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Meta-Analysis
. 2025 Dec 26;104(52):e46671.
doi: 10.1097/MD.0000000000046671.

Gastrointestinal side effects of the non-peptide GLP-1 receptor agonists: A systematic review and meta-analysis

Himal Bikram Bhattarai  1 , Basanta Sharma Paudel  2 , Sandesh Raman Parajuli  3 , Krishna Dahal  2 , Sangam Shah  2 , Madhur Bhattarai  2 , Bidisha Baral  4 , Bibek Karki  5 , Bibhusan Basnet  6 , Amit Bhandari  7 , Ranjit Sah  8   9 , Amit Khanal  10 , Khalid Ahmed  5 , Philip McDonald  5
Affiliations
Meta-Analysis

Gastrointestinal side effects of the non-peptide GLP-1 receptor agonists: A systematic review and meta-analysis

Himal Bikram Bhattarai et al. Medicine (Baltimore). .

Abstract

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists, commonly prescribed for diabetes mellitus and weight loss, often cause gastrointestinal side effects in both their oral and injectable forms. Recently, oral non-peptide GLP-1 receptor agonists like danuglipron and orforglipron, which are smaller and more stable, have been investigated. This study analyzes the gastrointestinal side effects of these newer, smaller molecules.

Methods: We performed a systematic review of the literature databases like PubMed, Cochrane, Embase, and clinicaltrials.gov until November 2023. Data related to different doses of oral danuglipron and orforglipron and their gastrointestinal side effects including nausea, vomiting, constipation, diarrhea, eructation, and dyspepsia were obtained. Analysis was done using RevMan v5.4 (The Cochrane Collaboration, Copenhagen, Denmark).

Results: We included a total of 4 studies of which 2 each were for danuglipron and orforglipron. The oral doses of orforglipron studied were 12 mg, 24 mg, 36 mg, and 45 mg, with nausea being the most common side effect in all groups. For the 45 mg dose of orforglipron, the odds ratio (OR) was 4.41 (95% CI: 2.90-6.71), while the 36 mg dose had an OR of 3.99 (95% CI: 2.22-7.18). The OR for the 24 mg dose was 5.66 (95% CI: 3.39-9.45), and the 12 mg dose showed an OR of 5.06 (95% CI: 3.31-7.73). Oral danuglipron at doses of 80 mg and 120 mg were also studied. The 120 mg dose of danuglipron had a pooled OR of 4.38 (95% CI: 2.30-8.34) while the 80 mg dose had an OR of 3.69 (95% CI: 1.77-7.67) indicating a significant decrease in gastrointestinal side effects.

Conclusion: Gastrointestinal side effects of the non-peptide GLP-1 receptor agonists were widely reported but less frequent compared to placebo/ standard treatment. There was no significant dose-dependent increase in the side effects of these medications.

Keywords: GLP-1 receptor agonists; danuglipron; gastrointestinal side effects; obesity; orforglipron; type 2 diabetes mellitus.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Preferred reporting items for systematic reviews and meta‐analyses (PRISMA) flowchart of the included studies.
Figure 2.
Figure 2.
Traffic light plot using ROB2 for risk of bias assessment of included studies.
Figure 3.
Figure 3.
Forest plot showing gastrointestinal side effects of 12 mg orforglipron.
Figure 4.
Figure 4.
Forest plot showing gastrointestinal side effects of 24 mg orforglipron.
Figure 5.
Figure 5.
Forest plot showing gastrointestinal side effects of 36 mg orforglipron.
Figure 6.
Figure 6.
Forest plot showing gastrointestinal side effects of 45 mg orforglipron.
Figure 7.
Figure 7.
Forest plot showing gastrointestinal side effects of 80 mg danuglipron.
Figure 8.
Figure 8.
Forest plot showing gastrointestinal side effects of 120 mg danuglipron.
See this image and copyright information in PMC

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