The Gastrointestinal Safety of Orforglipron, a GLP-1 Receptor Agonist, in Adults With or Without Type 2 Diabetes: A Network Meta-Analysis of Randomized Controlled Trials.

Hageen AW, Gadelmawla AF, Saleh AO, Abdallfatah A, Mohamed MR, El-Nemr AF, Maihoub O, Elsekhary A, Eladawi S, Ayalew BD, Mansour A, Radi AA, Abuelazm M, Flefel MG

Endocrinology, diabetes & metabolism1 May 2026Cited by 1 (Europe PMC)

PMID42116665PMCIDPMC13161550DOI10.1002/edm2.70222PepBankPUB-42116665

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Summary

Background and aimOrforglipron (OFG), an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1 RA), has demonstrated significant weight loss and glycemic benefits in adults with or without type 2 diabetes (T2DM). However, its gastrointestinal (GI), hepatic and pancreatic safety profile has not been systematically evaluated. This network meta-analysis aimed to assess GI adverse events (AEs), hepatic and pancreatic outcomes, and enzyme changes across different OFG doses.MethodsA frequentist network meta-analysis was conducted in accordance with the PRISMA guidelines. PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM. We considered random-effects models to express treatment effects as odds ratios (OR) and mean differences (MD) with 95% confidence intervals (95% CI). RStudio software (version 4.5.1) was used for analysis.ResultsAll OFG doses (3, 12, 24, 36 and 45 mg) increased GI AEs compared to placebo, with a clear dose-response trend. High-dose OFG (45 mg) markedly increased nausea (OR 11.48, 95% CI: 6.52-20.21), vomiting (OR 11.48, 95% CI: 6.52-20.21), diarrhoea (OR 3.99, 95% CI: 2.07-7.70) and discontinuation due to GI AEs (OR 10.22, 95% CI: 4.99-20.94). No dose increased pancreatitis risk (p > 0.05). Higher doses significantly reduced ALT, with the most significant reduction observed at 24 mg (MD -11.19 IU/L, 95% CI: -19.18 to -3.21). Doses ≥ 12 mg increased lipase (e.g., 24 mg: +28.52 IU/L, 95% CI: 12.02-45.01) and pancreatic amylase (45 mg: +18.20 IU/L, 95% CI: 9.49-26.91), without corresponding increases in clinical events. AST and ALP levels remained similar to those of the placebo. Subgroup analyses showed consistent effects in patients with or without T2DM.ConclusionOral OFG showed dose-dependent GI adverse effects over 26 weeks. Higher doses improve ALT and elevate pancreatic enzymes without clinical manifestations. The safety profile aligns with established GLP-1 RAs.

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

Results from this study15

15 results from studies that gave the peptide. 15 results from people.

01HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 3 mg increased gastrointestinal adverse events versus placebo.
In plain wordsIn adults with or without diabetes, orforglipron 3 mg increased gut-related adverse events compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseGastrointestinal adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
3 mg · oralAs given in this study (human).
Source sentences
Summary
All OFG doses (3, 12, 24, 36 and 45 mg) increased GI AEs compared to placebo, with a clear dose-response trend.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666501
02HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 12 mg increased gastrointestinal adverse events versus placebo.
In plain wordsIn adults with or without diabetes, orforglipron 12 mg increased gut-related adverse events compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseGastrointestinal adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
12 mg · oralAs given in this study (human).
Source sentences
Summary
All OFG doses (3, 12, 24, 36 and 45 mg) increased GI AEs compared to placebo, with a clear dose-response trend.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666502
03HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 24 mg increased gastrointestinal adverse events versus placebo.
In plain wordsIn adults with or without diabetes, orforglipron 24 mg increased gut-related adverse events compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseGastrointestinal adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
24 mg · oralAs given in this study (human).
Source sentences
Summary
All OFG doses (3, 12, 24, 36 and 45 mg) increased GI AEs compared to placebo, with a clear dose-response trend.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666503
04HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 36 mg increased gastrointestinal adverse events versus placebo.
In plain wordsIn adults with or without diabetes, orforglipron 36 mg increased gut-related adverse events compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseGastrointestinal adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
36 mg · oralAs given in this study (human).
Source sentences
Summary
All OFG doses (3, 12, 24, 36 and 45 mg) increased GI AEs compared to placebo, with a clear dose-response trend.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666504
05HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 45 mg increased gastrointestinal adverse events versus placebo.
In plain wordsIn adults with or without diabetes, orforglipron 45 mg increased gut-related adverse events compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseGastrointestinal adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
45 mg · oralAs given in this study (human).
Source sentences
Summary
All OFG doses (3, 12, 24, 36 and 45 mg) increased GI AEs compared to placebo, with a clear dose-response trend.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666505
06HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 45 mg increased nausea versus placebo, with OR 11.48.
In plain wordsIn adults with or without diabetes, orforglipron 45 mg increased nausea compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseNausea
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
45 mg · oralAs given in this study (human).
Measurements
Odds ratio
11.48
nausea
95% confidence interval for nausea odds ratio
6.52 to 20.21
orforglipron 45 mg vs placebo
Source sentences
Summary
High-dose OFG (45 mg) markedly increased nausea (OR 11.48, 95% CI: 6.52-20.21), vomiting (OR 11.48, 95% CI: 6.52-20.21), diarrhoea (OR 3.99, 95% CI: 2.07-7.70) and discontinuation due to GI AEs (OR 10.22, 95% CI: 4.99-20.94).
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666506
07HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 45 mg increased vomiting versus placebo, with OR 11.48.
In plain wordsIn adults with or without diabetes, orforglipron 45 mg increased vomiting compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseVomiting
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
45 mg · oralAs given in this study (human).
Measurements
Odds ratio
11.48
vomiting
95% confidence interval for vomiting odds ratio
6.52 to 20.21
orforglipron 45 mg vs placebo
Source sentences
Summary
High-dose OFG (45 mg) markedly increased nausea (OR 11.48, 95% CI: 6.52-20.21), vomiting (OR 11.48, 95% CI: 6.52-20.21), diarrhoea (OR 3.99, 95% CI: 2.07-7.70) and discontinuation due to GI AEs (OR 10.22, 95% CI: 4.99-20.94).
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666507
08HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 45 mg increased diarrhoea versus placebo, with OR 3.99.
In plain wordsIn adults with or without diabetes, orforglipron 45 mg increased diarrhoea compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseDiarrhoea
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
45 mg · oralAs given in this study (human).
Measurements
Odds ratio
3.99
diarrhoea
95% confidence interval for diarrhoea odds ratio
2.07 to 7.7
orforglipron 45 mg vs placebo
Source sentences
Summary
High-dose OFG (45 mg) markedly increased nausea (OR 11.48, 95% CI: 6.52-20.21), vomiting (OR 11.48, 95% CI: 6.52-20.21), diarrhoea (OR 3.99, 95% CI: 2.07-7.70) and discontinuation due to GI AEs (OR 10.22, 95% CI: 4.99-20.94).
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666508
09HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron 45 mg increased discontinuation due to GI adverse events versus placebo, with OR 10.22.
