Is there a risk of intraoperative aspiration with the use of GLP-1 receptor agonists?

Introduction
Glucagon-like peptide-1 (GLP-1) receptor agonists, a class of medications used for the treatment of type 2 diabetes (T2DM) and obesity, act by suppressing glucagon secretion, augmenting insulin secretion, increasing satiety, and slowing gastric emptying, resulting in positive effects on weight loss and glycemic levels.¹ Within the class, GLP-1 receptor agonists are categorized as either short or long-acting, primarily based on their elimination half-life. Short-acting agents include exenatide and lixisenatide, dosed at least once daily, and long-acting agents (dulaglutide, exenatide extended-release, semaglutide, tirzepatide), which when administered subcutaneously are all dosed once weekly, except for liraglutide. Gastrointestinal symptoms, particularly during dose escalation, are a concern with the use of these agents, as well as residual gastric content (RGC), a potential risk factor for pulmonary aspiration.^2-5 Of the GLP-1 receptor agonists, longer-acting agents appear to have improved gastrointestinal tolerability.⁶ Several recent case reports and studies have highlighted the concern for the presence of RGC in patients using GLP-1 receptor agonists, and subsequently, the perioperative management of GLP-1 receptor agonist therapy has been recently addressed in guidelines.^2-4,7-12

Guidelines
Practice guidelines are available from several organizations that address perioperative fasting and medication management to reduce the risk of aspiration under anesthesia.^10,13-15  Guidelines from the American Society of Anesthesiologists (ASA) to reduce the risk of pulmonary aspiration in adults generally recommend fasting from heavier foods for ≥ 8 hours prior and for ≥ 2 hours from clear liquids prior to procedures.¹⁵ A 2023 ASA guideline update additionally provides recommendations for children at low risk of aspiration to receive clear fluids as close to 2 hours prior to procedures as possible.¹⁴

In regard to medication management, the 2021 Society for Perioperative Assessment and Quality Improvement (SPAQI) consensus statement on urologic and endocrine medications recommends that GLP-1 receptor agonists be held the morning of surgery, or for 7 days prior if given weekly and undergoing gastrointestinal surgery, or nausea/vomiting, or if a concern for gut dysfunction is present.¹³ Recently, however, the ASA Task Force on Preoperative Fasting issued new guidance on perioperative GLP-1 receptor agonist management due to concerns that have been raised based on reports regarding the risk of regurgitation and pulmonary aspiration.¹⁰ Based on their findings, the Task Force states that the presence of gastrointestinal adverse effects (eg, nausea, vomiting, dyspepsia, abdominal distention) is predictive of residual gastric content. The Task Force recommends that in patients undergoing elective procedures, daily dosing of GLP-1 receptor agonists be held on the day of surgery, and for GLP-1 receptor agonists given weekly, the medication should be held for a week prior. These recommendations are irrespective of the indication for which the GLP-1 receptor agonist is being used (T2DM versus obesity), and the type of surgery being performed. On the day of the elective procedure, the Task Force also advises that if gastrointestinal symptoms are present, delay of the procedure should be considered, and concerns regarding the risk of aspiration and regurgitation should be discussed with the patient. If the medication was held and no gastrointestinal symptoms present, providers may proceed as usual. If the medication was not held as instructed, but the patient also has no gastrointestinal symptoms, it is advised to proceed with ‘full stomach’ precautions, or to consider an ultrasound to evaluate gastric volume. Based on ultrasound findings, full stomach precautions should be used, or the procedure delayed as necessary.

Literature Review
In addition to case reports describing RGC resulting in subsequent pulmonary aspiration, regurgitation and procedural delays, 4 observational studies have evaluated the presence of RGC in patients undergoing esophagogastroduodenoscopy (EGD) and its correlation with GLP-1 receptor agonist use.^{3,4,7-9,11,12} These studies are summarized in the Table, and several are referenced in the ASA Task Force on Preoperative Fasting guidelines.^3,4,10-12 In the matched pair case-control study of patients with T2DM undergoing EGD, patients were evaluated for the presence of RGC after propensity score matching.³ All patients in the study fasted for ≥ 12 hours prior to EGD. Based on the propensity score matched comparison (N=205 pairs), the proportion of patients with RGC was higher in patients who received a GLP-1 receptor agonist (5.4%) versus those who did not (0.49%; p=0.004). Those treated with a GLP-1 receptor agonist who developed RGC were also shown to be significantly younger than those without RGC.

In a single-center retrospective chart review of 404 EGDs, the presence of RGC despite adequate preoperative fasting and semaglutide use was evaluated.⁴ Out of the 404 EGDs, 33 were categorized as receiving semaglutide within 30 days, and 371 as not receiving semaglutide within the previous 30 days. The majority of patients receiving semaglutide were using the medication for weight loss (87.8%); all were instructed to discontinue the medication for 10 to 14 days prior to the EGD. All patients fasted for > 8 hours from solids and fluids with residue, and for ≥ 2 hours from clear fluids prior to the procedure. Increased RGC was observed in a total of 27 patients (6.7%) undergoing EGD, with solid content observed in 85.2% of these patients. Out of the patients who had received semaglutide within 30 days, there was a larger proportion with RGC (8 patients out of 33; 24.2%) compared to those with RGC who had not received semaglutide within 30 days prior (19 patients out of 371, 5.1%; p<0.001). In a weighted analysis, the use of semaglutide and the presence of ongoing digestive symptoms was associated with increased RGC (prevalence ratio [PR], 5.15; 95% confidence interval [CI], 1.92 to 12.92), although upper endoscopy in combination with colonoscopy was shown to have a protective effect (PR, 0.25; 95% CI, 0.16 to 0.39).

