Comparative gastrointestinal adverse effects of GLP-1 receptor agonists and multi-target analogs in type 2 diabetes: a Bayesian network meta-analysis.

Xie X, Yang S, Deng S, Liu Y, Xu Z, He B

Frontiers in pharmacology19 Sept 2025Cited by 30 (Europe PMC)

PMID41050409PMCIDPMC12491879DOI10.3389/fphar.2025.1613610PepBankPUB-41050409

Summary

ObjectiveThis study aims to evaluate and compare the gastrointestinal adverse effects associated with different GLP-1 receptor agonists (GLP-1RAs) and multi-target analogs in patients with type 2 diabetes mellitus (T2DM) using a Bayesian network meta-analysis.MethodsA systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients. Inclusion criteria included adult patients with confirmed T2DM receiving any GLP-1RA, with the outcomes focused on gastrointestinal adverse events such as nausea, vomiting, diarrhea, constipation, dyspepsia, and reduced appetite. Bayesian network meta-analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the comparison of gastrointestinal side effects among different GLP-1RAs.ResultsA total of 48 RCTs involving 27,729 participants were included in the analysis. The overall incidence of gastrointestinal adverse events was 11.66%, with nausea being the most frequent (21.49%) and reduced appetite the least frequent (5.49%). Tirzepatide had the highest risk of inducing nausea and diarrhea, while dulaglutide and lixisenatide had the lowest risks. Exenatide exhibited the highest incidence of vomiting, while dulaglutide showed a lower risk. Semaglutide demonstrated a significantly higher risk of diarrhea compared to other GLP-1RAs.ConclusionThis study highlights significant differences in the gastrointestinal adverse event profiles of various GLP-1RAs. Tirzepatide exhibited the highest risk of gastrointestinal side effects, whereas dulaglutide and exenatide showed relatively better tolerability. These findings provide valuable insights for clinicians to make informed treatment decisions, emphasizing the importance of individualized therapy based on patient tolerance.Systematic review registrationCRD42024592308.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study9

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

01HumanSystematic reviewSafety outcome
In adults with type 2 diabetes, tirzepatide had the highest risk of nausea among the GLP-1 receptor agonists and multi-target analogs in the network meta-analysis.
In plain wordsIn type 2 diabetes trials, tirzepatide had a higher risk of nausea than the other GLP-1 type drugs.
Peptide
Tirzepatide
Outcome
IncreaseNausea risk ranking
Study
n: not reported in source
Comparator
Other GLP-1 receptor agonists
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
Tirzepatide had the highest risk of inducing nausea and diarrhea, while dulaglutide and lixisenatide had the lowest risks.
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
Show in the study text Report a problemFND-4105040907
02HumanSystematic reviewSafety outcome
In adults with type 2 diabetes, tirzepatide had the highest risk of diarrhea among the GLP-1 receptor agonists and multi-target analogs in the network meta-analysis.
In plain wordsIn type 2 diabetes trials, tirzepatide had a higher risk of diarrhea than the other GLP-1 type drugs.
Peptide
Tirzepatide
Outcome
IncreaseDiarrhea risk ranking
Study
n: not reported in source
Comparator
Other GLP-1 receptor agonists
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
Tirzepatide had the highest risk of inducing nausea and diarrhea, while dulaglutide and lixisenatide had the lowest risks.
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
Show in the study text Report a problemFND-4105040908
03HumanSystematic reviewSafety outcome
In adults with type 2 diabetes, semaglutide carried a significantly higher risk of diarrhea than other GLP-1 receptor agonists.
In plain wordsIn type 2 diabetes trials, semaglutide was linked to a higher risk of diarrhea than the other GLP-1 type drugs.
Peptide
Semaglutide
Outcome
IncreaseDiarrhea risk versus other GLP-1RAs
Study
n: not reported in source
Comparator
Other GLP-1 receptor agonists
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
Dose not stated
Source sentences
Summary
Semaglutide demonstrated a significantly higher risk of diarrhea compared to other GLP-1RAs.
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
Show in the study text Report a problemFND-4105040909

Studies that did not test the peptide alone6

In this study, the peptide 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 the peptide.