In plain wordsIn adults with or without diabetes, orforglipron 45 mg increased treatment discontinuation due to gut-related adverse events compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseDiscontinuation due to GI adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Adverse events · Gastrointestinal
Studied dose
45 mg · oralAs given in this study (human).
Measurements
Odds ratio
10.22
discontinuation due to GI AEs
95% confidence interval for discontinuation due to GI adverse events odds ratio
4.99 to 20.94
orforglipron 45 mg vs placebo
Source sentences
Summary
High-dose OFG (45 mg) markedly increased nausea (OR 11.48, 95% CI: 6.52-20.21), vomiting (OR 11.48, 95% CI: 6.52-20.21), diarrhoea (OR 3.99, 95% CI: 2.07-7.70) and discontinuation due to GI AEs (OR 10.22, 95% CI: 4.99-20.94).
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666509
10HumanSystematic reviewSafety outcome
In adults with or without T2DM, no orforglipron dose increased pancreatitis risk versus placebo.
In plain wordsIn adults with or without diabetes, no orforglipron dose increased pancreatitis risk compared with placebo.
Peptide
Orforglipron
Outcome
No significant changePancreatitis risk
Study
n: not reported in source
Comparator
Placebo
Outcome group
Adverse events · Gastrointestinal
Studied dose
Dose not stated · oralAs given in this study (human).
Measurements
p value
> 0.05
pancreatitis risk, all doses
Source sentences
Summary
No dose increased pancreatitis risk (p > 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666510
11HumanSystematic reviewSafety outcome
In adults with or without T2DM, higher orforglipron doses reduced ALT, with the greatest reduction at 24 mg versus placebo.
In plain wordsIn adults with or without diabetes, orforglipron reduced ALT compared with placebo, most strongly at 24 mg.
Peptide
Orforglipron
Outcome
DecreaseALT
Study
n: not reported in source
Comparator
Placebo
Outcome group
Liver fat and liver function · Liver
Studied dose
24 mg · oralAs given in this study (human).
Measurements
ALT mean difference
−11.19 IU/L
24 mg
95% confidence interval for ALT mean difference
−19.18 to −3.21 IU/L
orforglipron 24 mg vs placebo
Source sentences
Summary
Higher doses significantly reduced ALT, with the most significant reduction observed at 24 mg (MD -11.19 IU/L, 95% CI: -19.18 to -3.21).
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666511
12HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron doses ≥ 12 mg increased lipase, including +28.52 IU/L at 24 mg.
In plain wordsIn adults with or without diabetes, orforglipron increased lipase compared with placebo.
Peptide
Orforglipron
Outcome
IncreaseLipase
Study
n: not reported in source
Comparator
Placebo
Outcome group
Adverse events · Gastrointestinal
Studied dose
≥12 mg · oralAs given in this study (human).
Measurements
Lipase change
28.52 IU/L
24 mg
95% confidence interval for lipase change
12.02 to 45.01 IU/L
orforglipron 24 mg vs placebo
Source sentences
Summary
Doses ≥ 12 mg increased lipase (e.g., 24 mg: +28.52 IU/L, 95% CI: 12.02-45.01) and pancreatic amylase (45 mg: +18.20 IU/L, 95% CI: 9.49-26.91), without corresponding increases in clinical events.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666512
13HumanSystematic reviewSafety outcome
In adults with or without T2DM, orforglipron doses ≥ 12 mg increased pancreatic amylase, including +18.20 IU/L at 45 mg.
In plain wordsIn adults with or without diabetes, orforglipron increased pancreatic amylase compared with placebo.
Peptide
Orforglipron
Outcome
IncreasePancreatic amylase
Study
n: not reported in source
Comparator
Placebo
Outcome group
Adverse events · Gastrointestinal
Studied dose
≥12 mg · oralAs given in this study (human).
Measurements
Pancreatic amylase change
18.2 IU/L
45 mg
95% confidence interval for pancreatic amylase change
9.49 to 26.91 IU/L
orforglipron 45 mg vs placebo
Source sentences
Summary
Doses ≥ 12 mg increased lipase (e.g., 24 mg: +28.52 IU/L, 95% CI: 12.02-45.01) and pancreatic amylase (45 mg: +18.20 IU/L, 95% CI: 9.49-26.91), without corresponding increases in clinical events.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666513
14HumanSystematic reviewSafety outcome
In adults with or without T2DM, AST remained similar with orforglipron and placebo.
In plain wordsIn adults with or without diabetes, AST levels were similar with orforglipron and placebo.
Peptide
Orforglipron
Outcome
No significant changeAST
Study
n: not reported in source
Comparator
Placebo
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
AST and ALP levels remained similar to those of the placebo.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666515
15HumanSystematic reviewSafety outcome
In adults with or without T2DM, ALP remained similar with orforglipron and placebo.
In plain wordsIn adults with or without diabetes, ALP levels were similar with orforglipron and placebo.
Peptide
Orforglipron
Outcome
No significant changeALP
Study
n: not reported in source
Comparator
Placebo
Outcome group
Liver fat and liver function · Liver
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
AST and ALP levels remained similar to those of the placebo.
1 context sentence(design, population, supporting numbers)
Summary · context
PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM.
Show in the study text Report a problemFND-4211666516

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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
14 Oct 2026, 05:02 UTC
Study results updated
Version 1
14 Oct 2026, 01:46 UTC
First added · source update from Europe PMC

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