Once‑weekly IcoSema versus once‑weekly insulin icodec in type 2 diabetes management (COMBINE 1): an open‑label, multicentre, treat‑to‑target, randomised, phase 3a trial.

Mathieu C, Giorgino F, Kim SG, Larsen JH, Philis-Tsimikas A, Ramachandran A, Pagliaro Rocha TM, Shankarappa VB, Terauchi Y, Ji L

The lancet. Diabetes & endocrinology4 Jun 2025Cited by 20 (Europe PMC)

PMID40482671DOI10.1016/s2213-8587(25)00096-8PepBankPUB-40482671

Publisher page PubMedAsk about this study

Jump to 5 results

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

3 results from studies that gave the peptide. 3 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes on daily basal insulin, once-weekly IcoSema (icodec plus semaglutide) lowered HbA1c more than icodec alone at week 52 (estimated difference -0·66 percentage points).
In plain wordsIn adults with type 2 diabetes, weekly insulin with semaglutide lowered HbA1c more than weekly insulin icodec alone.
Peptide
Semaglutide
Outcome
DecreaseHbA1c change from baseline to week 52
Study
n = 1,291
Comparator
Once-weekly insulin icodec
Analysis
Primary
Outcome group
Glycemic control · Metabolic and weight
Studied dose
IcoSema 700 U/mL icodec plus 2 mg/mL semaglutide · subcutaneous · 52 weeksAs given in this study (human).
Measurements
HbA1c change
−1.55 percentage points
IcoSema
HbA1c change
−0.89 percentage points
icodec
Estimated treatment difference
−0.66 percentage points
IcoSema versus icodec
Source sentences
Summary
estimated mean change in HbA_1c was -1·55 percentage points (SE 0·03; -16·9 mmol/mol [0·4]) with IcoSema and -0·89 percentage points (SE 0·03]; -9·7 mmol/mol [0·4]) with icodec (estimated treatment difference [ETD] -0·66 percentages points [95% CI -0·76 to -0·57]; -7·3 mmol/mol [-8·3 to -6…
2 context sentences(design, population, supporting numbers)
Summary · context
COMBINE 1 compared the efficacy and safety of IcoSema with once‑weekly icodec alone in adults with inadequately controlled type 2 diabetes on daily basal insulin therapy.
Summary · context
Between June 1, 2022, and March 13, 2023, 1671 individuals were screened, of whom 1291 (mean age 60·6 years [SD 10·3]; 799 [62%] males and 492 [38%] females) were randomly assigned to IcoSema (n=646) or icodec (n=645).
Report a problemFND-4048267101
02HumanRandomized controlled trialSafety outcome
In adults with type 2 diabetes on daily basal insulin, IcoSema (icodec plus semaglutide) had a lower rate of clinically significant or severe hypoglycaemia than icodec alone (0·14 vs 0·63 episodes per person-year).
In plain wordsIn adults with type 2 diabetes, weekly insulin with semaglutide caused fewer low blood sugar events than weekly insulin icodec alone.
Peptide
Semaglutide
Outcome
DecreaseClinically significant or severe hypoglycaemia rate to week 57
Study
n = 1,291
Comparator
Once-weekly insulin icodec
Outcome group
Adverse events · Metabolic and weight
Studied dose
IcoSema 700 U/mL icodec plus 2 mg/mL semaglutide · subcutaneous · 52 weeksAs given in this study (human).
Measurements
Hypoglycaemia rate
0.14 episodes per person-year
IcoSema
Hypoglycaemia rate
0.63 episodes per person-year
icodec
Estimated rate ratio
0.22 ratio
IcoSema versus icodec
Source sentences
Summary
The rate of combined clinically significant or severe hypoglycaemia from baseline to week 57 was significantly lower with IcoSema than with icodec (0·14 vs 0·63 episodes per person‑year of exposure; estimated rate ratio 0·22 [95% CI 0·14 to 0·36]; p<0·0001; superiority confirmed).
2 context sentences(design, population, supporting numbers)
Summary · context
COMBINE 1 compared the efficacy and safety of IcoSema with once‑weekly icodec alone in adults with inadequately controlled type 2 diabetes on daily basal insulin therapy.
Summary · context
Between June 1, 2022, and March 13, 2023, 1671 individuals were screened, of whom 1291 (mean age 60·6 years [SD 10·3]; 799 [62%] males and 492 [38%] females) were randomly assigned to IcoSema (n=646) or icodec (n=645).
Report a problemFND-4048267102
03HumanRandomized controlled trialSafety outcome
In adults with type 2 diabetes, serious adverse events occurred in 59 (9%) participants with IcoSema and 69 (11%) with icodec alone.
In plain wordsIn adults with type 2 diabetes, serious side effects occurred in 9% on weekly insulin with semaglutide and 11% on icodec alone.
Peptide
Semaglutide
Outcome
Not applicableSerious adverse events
Study
n = 1,288
Comparator
Once-weekly insulin icodec
Outcome group
Adverse events · Whole body
Studied dose
IcoSema 700 U/mL icodec plus 2 mg/mL semaglutide · subcutaneous · 52 weeksAs given in this study (human).
Measurements
Participants with serious adverse events
59 participants
IcoSema
Participants with serious adverse events
69 participants
icodec
Source sentences
Summary
59 (9%) participants in the IcoSema group and 69 (11%) participants in the icodec group had a serious adverse event.
2 context sentences(design, population, supporting numbers)
Summary · context
COMBINE 1 compared the efficacy and safety of IcoSema with once‑weekly icodec alone in adults with inadequately controlled type 2 diabetes on daily basal insulin therapy.
Summary · context
Between June 1, 2022, and March 13, 2023, 1671 individuals were screened, of whom 1291 (mean age 60·6 years [SD 10·3]; 799 [62%] males and 492 [38%] females) were randomly assigned to IcoSema (n=646) or icodec (n=645).
Report a problemFND-4048267104

