Source of Adverse effects of GLP-1 receptor agonists

{{Infobox concept | name = Adverse effects of GLP-1 receptor agonists | subtitle = Clinical practice | Most common = Nausea, vomiting, diarrhoea, constipation | Timing = Concentrated during escalation | Commonest reason for discontinuation = Gastrointestinal intolerance }} The adverse effects of [[GLP-1 receptor agonist|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 [[Dose escalation schedule|escalation]], and diminish with time at a stable dose.{{r|drucker2018}} 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|gastric emptying]] and area postrema signalling are the proposed contributors.{{r|drucker2018}} 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.{{r|wilding2021}} == Gastrointestinal effects == | 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.{{r|wilding2021}} 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]].{{r|drucker2018}} Discontinuation for adverse events ran at about 7% in [[STEP trial programme|STEP 1]] and 16.6% in [[SELECT trial|SELECT]], where treatment continued for over three years. Longer exposure produces more cumulative discontinuation even where per-period tolerability is similar.{{r|lincoff2023}} == Less common but significant == Gallbladder disease — cholelithiasis and cholecystitis — occurs more often than on placebo. Rapid weight loss by any means increases biliary cholesterol saturation and reduces gallbladder motility, so the effect is at least partly attributable to the weight change rather than to the drug directly.{{r|wilding2021}} Acute pancreatitis has been reported and is uncommon. Trial data have not established a causal relationship, and the background rate in populations with obesity and type 2 diabetes is itself elevated, which makes a modest excess hard to detect.{{r|nauck2016}} The medullary thyroid carcinoma contraindication derives from rodent C-cell hyperplasia and tumours at high exposure. Rodent C cells express the receptor at much higher density than human C cells, and no human signal has been established; the contraindication is precautionary. See [[Medullary thyroid carcinoma]].{{r|drucker2018}} A signal for non-arteritic anterior ischaemic optic neuropathy has been reported in observational data and remains under evaluation; observational designs cannot exclude confounding by indication.{{r|nauck2016}} == Body composition and other effects == Loss of lean mass accompanies loss of fat mass, in a proportion broadly comparable with that seen in other forms of substantial caloric restriction. Whether the proportion differs from diet-induced loss is disputed and the trials were not designed to settle it. See [[Sarcopenia]] and [[Lean mass preservation]].{{r|wilding2021}} A resting heart-rate increase of two to four beats per minute is reported across the class, attributed to direct sinoatrial action. No adverse outcome has been associated with it in the completed outcome trials.{{r|drucker2018}} Injection-site reactions are generally mild and transient except with the microsphere formulation of [[Exenatide|exenatide]], where persistent nodules are attributable to the polymer matrix. Delayed gastric emptying has prompted revised preoperative guidance; see [[Aspiration risk under anaesthesia]]. Nothing here is medical advice.{{r|ada2024}} == References == {{reflist}} <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> <ref name="wilding2021">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.</ref> <ref name="nauck2016">Nauck MA, Meier JJ. "The incretin effect in healthy individuals and those with type 2 diabetes." ''The Lancet Diabetes & Endocrinology'' 4(6):525–536 (2016). PMID 26876794.</ref> <ref name="ada2024">American Diabetes Association. "Standards of Care in Diabetes." ''Diabetes Care'' 47(Suppl 1) (2024).</ref> <ref name="lincoff2023">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.</ref> == See also == * [[GLP-1 receptor agonist]] * [[Dose escalation schedule]] * [[Gastric emptying]] * [[Aspiration risk under anaesthesia]] * [[Hypoglycaemia]] * [[Sarcopenia]] {{DEFAULTSORT:Adverse effects of GLP-1 receptor agonists}} [[Category:Adverse effects]] [[Category:Gastrointestinal adverse effects]] [[Category:Clinical practice]]