Adverse effects of GLP-1 receptor agonists (revision 9)
Old revision·10:23, 5 Sep 2024·RegainRomilly
| Adverse effects of GLP-1 receptor agonists | |
|---|---|
| Most common | Nausea, vomiting, diarrhoea, constipation |
| Timing | Concentrated during escalation |
| Commonest reason for discontinuation | Gastrointestinal intolerance |
| Topic infobox · conventions | |
The adverse effects of GLP-1 receptor agonists are dominated by gastrointestinal events. Nausea, vomiting, diarrhoea and constipation are reported by between a fifth and a half of participants in trials depending on agent and dose, are most frequent during escalation, and diminish with time at a stable dose.[1]
Their mechanism is receptor-level rather than route-level: the same effects occur with an orally administered small-molecule agonist, which argues against a local gastrointestinal irritation explanation. Delayed gastric emptying and area postrema signalling are the proposed contributors.[1]
Less common concerns include gallbladder disease, acute pancreatitis, and a labelled contraindication derived from rodent thyroid C-cell findings. Several of these are shared with rapid weight loss by other means, which complicates attribution.[2]
Gastrointestinal effects
[edit]| Effect | Approximate frequency at higher doses | Course |
|---|---|---|
| Nausea | 30–45% | Peaks in escalation, declines |
| Vomiting | 20–25% | Follows nausea |
| Diarrhoea | 25–30% | Variable |
| Constipation | 20–25% | May persist |
Frequencies are from placebo-controlled trials and the placebo arms are not zero — nausea is reported by 10–20% of placebo participants in the same trials, so the attributable excess is smaller than the raw figure.[2]
Attenuation over time parallels the attenuation of the gastric-emptying delay, and is the reason escalation schedules work: adaptation to the gastrointestinal effect occurs while the appetite and glycaemic effects persist. See Dose escalation schedule.[1]
Discontinuation for adverse events ran at about 7% in STEP 1 and 16.6% in SELECT, where treatment continued for over three years. Longer exposure produces more cumulative discontinuation even where per-period tolerability is similar.[3]
References
- ^ a b c Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell Metabolism 27(4):740–756 (2018). PMID 29617641.
- ^ a b Wilding JPH, Batterham RL, Calanna S, et al. "Once-weekly semaglutide in adults with overweight or obesity." New England Journal of Medicine 384(11):989–1002 (2021). PMID 33567185.
- ^ Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. "Semaglutide and cardiovascular outcomes in obesity without diabetes." New England Journal of Medicine 389(24):2221–2232 (2023). PMID 37952131.