Studies that did not test the peptide alone2

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.

04HumanNot a test of Semaglutide aloneRandomized controlled trialSafety outcome
In adults with type 2 diabetes on daily basal insulin, gastrointestinal disorders were the most frequently reported adverse events with IcoSema (303 [47%] of 644 participants).
In plain wordsIn adults with type 2 diabetes, stomach and gut problems were the most common side effects of weekly insulin with semaglutide.
Peptide
Semaglutide
Outcome
Not applicableGastrointestinal adverse events with IcoSema
Study
n = 1,288
Comparator
Once-weekly insulin icodec
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Participants with gastrointestinal adverse events
303 participants
IcoSema, n=644
Source sentences
Summary
The most frequently reported adverse events were within the system organ class of gastrointestinal disorders in the IcoSema group (303 [47%] of 644 participants had 1033 events
2 context sentences(design, population, supporting numbers)
Summary · context
COMBINE 1 compared the efficacy and safety of IcoSema with once‑weekly icodec alone in adults with inadequately controlled type 2 diabetes on daily basal insulin therapy.
Summary · context
Between June 1, 2022, and March 13, 2023, 1671 individuals were screened, of whom 1291 (mean age 60·6 years [SD 10·3]; 799 [62%] males and 492 [38%] females) were randomly assigned to IcoSema (n=646) or icodec (n=645).
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-4048267103
05HumanNot a test of Semaglutide aloneRandomized controlled trialSafety outcome
In adults with type 2 diabetes, no treatment-related deaths occurred in the IcoSema or icodec groups.
In plain wordsIn adults with type 2 diabetes, no deaths were linked to the treatments.
Peptide
Semaglutide
Outcome
No significant changeTreatment-related deaths
Study
n = 1,288
Comparator
Once-weekly insulin icodec
Outcome group
Mortality · Whole body
Source sentences
Summary
No treatment-related deaths occurred.
2 context sentences(design, population, supporting numbers)
Summary · context
COMBINE 1 compared the efficacy and safety of IcoSema with once‑weekly icodec alone in adults with inadequately controlled type 2 diabetes on daily basal insulin therapy.
Summary · context
Between June 1, 2022, and March 13, 2023, 1671 individuals were screened, of whom 1291 (mean age 60·6 years [SD 10·3]; 799 [62%] males and 492 [38%] females) were randomly assigned to IcoSema (n=646) or icodec (n=645).
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-4048267105

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 · 1 with posted results · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3Results postedNCT05352815

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 Weekly Insulin Icodec

Novo Nordisk A/Sn = 1,2911 Jun 2022 to 23 Apr 2024

Diabetes Mellitus, Type 2

Trial page ClinicalTrials.govUpdated 4 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

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