Should We Stop Glucagon-Like Peptide-1 Receptor Agonists Before Surgical or Endoscopic Procedures? Balancing Limited Evidence With Clinical Judgment

Abstract

The American Society of Anesthesiologists (ASA) Task Force recently recommended discontinuing glucagon-like peptide-1 receptor agonist (GLP-1 RA) agents before surgery because of the potential risk of pulmonary aspiration. However, there is limited scientific evidence to support this recommendation, and holding GLP-1 RA treatment may worsen glycemic control in patients with diabetes. As we await further safety data to manage GLP-1 RA in the perioperative period, we suggest an alternative multidisciplinary approach to manage patients undergoing elective surgery. Well-conducted observational and prospective studies are needed to determine the risk of pulmonary aspiration in persons receiving GLP-1 RA for the treatment of diabetes and obesity, as well as the short-term impact of discontinuing GLP-1 RA on glycemic control before elective procedures in persons with diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the recently approved dual agonist tirzepatide (GIP/GLP-1 RA) have revolutionized diabetes care. These agents not only exhibit exceptional efficacy for glucose control but also help people with and without diabetes to lose weight.^1,2 However, concerns have been raised about potential side effects beyond common gastrointestinal (GI) symptoms, including serious complications such as small bowel obstruction and risk of aspiration during the perioperative period.

The American Society of Anesthesiologists (ASA) Task Force on Preoperative Fasting has recommended holding GLP-1 RA therapy before surgery and deep sedation. ³ This recommendation was mostly supported by case reports and retrospective studies that have shown an increased risk of complications such as retained gastric content, regurgitation, and pulmonary aspiration. The ASA Task Force recommends, “For patients on daily dosing consider holding GLP-1 agonists on the day of the procedure/surgery. For patients on weekly dosing consider holding GLP-1 agonists a week before the day of the procedure/surgery.” In cases where the GLP-1 RA was not stopped, a risk/benefit evaluation is recommended based on GI symptoms, gastric ultrasound (if available), and case urgency. Based on patient risk, the anesthesiologist may recommend case postponement or proceed with the procedure following full stomach precautions. These recommendations are applicable regardless of the indication for medication use for diabetes or weight loss, prescribed dosage, or time since medication initiation.

Several randomized controlled trials (RCTs) and meta-analyses have reported on the safety and effectiveness of GLP-1 RA for managing hyperglycemia in hospitalized patients in critical care and general medicine and surgery settings.^4-6 In cardiac surgery patients, the administration of continuous intravenous infusion of GLP-1, starting 8 to 12 hours before surgery and continuing for 48 to 72 hours afterward, resulted in lower mean glucose levels during the perioperative period and reduced insulin requirements by almost half, without an increased risk of hypoglycemia.^7,8 The use of preoperative and intraoperative subcutaneous insulin infusion also led to improved glycemic control without an increased incidence of GI adverse events, compared with intravenous insulin infusion. ⁴ In general medicine and surgery patients, an RCT comparing hospital initiation of short-acting GLP-1 RA exenatide with basal-bolus insulin therapy reported improved glycemic control without an increased risk of hypoglycemia.^6,9 However, the administration of short-acting exenatide was associated with high rates of nausea and vomiting, reported in 12% of general medicine and surgery patients. ⁶

The recent ASA Task Force recommendations have opened an at-large conversation raising awareness of the potential risk of aspiration in patients treated with GLP-1 RAs. ¹⁰ However, there is limited evidence to support that holding daily or weekly dosages will reduce the risk of retained gastric contents. Current evidence is limited to case reports, small retrospective analyses, and a small single-site prospective study examining residual gastric contents in patients using GLP-1 RA agents despite several hours of fasting (Table 1). However, discontinuation of these agents does not guarantee safety and may worsen glycemic control in patients with diabetes.^11,12

Table 1.

Reports on GLP1-RA Therapy and Risk of Regurgitation and Pulmonary Aspiration During General Anesthesia and Deep Sedation.

	GLP-1 RA	Setting	Indication for GLP-1 RA	Procedure	Length of fasting	Findings
Gulak and Murphy 13	SG	Case report	Weight loss, no DM	General anesthesia	N/A	Regurgitation of gastric contents
Klein and Hobai 14	SG	Case report	Weight loss no DM	Upper endoscopy	18 hours	Increased RGC before endotracheal intubation
Fujino et al 15	SG	Case report	Weight loss and T2DM	Upper endoscopy	10 hours	RGC present after overnight fast
Kittner et al 16	SG (n = 3)	Case report	Weight loss and T2DM	Gastric ultrasound	10-14 hours	RGC by gastric ultrasound after 10-hour fast.
Stark et al 17	SG, DU, LI, EXE (n = 59) No GLP-1 RA (n = 118)	Retrospective, single center	T2DM	Upper endoscopy	N/A	RGC in 4.6% of GLP-1 RA and 1.7% in no GLP-1 RA, P = .08
Silveira et al 18	SG (n = 33) No SG (n = 371)	Retrospective, single center		Upper endoscopy	9 hours for clear fluids and 14 hours for solids	RGC in SG (24.2%) vs non-SG (5.1%), P < .001
Sherwin et al 19	SG (n = 10)No SG (n = 10)90% <eight weeks	Prospective, single center	Weight loss, no DM	Gastric ultrasound	8 hours	RGC in SG (70%) and no SG (20%), P = .005
Kobori et al 20	SG, DU, LI (n = 205)No GLP-1 RA (n = 205)	Retrospective, single center	T2DM	Upper endoscopy	>12 hours	RGC in GLP-1 RA (5.4%) vs no GLP-1 RA (0.49%), P = .004

