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Glucagon-like Peptide-1 (GLP-1) Receptor Agonists (Dulaglutide, Liraglutide, Lixisenatide, Semaglutide, and Tirzepatide): Aspiration and Pneumonia Aspiration during General Anaesthesia or Deep Sedation

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DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Overview of Product(s)

Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs), including dulaglutide, liraglutide, lixisenatide, semaglutide, and tirzepatide (a dual glucose-dependent insulinotropic polypeptide [GIP] and GLP-1 RA), are mainly used for the management of type 2 diabetes mellitus alongside dietary changes and exercise.1 Certain GLP-1 RA products are also indicated for chronic weight management in combination with a reduced-calorie or healthy diet and increased physical activity.2-4 GLP-1 RAs work by imitating the natural hormone GLP-1 to lower blood glucose by stimulating insulin production and reducing glucagon release.1,5 At higher doses, they suppress appetite, reduce food intake, and promote weight loss through their combined effects on hunger centres in the brain and delayed stomach emptying.

In Malaysia, there are a total of 34 products containing GLP-1 RAs registered with the Drug Control Authority (DCA), available in oral or injectable form.6 These comprise five (5) types of GLP-1 RAs, namely dulaglutide (2 products), liraglutide (3), lixisenatide (2), semaglutide (15), and tirzepatide (12).

 

Overview of Safety Concern

Aspiration describes the unintentional inhalation of food or liquid into the trachea and lungs, instead of going down the oesophagus into the stomach.7,8 It can also happen when stomach contents are regurgitated into the throat. Aspiration may lead to pneumonia aspiration, a potentially life-threatening lung infection causing inflammation and fluid build-up.

Aspiration is the leading cause (≈50%) of airway-related mortality during anaesthesia.9 Pulmonary aspiration affects between 1 in 900 and 1 in 10,000 general anaesthetics, depending on risk factors such as patient-related factors (including a full stomach and delayed gastric emptying), as well as surgical, anaesthetic, and device-related factors. During anaesthesia, normal physiological mechanisms that prevent aspiration of gastric contents—such as the gastro-oesophageal junction, upper oesophageal sphincter and protective laryngeal reflexes—are diminished by anaesthetic medications, increasing the risk of aspiration.

 

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) learned from the European Medicines Agency (EMA), Pharmacovigilance Risk Assessment Committee (PRAC) regarding the risk of aspiration and pneumonia aspiration associated with the use of GLP-1 RAs during general anaesthesia or deep sedation.8,10,11 The PRAC has required that product information for all GLP-1 RA-containing products, including combination products, should include a warning to address this risk.

This regulatory action followed a review of available evidence from case reports in the European pharmacovigilance database (EudraVigilance), scientific literature, as well as clinical and non-clinical data submitted by product registration holders (PRH).8,10,11 The PRAC concluded that while a causal association between GLP-1 RAs and aspiration could not be confirmed, the known delayed gastric emptying effect associated with these drugs may increase the risk of aspiration and aspiration pneumonia during anaesthesia or deep sedation. The PRAC recommended informing healthcare professionals and patients on this potential consequence of delayed gastric emptying and highlighted the need to carefully consider the increased risk of residual gastric contents before performing procedures involving general anaesthesia or deep sedation.

 

Background of Safety Issue

Clinical trial, literature, and post-marketing cases of pulmonary aspiration have been reported in patients receiving GLP-1 RAs undergoing general anaesthesia or deep sedation.8,12 A United States (U.S.) cohort study reported the rare occurrence of pulmonary aspiration (4.2 per 1000 patients) among more than 43,000 adults with type 2 diabetes using GLP-1 RAs within 30 days before upper endoscopy.12 Additionally, there are concerns that retained gastric contents associated with GLP-1 RAs may result in endoscopy discontinuation, leading to delayed diagnoses, higher healthcare costs, and socio-economic impacts such as missed workdays.12,13

In the gastrointestinal tract, GLP-1 signals are part of the “ileal brake,” which increase gastric emptying time.13 As part of their action, GLP-1 RAs delay gastric emptying and there is a biologically plausible increased risk for aspiration in association with anaesthesia and deep sedation.5,8,13

At present, there is little evidence on the optimal perioperative management of GLP-1 RAs.13 Based on current pharmacology and clinical experience, the U.S. Multi-Society Clinical Practice Guidance recommends shared decision-making between patients and care teams to ensure safe surgery while balancing patient-specific metabolic needs and risks.13,14 Preoperative assessments should allow time for adjustments, including diet modification and evaluation of the feasibility of medication bridging if GLP-1 RA discontinuation is indicated. The safe use of GLP-1 RAs in the perioperative period should include efforts to minimise the aspiration risk, such as having high-risk patients to follow a liquid-only diet for 24 hours before surgery, use point-of-care ultrasound to assess stomach contents before the procedure, and adjust anaesthesia plans.

 

Local Adverse Drug Reaction Reports15

To date, the NPRA has received a total of 411 reports with 851 adverse events for dulaglutide, liraglutide, semaglutide, and lixisenatide. No reports have been received for tirzepatide. None of the reports involved aspiration or aspiration pneumonia. The most frequently reported adverse events were nausea (136 reports), followed by vomiting (98) and dizziness (29).

