Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials

Diabetes Obes Metab. 2017 Mar;19(3):336-347. doi: 10.1111/dom.12824. Epub 2016 Dec 19.


Aim: GLP-1 receptor agonists (RAs) may cause nausea, vomiting or diarrhoea. The aim of this study was to assess the risk of adverse events (AEs) with GLP-1 RAs and their relation to dose, background medication and duration of action.

Research design and methods: The PubMed database was searched and 32 clinical trials with GLP-1 RAs (phase 3) were selected. We performed a systematic analysis and compared the proportion of patients reporting nausea, vomiting or diarrhoea, for different doses and glucose-lowering background medications, and relative to a reference compound within the subclasses of short- (exenatide b.i.d.) and long-acting (liraglutide) GLP-1 RAs, calculating the relative risks ± 95% confidence intervals.

Results: The risk of nausea was dose-dependent for long-acting (P = .0063) and across all GLP-1 RAs (P = .0017), and a similar trend was observed for vomiting (P = .23). Diarrhoea was dose-dependent (P = .031). Background treatment with metformin was associated with more nausea (P = .04) and vomiting (P = .0009). Compared to exenatide b.i.d., there was less nausea and diarrhoea with lixisenatide. Compared to liraglutide, there was a similar risk associated with dulaglutide, and less with exenatide q.w. and albiglutide. Long-acting GLP-1 RAs were associated with less nausea and vomiting, but with more diarrhoea than short-acting agents.

Conclusions: GLP-1 RAs are associated with gastrointestinal AEs that are related to dose and background medications (especially metformin) and may vary in a compound-specific manner. Long-acting agents are associated with less nausea and vomiting but with more diarrhoea.

Keywords: GLP-1 analogues; GLP-1 receptor agonists; gastrointestinal adverse events; incretin mimetics; side effects.

Publication types

  • Review

MeSH terms

  • Clinical Trials as Topic
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diarrhea / chemically induced*
  • Drug Therapy, Combination
  • Exenatide
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Liraglutide / adverse effects*
  • Metformin / therapeutic use
  • Nausea / chemically induced*
  • Peptides / adverse effects*
  • Venoms / adverse effects*
  • Vomiting / chemically induced*


  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptides
  • Venoms
  • Liraglutide
  • Metformin
  • Exenatide