In a retrospective cohort study of 59 patients prescribed a GLP-1 receptor agonist with 118 matched controls (matched for T2DM and presence of cirrhosis), the primary endpoint of retained food during EGD was significantly increased with GLP-1 receptor agonist use (6.8%) versus non-use (1.7%), although this did not reach statistical significance (odds ratio; 4.2; 95% CI, 0.87 to 20.34).¹¹ In patients who had documented food retention, 2 were receiving dulaglutide, and 2 liraglutide.

A retrospective study evaluated the overall prevalence of RGC during EGD, risk factors for RGC, and the association between delayed gastric emptying and RGC. Of 85,116 EGDs performed between 2012 and 2018, RGC was present in 3% of cases.¹² The odds of RGC were significantly increased in patients with type 1 diabetes mellitus, T2DM, gastroparesis, amyloidosis, and structural foregut abnormalities. The positive predictive value of RGC for delayed gastric emptying was 55%. A multivariate analysis of medications showed that the presence of RGC was significantly associated with the use of opioids (OR, 3.6; 95% CI, 1.7 to 7.6), antacids (OR, 1.9; 95% CI, 1.0 to 4.3), and cardiovascular medications (OR, 2.1; 95% CI, 1.0 to 4.5), but not GLP-1 receptor agonists, antiemetics, or anticholinergics.

Conclusion
Updated perioperative management recommendations are available for patients receiving GLP-1 receptor agonists. These guidelines address the concerns with the use of these agents regarding the risk of RGC during elective procedures, a risk factor for aspiration and regurgitation under anesthesia. The guidelines currently recommend withholding GLP-1 receptor agonists for 1 week prior to elective procedures if administered once weekly, or the day of the procedure if administered once daily. If gastrointestinal symptoms are present the day of the procedure, procedural delay should be considered. Clinicians should closely monitor for updated guidance on the use of these medications as more evidence becomes available.

References

1. Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Mol Metab. 2021;46:101102. doi:10.1016/j.molmet.2020.101102.
2. Moyad MA. Embracing the pros and cons of the new weight loss medications (Semaglutide, tirzepatide, etc.).Curr Urol Rep. 2023;10.1007/s11934-023-01180-7. doi:10.1007/s11934-023-01180-7.
3. Kobori T, Onishi Y, Yoshida Y, et al. Association of glucagon-like peptide-1 receptor agonist treatment with gastric residue in an esophagogastroduodenoscopy. J Diabetes Investig. 2023;14(6):767-773. doi:10.1111/jdi.14005.
4. Silveira SQ, da Silva LM, de Campos Vieira Abib A, et al. Relationship between perioperative semaglutide use and residual gastric content: A retrospective analysis of patients undergoing elective upper endoscopy.J Clin Anesth. 2023;87:111091. doi:10.1016/j.jclinane.2023.111091.
5. Feighery AM, Oblizajek NR, Vogt MNP, et al. Retained food during esophagogastroduodenoscopy is a risk factor for gastric-to-pulmonary aspiration. Dig Dis Sci. 2023;68(1):164-172. doi:10.1007/s10620-022-07536-2.
6. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728-742. doi:10.1038/nrendo.2012.140.
7. Klein SR, Hobai IA. Semaglutide, delayed gastric emptying, and intraoperative pulmonary aspiration: A case report. Can J Anesth. 2023. DOI: 10.1007/s12630-023-02440-3.
8. Gulak MA, Murphy P. Regurgitation under anesthesia in a fasted patient prescribed semaglutide for weight loss: a case report. Can J Anaesth. 2023;70(8):1397-1400. doi:10.1007/s12630-023-02521-3.
9. Fujino E, Cobb KW, Schoenherr J, et al. Anesthesia considerations for a patient on semaglutide and delayed gastric emptying. Cureus. 2023;15(7):e42153. doi:10.7759/cureus.42153.
10. American Society of Anesthesiologists. American Society of Anesthesiologists Consensus-Based Guidance on Preoperative Management of Patients (Adults and Children) on Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists. Published June 29, 2023. Accessed September 23, 2023. https://www.asahq.org/about-asa/newsroom/news-releases/2023/06/american-society-of-anesthesiologists-consensus-based-guidance-on-preoperative.
11. Stark JE, Cole JL, Ghazarian RN, et al. Impact of glucagon-like peptide-1 receptor agonists (GLP-1RA) on food content during esophagogastroduodenoscopy (EGD). Ann Pharmacother. 2022;56(8):922-926. doi:10.1177/10600280211055804.
12. Bi D, Choi C, League J, et al. Food residue during esophagogastroduodenoscopy is commonly encountered and is not pathognomonic of delayed gastric emptying. Dig Dis Sci. 2021;66(11):3951-3959. doi:10.1007/s10620-020-06718-0.
13. Pfeifer KJ, Selzer A, Mendez CE, et al. Preoperative management of endocrine, hormonal, and urologic medications: Society for Perioperative Assessment and Quality Improvement (SPAQI) consensus statement. Mayo Clin Proc. 2021;96(6):1655-1669. doi:10.1016/j.mayocp.2020.10.002
14. Joshi GP, Abdelmalak BB, Weigel WA, et al. 2023 American Society of Anesthesiologists practice guidelines for preoperative fasting: Carbohydrate-containing clear liquids with or without protein, chewing gum, and pediatric fasting duration-A modular update of the 2017 American Society of Anesthesiologists practice guidelines for preoperative fasting.Anesthesiology. 2023;138(2):132-151. doi:10.1097/ALN.0000000000004381.
15. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: Application to healthy patients undergoing elective procedures: An updated report by the American Society of Anesthesiologists Task Force on preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration. Anesthesiology. 2017;126(3):376-393. doi:10.1097/ALN.0000000000001452.

Prepared by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2023

The information presented is current as of September 20, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.