04HumanNot a test of Semaglutide aloneSystematic reviewSafety outcome
In adults with type 2 diabetes, pooled across 48 RCTs of GLP-1 receptor agonists and multi-target analogs (including semaglutide), the incidence of gastrointestinal adverse events was 11.66%.
In plain wordsAcross many trials of GLP-1 type drugs in type 2 diabetes, 11.66% of people had a gut side effect.
Peptide
Semaglutide
Outcome
Not applicableOverall incidence of gastrointestinal adverse events (all GLP-1RAs)
Study
n = 27,729
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Overall GI adverse event incidence
11.66%
all agents pooled
Source sentences
Summary
The overall incidence of gastrointestinal adverse events was 11.66%, with nausea being the most frequent (21.49%) and reduced appetite the least frequent (5.49%).
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
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.
Show in the study text Report a problemFND-4105040901
05HumanNot a test of Tirzepatide aloneSystematic reviewSafety outcome
In adults with type 2 diabetes, pooled across 48 RCTs of GLP-1 receptor agonists and multi-target analogs (including tirzepatide), the incidence of gastrointestinal adverse events was 11.66%.
In plain wordsAcross many trials of GLP-1 type drugs in type 2 diabetes, 11.66% of people had a gut side effect.
Peptide
Tirzepatide
Outcome
Not applicableOverall incidence of gastrointestinal adverse events (all GLP-1RAs)
Study
n = 27,729
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Overall GI adverse event incidence
11.66%
all agents pooled
Source sentences
Summary
The overall incidence of gastrointestinal adverse events was 11.66%, with nausea being the most frequent (21.49%) and reduced appetite the least frequent (5.49%).
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
In this study, Tirzepatide 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 Tirzepatide.
Show in the study text Report a problemFND-4105040902
06HumanNot a test of Semaglutide aloneSystematic reviewSafety outcome
In adults with type 2 diabetes, across pooled GLP-1 receptor agonists and multi-target analogs (including semaglutide), nausea was the most frequent gastrointestinal adverse event (21.49%).
In plain wordsAcross many trials of GLP-1 type drugs in type 2 diabetes, nausea was the most common gut side effect (21.49%).
Peptide
Semaglutide
Outcome
Not applicableNausea incidence (all GLP-1RAs)
Study
n = 27,729
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Nausea incidence
21.49%
all agents pooled
Source sentences
Summary
with nausea being the most frequent (21.49%) and reduced appetite the least frequent (5.49%).
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
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.
Show in the study text Report a problemFND-4105040903
07HumanNot a test of Tirzepatide aloneSystematic reviewSafety outcome
In adults with type 2 diabetes, across pooled GLP-1 receptor agonists and multi-target analogs (including tirzepatide), nausea was the most frequent gastrointestinal adverse event (21.49%).
In plain wordsAcross many trials of GLP-1 type drugs in type 2 diabetes, nausea was the most common gut side effect (21.49%).
Peptide
Tirzepatide
Outcome
Not applicableNausea incidence (all GLP-1RAs)
Study
n = 27,729
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Nausea incidence
21.49%
all agents pooled
Source sentences
Summary
with nausea being the most frequent (21.49%) and reduced appetite the least frequent (5.49%).
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
In this study, Tirzepatide 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 Tirzepatide.
Show in the study text Report a problemFND-4105040904
08HumanNot a test of Semaglutide aloneSystematic reviewSafety outcome
In adults with type 2 diabetes, across pooled GLP-1 receptor agonists and multi-target analogs (including semaglutide), reduced appetite was the least frequent gastrointestinal adverse event (5.49%).
In plain wordsAcross many trials of GLP-1 type drugs in type 2 diabetes, reduced appetite was the least common gut side effect (5.49%).
Peptide
Semaglutide
Outcome
Not applicableReduced appetite incidence (all GLP-1RAs)
Study
n = 27,729
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Reduced appetite incidence
5.49%
all agents pooled
Source sentences
Summary
reduced appetite the least frequent (5.49%).
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
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.
Show in the study text Report a problemFND-4105040905
09HumanNot a test of Tirzepatide aloneSystematic reviewSafety outcome
In adults with type 2 diabetes, across pooled GLP-1 receptor agonists and multi-target analogs (including tirzepatide), reduced appetite was the least frequent gastrointestinal adverse event (5.49%).
In plain wordsAcross many trials of GLP-1 type drugs in type 2 diabetes, reduced appetite was the least common gut side effect (5.49%).
Peptide
Tirzepatide
Outcome
Not applicableReduced appetite incidence (all GLP-1RAs)
Study
n = 27,729
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Measurements
Reduced appetite incidence
5.49%
all agents pooled
Source sentences
Summary
reduced appetite the least frequent (5.49%).
2 context sentences(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted to identify randomized controlled trials (RCTs) assessing the gastrointestinal adverse events of GLP-1RAs in T2DM patients.
Summary · context
A total of 48 RCTs involving 27,729 participants were included in the analysis.
In this study, Tirzepatide 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 Tirzepatide.
Show in the study text Report a problemFND-4105040906

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

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 4Current
21 Oct 2026, 18:59 UTC
Study data updated · source update from Europe PMC
Version 3
11 Oct 2026, 00:04 UTC
Study results updated
Version 2
9 Oct 2026, 03:07 UTC
Study data updated · source update from Europe PMC
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

Comparative gastrointestinal adverse effects of GLP-1 receptor agonists and multi-target analogs in type 2 diabetes: a Bayesian network meta-analysis.

Summary

Results from this study9

Studies that did not test the peptide alone6

Version history

Subjects

Publication types

Keywords