Abbreviations: DM, diabetes mellitus; DU, dulaglutide; EXE, exenatide; GLP-1 RA, glucagon-like peptide-1 receptor agonists; LI, liraglutide; RGC, residual gastric content; SG, semaglutide; T2DM, type 2 diabetes mellitus; US, ultrasound.

As we await further safety data to manage these agents in the perioperative period, we suggest an alternative multidisciplinary approach to manage patients using GLP-1 RA agents undergoing elective surgery. Preoperative protocols should evaluate and consider the following:

1. The duration of GLP-1 RA therapy and the presence/persistence of GI side effects. Delayed gastric emptying effect is usually limited to the first weeks of therapy, with less than 10% of patients having persistent side effects due to tachyphylaxis of the GLP-1-induced deceleration of gastric emptying in humans. ²¹ Tachyphylaxis usually occurs with long-acting GLP-1 RAs (liraglutide and all once-weekly injected preparations), not with short-acting ones (exenatide, lixisenatide). ²² During the first few weeks of therapy, patients may be at a higher risk for aspiration, which should be considered when scheduling elective surgery.

2. Fasting time for solid versus clear liquid diets. There is no conclusive evidence regarding the ideal duration of fasting, but it has been shown that colonoscopy prep, which typically requires patients to transition to a clear liquid diet the day before the procedure, may be protective against residual gastric contents. ²³ If a patient is at high risk of aspiration, such as those with a history of gastroparesis or obesity, prolonged fasting time for solids may be advisable.

3. An open discussion with the patient and prescribing physician is necessary. For patients using therapy for weight loss versus blood glucose control, continuation and discontinuation portend different risks based on the medication indication, alternative therapies, and length of discontinuation.

4. An evaluation of patients on the day of surgery for GI symptoms. GLP-1 agents used in combination with GI symptoms appear to be more predictive of residual gastric contents than GLP-1 use alone. ²³ When available, gastric ultrasound can be used to assess gastric content and risk of aspiration. There is mounting evidence to support the role of bedside gastric ultrasound as a sensitive and specific tool to positively identify or rule out a full stomach and guide anesthetic management to prevent pulmonary aspiration.

5. The adoption of protocols for perioperative management of hyperglycemia after holding GLP-1 RA before elective surgery. ²⁴ Coordinate with primary care providers to overcome care fragmentation. Provide follow-up recommendations for safe re-start of GLP-1 RA agents based on patient risk factors, type of surgery, GI symptoms, and blood glucose control.

The American Gastroenterological Association (AGA) recently released a rapid clinical practice update (CPU) addressing the management of patients taking GLP-1 RAs before endoscopic procedures. The AGA does not endorse all patients stopping GLP-1 RAs before elective endoscopy procedures ²⁵ ; instead, an individualized approach should be taken to managing patients on GLP-1 RAs in the pre-endoscopic setting. Generally, in patients on GLP-1 RAs who have followed standard perioperative procedures (typically an eight-hour solid-food fast and a two-hour liquid fast) and who do not have symptoms of nausea, vomiting, dyspepsia, or abdominal distention, the AGA advises proceeding with upper and/or lower endoscopy. ²⁵ The AGA recommends that in persons with symptoms suggesting possible retained gastric contents, transabdominal ultrasonography can be used to assess the stomach. In addition, when possible, placing patients on a liquid diet the day before sedated procedures may be a more acceptable strategy, instead of stopping GLP-1 RAs.

The growing use of incretin agonists, including off-label use, is likely to result in more incretin agonist users undergoing surgery or endoscopic procedures. This poses a small but possible risk of aspiration during the perioperative period, which must be balanced against the likelihood of worsening glycemic control, increased rates of hyperglycemia-associated complications, patient dissatisfaction, and higher health care costs. “ASA’s suggestions are expert opinions, which may inform but should not replace clinical judgment.” To reduce the risk of poor glycemic control and pulmonary complications, a careful assessment and implementation of multidisciplinary perioperative management of diabetes as well as airway-protective protocols are necessary. Larger and well-conducted observational and prospective studies are needed to determine the risk of pulmonary aspiration and perioperative complications in persons receiving GLP-1 RA for the treatment of diabetes and obesity, as well as the short-term impact of discontinuing GLP-1 RA on glycemic control before elective procedures in persons with diabetes. Furthermore, reliable information is also needed to accurately assess the effects of GLP-1 RAs on gastric emptying using validated instruments, not just relying on participant self-reports. ²⁶