Gastrointestinal adverse events with incretin receptor agonists
What is the incidence of gastrointestinal adverse events and of discontinuation for adverse events with incretin receptor agonists compared with placebo?
§1Abstract
§1.1Review question
What is the incidence of gastrointestinal adverse events and of discontinuation for adverse events with incretin receptor agonists compared with placebo?
§1.2PICO frame
Table 1. The registered PICO frame. Any change made after protocol registration is recorded in the amendment log at §5 and is identified there as post hoc.
| Element | As registered |
|---|---|
| Population | Adults randomised in a placebo-controlled trial of an incretin receptor agonist. |
| Intervention | Any incretin receptor agonist at any evaluated dose. |
| Comparator | Placebo. |
| Outcomes | Nausea, vomiting, diarrhoea, constipation, discontinuation for adverse events, and serious gastrointestinal events including acute pancreatitis and gallbladder disease. |
§1.3Method in brief
A review of harms, in which the absence of an event in a trial of conventional size is treated as uninformative rather than as reassurance. The protocol was registered with the Institute's secretariat before the search was executed. The search was run on 5 April 2025 across 8 sources and is reproduced in full at §2. Screening, extraction and certainty assessment were performed independently by two members of the secretariat with disagreement resolved by a third.[1,2]
§1.4Conclusion
High certainty evidence indicates that nausea, vomiting, diarrhoea and constipation are substantially more frequent with incretin receptor agonists than with placebo, that they are dose- and titration-rate-dependent, and that they attenuate with continued exposure in most but not all participants. Discontinuation for adverse events is consistently in the range of 4 to 10 % in injectable programmes and materially higher in the oral small-molecule programmes, where it has exceeded 50 % in some dose arms.
The conclusion rests on 24 contributing studies, listed with their extracted data at §3 and summarised outcome by outcome at §4.
§1.5Limitations
§1.6Consultation
This review was released for public comment before ratification. Draft synthesis: Gastrointestinal adverse events with incretin receptor agonists received 12 submissions. Amendments arising are recorded in the amendment log and are traceable to a numbered submission.
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF. Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine 2021;384(11):989–1002. doi:10.1056/NEJMoa2032183 · PMID 33567185
- Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine 2022;387(3):205–216. doi:10.1056/NEJMoa2206038 · PMID 35658024
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