This is the second of a series of blog posts on new research in emergency toxicology. The last post was about caustic ingestions, and can be found here. We deal with all sorts of poisons here in Virchester, so be prepared for anything.
The use of injectable glucagon-like-peptide-1 agonists (GLP-1As) such as semaglutide (Ozempic® / Wegovy®) is rapidly increasing among adolescents and young adults who want to lose weight. There is trial evidence to suggest that semaglutide is effective and it is licensed in the US and UK for use in overweight adults.
GLP-1As are not particularly difficult to acquire from online pharmacies or illicit sources. They come in the form of pre-filled pens for subcutaneous administration. The price varies, but from what I can tell, a month’s supply currently costs £150-250.
The surge in popularity of GLP-1As has implications for emergency care. One is the airway risk associated with delayed gastric emptying, which has been discussed recently in Annals of Emergency Medicine. Another is the possibility of GLP-1A overdose. Some patients will, inevitably, inject too much of their medication. They may do this by accident, or in the hope of accelerating their weight loss.
The problem is that we do not know much about GLP-1A toxicity. The UK National Poisoning Information Service (NPIS) classifies drugs such as semaglutide as ‘products of interest.’ This means that there is limited evidence on which to base recommendations for emergency clinicians. Helpfully, a paper on GLP-1A overdoses was published in Medical Toxicology this year.
Abstract
What kind of study are we looking at?
This was a retrospective analysis of five years’ data (2017-2022) entered into the US National Poison Data System (NPDS).
Each “case” in this system represents a single consultation with a toxicologist at a regional poison centre. This could be instigated by another health professional or a member of the public. The NPDS functions similarly to the UK NPIS.
Can you tell me about the patients?
The study involved 5,713 single-substance exposures to a GLP-1A – most commonly (42.%) semaglutide. The number of reported cases tripled between 2017 and 2021, then increased by 80% again in 2022.
Most patients (71.3%) were female. They were relatively young, with 29.3% aged 20-49 and 50.8% aged 50-69.
Only a small number of overdoses (3.8%) were intentional. The majority (79.9%) were accidental, with nearly a third occurring in patients who had unintentionally taken their GLP-1A twice.
What outcome measures were used?
There was no defined primary outcome in this study. Data collected included the clinical effects of the overdose, the disposition of the patient, and the overall case outcome.
The researchers used an NPDS-specific system for coding patient outcomes, but grouped together ‘moderate effect,’ ‘major effect’ and ‘death’ under their own composite heading of ‘serious medical outcome.’ I will come back to this later.
What were the main results?
Relatively few patients (25.1%) were referred to emergency care after GLP-1A overdose. Of those who were, only a minority required admission under medicine (4.1%), psychiatry (0.4%) or critical care (0.9%).
The most commonly reported symptoms were nausea (17.4%) and vomiting (13.9%). Hypoglycaemia was reported in 4.9% of patients presenting to emergency care, and there were individual cases of pancreatitis, renal failure, and ileus.
The composite ‘serious medical outcome’ was encountered in 6.2% of patients, although most of this (5.9%) was accounted for patients whose overdose had a ‘moderate effect.’ Semaglutide was statistically associated with a greater likelihood of a ‘serious medical outcome’ (OR 1.45; 95% 1.17-1.81).
Only one patient included in this study died. The cause was faecal impaction resulting in bowel ischaemia.
What should we take away from this study?
It is clear from this study that GLP-1As are not without risk. They are modified-release drugs that work by increasing insulin production and suppressing the release of glucagon. It is unsurprising that, if overdosed, they can cause significant hypoglycaemia. I will certainly be adding GLP-1As to my list of differentials for unexplained drops in blood glucose, given their increasing popularity.
With that said: this study is a retrospective database review, and it has some key limitations. The most important, in my view, is the authors’ inclusion criteria, and the potential bias this may have introduced. To be eligible for this study, a GLP-1A overdose needed to be disclosed to an emergency clinician or toxicologist. Suspected overdoses were excluded. As a result, this study tells us very little about patients who conceal their use of GLP-1As. I would imagine that these patients are higher risk. Concerns have been expressed that GLP-1As will be misused by patients with eating disorders in the same way that other medications (e.g. laxatives) have been.
The mortality rate may also have been under-estimated by this study. Death is a tricky outcome in toxicology research, because in fatal cases clinicians often do not know what their patients have taken, and post-mortem findings are infrequently communicated to poison services. It is possible that between 2017 and 2021 there were many deaths attributable to GLP-1As overlooked by the NPDS. This is a limitation of virtually every toxicology study that does not use analytical methods.
Finally, the researchers used a composite outcome – ‘serious medical outcome’ – that I suspect many emergency clinicians would take issue with. As a reminder, they grouped ‘moderate effect,’ ‘major effect,’ and ‘death’ under this heading. Looking through the NPDS coding book, a ‘moderate effect’ is described as follows:
“The patient exhibited symptoms as a result of the exposure which are more pronounced, more prolonged or more of a systemic nature than minor symptoms. Usually some form of treatment is or would have been indicated. Symptoms were not life-threatening and the patient has returned to a pre-exposure state of well-being with no residual disability or disfigurement.”
An example of a ‘moderate effect’ provided by NPDS is a paracetamol overdose causing abnormal liver function blood tests, but no other adverse effects. By contrast, a ‘major effect’ would be a paracetamol overdose causing organ failure. I am not sure that I would describe the former as a ‘serious’ overdose – much less group it in with the latter.
Should this study change our practice?
Maybe….
Hypoglycaemia may be more common in GLP-1A toxicity than has been suggested by NPIS. We should monitor blood glucose in patients who have over-injected, and think about GLP-1As in patients with unexplained hypoglycaemia – even if they are not diabetic.
It is unfortunate that the researchers could not provide information about the timing of their ‘serious medical outcomes.’ GLP-1As are modified-release drugs. NPIS currently recommends observing patients for eight hours after exposure, but it remains unclear to me whether this is enough time.
I will be keeping an eye out for more research on this topic. At present, semaglutide is only licensed in the UK for a narrow subset of overweight patients. This will inevitably change, and when it does, we are likely to see many more GLP-1A related problems here in Virchester. We may also see illicit use in practice as there are reports of patients buying GLP-1A drugs over the internet.
Greg Yates
References and further reading
- Gaw CE, Hays HL, Kemp CA, Kistamgari S, Spiller HA, Rine NI, Rhodes AL, Zhu M, Smith GA. Glucagon-Like Peptide-1 Receptor Agonist Cases Reported to United States Poison Centers, 2017-2022. J Med Toxicol. 2024 Apr;20(2):193-204. doi: 10.1007/s13181-024-00999-x. Epub 2024 Feb 29. PMID: 38421490; PMCID: PMC10959851.
- Marshall, S., Ryan, E., Rivera, J. et al. GLP-1 Receptor Agonist Exposures Are Increasingly Common and Generally Associated with Mild Symptoms: A Single Poison Center Experience. J. Med. Toxicol. 20, 278–285 (2024). https://doi-org.manchester.idm.oclc.org/10.1007/s13181-024-01008-x
- Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. 2023;330(18):1795–1797. doi:10.1001/jama.2023.19574