 

Advice for Healthcare Professionals

  • Be aware of the potential risk of aspiration and pneumonia aspiration associated with the use of GLP-1 RAs during general anaesthesia or deep sedation. This risk is linked to the delayed gastric emptying caused by GLP-1 RAs, which can result in residual gastric content.
  • When prescribing GLP-1 RAs, educate patients to inform their doctors if they are scheduled for procedures under anaesthesia while taking any GLP-1 RA medication.
  • Current evidence on optimal perioperative management of GLP-1 RAs is limited. It is recommended to engage patients and care teams in shared decision-making to align perioperative GLP-1 RA management with patient-specific risks and needs.
  • Carefully consider the increased risk of residual gastric content due to delayed gastric emptying prior to performing procedures with general anaesthesia or deep sedation.
  • Report all suspected adverse events associated with GLP-1 RA-containing products to the NPRA.

 

References:

  1. Jones PM, Hobai IA, Murphy PM. . Anesthesia and glucagon-like peptide-1 receptor agonists: proceed with caution! Can J Anesth. 2023 Aug;70:1281–1286. Available from: https://doi.org/10.1007/s12630-023-02550-y
  2. National Pharmaceutical Regulatory Agency (NPRA). SAXENDA (liraglutide) 6mg/ml solution for injection in pre-filled pen [Package Insert]. 2023 Aug [cited 2024 Nov 11]. The Malaysian Product Registration Database (QUEST). Available from: https://www.npra.gov.my
  3. National Pharmaceutical Regulatory Agency (NPRA). WEGOVY (semaglutide) 0.25mg / 0.5 mg / 1mg / 1.7mg / 2.4mg solution for injection in pre-filled pen [Package Insert]. 2024 Apr [cited 2024 Nov 11]. The Malaysian Product Registration Database (QUEST). Available from: https://www.npra.gov.my
  4. National Pharmaceutical Regulatory Agency (NPRA). MOUNJARO (tirzepatide) 2.5mg / 5mg / 7.5mg / 10mg / 12.5mg / 15mg solution for injection in vial. [Package Insert]. 2024 Aug [cited 2024 Nov 11]. The Malaysian Product Registration Database (QUEST). Available from: https://www.npra.gov.my
  5. Mendes FF, Carvalho LIM, Lopes MB.. Glucagon-like peptide-1 agonists in perioperative medicine: to suspend or not to suspend, that is the question. Braz J Anesthesiol 2024;74(6):844538. Available from: https://doi.org/10.1016/j.bjane.2024.844538
  6. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Nov11]. Available from: https://www.npra.gov.my
  7. Will Blair. Lung Disease & Respiratory Health/Reference - Aspiration. [Internet] 2023 Dec 3 [cited 2024 Nov11]. Available from: https://www.webmd.com/lung/what-is-aspiration
  8. European Medicines Agency (EMA). Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 8-11 July 2024 [Internet]. 2024 Jul 14 [cited 2024 Nov 11]. Available from: https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-8-11-july-2024
  9. Robinson M, Davidson A. Aspiration under anaesthesia: risk assessment and decision-making. BJA Educ; 2014;14(4). Available from: https://www.bjaed.org/article/S1743-1816(17)30092-6/pdf
  10. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) recommendations on signals. Adopted at the 8-11 July 2024 PRAC meeting [Internet]. 2024 Aug 12 [cited 2024 Nov 11]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-8-11-july-2024-prac-meeting_en.pdf
  11. European Medicines Agency (EMA). Human Medicines Division, Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of PRAC meeting on 8-11 July 2024 [Internet]. 2024 Aug 23 [cited 2024 Nov 11]. Available from: https://www.ema.europa.eu/system/files/documents/minutes/minutes-prac-meeting-8-11-july-2024-en.pdf
  12. Alkabbani W, Suissa K, Gu KD, Cromer SJ, Paik JM, Bykov K, Hobai I, Thompson CC, Wexler DJ, Patorno E. Glucagon-like peptide-1 receptor agonists before upper gastrointestinal endoscopy and risk of pulmonary aspiration or discontinuation of procedure: cohort study. BMJ. 2024 Oct 22;387:e080340. Available from: https://doi.org/10.1136/bmj-2024-080340
  13. Kindel TL, Wang AY, Wadhwa A, et al. Multisociety clinical practice guidance for the safe use of glucagon-like peptide-1 receptor agonists in the perioperative period. Surgery for Obesity and Related Diseases. 2024;20(12):1183-1186. Available from: https://doi.org/10.1016/j.soard.2024.08.033
  14. American Society of Anesthesiologists (ASA). News: Most Patients Can Continue Diabetes, Weight Loss GLP-1 Drugs Before Surgery, Those at Highest Risk for GI Problems Should Follow Liquid Diet Before Procedure [Internet]. 2024 Oct 29. [cited 2024 Nov 11]. Available from: https://www.asahq.org/about-asa/newsroom/news-releases/2024/10/new-multi-society-glp-1-guidance
  15. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Nov 13]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wang Khee Ing

Reviewed/Edited by: Choo Sim Mei, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali

 

 

National Pharmaceutical Regulatory Agency (NPRA)

Lot 36, Jalan Universiti (Jalan Prof Diraja Ungku Aziz), 46200 Petaling Jaya, Selangor, Malaysia.

  • Phone: +603-7883 5400

 

 

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