Semaglutide
Outcome
DecreaseClinically significant or severe hypoglycaemia rate to week 57
Study
n = 679
Comparator
Basal-bolus therapy (insulin glargine U100 plus insulin aspart)
Analysis
Secondary
Outcome group
Adverse events · Metabolic and weight
Measurements
Hypoglycaemia rate
0.21 episodes per person-year
IcoSema
Hypoglycaemia rate
2.23 episodes per person-year
BBT
Estimated rate ratio
0.12 ratio
IcoSema versus BBT
Source sentences
Summary
overall rate of clinically significant or severe hypoglycaemia from baseline to week 57 (0·21 vs 2·23 episodes per person-year of exposure; estimated rate ratio 0·12 [0·08 to 0·17]; p<0·0001).
2 context sentences(design, population, supporting numbers)
Summary · context
We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin.
Summary · context
COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries.
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-4048267004
05HumanNot 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 (148 [44%] of 340 participants).
In plain wordsIn adults with type 2 diabetes, stomach and gut problems were the most common side effects of a weekly insulin-plus-semaglutide product.
Peptide
Semaglutide
Outcome
Not applicableGastrointestinal adverse events with IcoSema
Study
n = 340
Comparator
Basal-bolus therapy (insulin glargine U100 plus insulin aspart)
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Participants with gastrointestinal adverse events
148 participants
IcoSema, n=340
Source sentences
Summary
The most frequently reported adverse events during the trial were gastrointestinal disorders with IcoSema (148 [44%] of 340 participants had 443 events
2 context sentences(design, population, supporting numbers)
Summary · context
We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin.
Summary · context
COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries.
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-4048267005

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 3NCT05013229

A Research Study to See How Well the New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Level in People With Type 2 Diabetes Compared to Insulin Glargine Taken Daily With Insulin Aspart (COMBINE 3)

Novo Nordisk A/Sn = 67930 Nov 2021 to 14 Nov 2023

Diabetes Mellitus, Type 2

Trial page ClinicalTrials.govUpdated 2 Dec 2025

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.

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