Sunnybrook Health Sciences Centre Perioperative Protocol for Patients on GLP-1 Receptor Agonists

By Dr. J Huang & Dr. M Gulak - October 2023

Background:

- Glucagon-like peptide 1 receptor agonists (GLP-1 RAs or GLP-1 agonists) such as Ozempic (semaglutide) are prescribed for type 2 diabetes and more recently weight loss, with a large surge in prescribing in the last year

- GLP-1 agonists delay gastric emptying and can have very long half-lives (i.e., 7 days for semaglutide)

- There is increasing concern for patients presenting for elective procedures with full stomachs and experiencing regurgitation/pulmonary aspiration despite appropriately fasting (up to 20h)^1-3

Scope:

- Elective and planned surgeries and procedures requiring anesthesia

Aim:

- To minimize the risk of regurgitation/pulmonary aspiration under anesthesia in patients taking GLP-1 agonists while accounting for the practical challenges of a prolonged medication hold

Preoperative Recommendations:

1. Patients taking GLP-1 agonists for weight loss

Recommendation: Hold GLP-1 agonist for ≥3 half-lives prior to surgery, i.e., 3 weeks for Ozempic (semaglutide)

2. Patients taking GLP-1 agonists for type 2 diabetes

Consider:

- How recently has the GLP-1 agonist been started?

- What is the risk of hyperglycemia if the GLP-1 agonist is held?

- Does the patient take insulin and can they self-regulate their glycemic control if the GLP-1 agonist is held?

Recommendations (to be adjusted based on above considerations):

- If Hb1AC <7%: Hold GLP-1 agonist for ≥3 half-lives prior to surgery, i.e., 3 weeks for Ozempic (semaglutide)

- If HbA1C ≥7% and taking insulin:

~ Hold GLP-1 agonist for ≥3 half-lives AND instruct patient to self-regulate glycemic control

- If HbA1C ≥7% and NOT taking insulin:

~ Refer to RADAR clinic (rapid referral endocrinology clinic) preoperatively

- If no HbA1C available, draw one in PAC, refer to RADAR if necessary. If not enough time before surgery, treat as per perioperative diabetic protocol. Hold GLP-1 agonist.

Day of Procedure Recommendations:

3. GLP-1 agonist appropriately held

Recommendation: Proceed as usual

4. GLP-1 agonist NOT appropriately held

Recommendation: Anesthesiologist should use clinical judgement regarding proceeding vs. delaying

- Consider treating patient as a full stomach if proceeding

- Consider delaying if any GI symptoms (nausea, vomiting, bloating, abdominal pain)

- Consider use of gastric ultrasound to determine stomach contents

Additional Considerations:

- Currently, no evidence to guide modification of fasting duration/regimens for these patients

- Avoid increasing the dose of GLP-1 agonist prior to elective surgery as this tends to precipitate side effects

- Although Ozempic (semaglutide) is most likely to be encountered, other GLP-1 agonists have varying half-lives which should be accounted for (see algorithm below)

Proposed Algorithm for Patients Presenting to Preassessment Clinic on GLP-1 agonists:

* The recommendation for 3 half-lives is adapted from Jones et al. (CJA 2023)⁴ and is based on balancing pharmacokinetic principles (87.5% drug elimination) with the practicality of a prolonged medication hold. It should be determined based on the following:

- Semaglutide (Ozempic, Wegovy) – weekly injection, half-life = 7 days

- Semaglutide (Rybelsus) – daily oral tablet, half-life = 7 days

- Tirzepatide (Mounjaro) – weekly injection, half-life = 5 days

- Dulaglutide (Trulicity) – weekly injection, half-life = 4.5 days

- Liraglutide (Victoza, Saxenda) – daily injection, half-life = 12.5 hours

- Lixisenatide (Adylxin) – daily injection, half-life = 3 hours

** RADAR clinic is the rapid referral endocrinology clinic at Sunnybrook

References:

1. Klein SR, Hobai IA. Semaglutide, delayed gastric emptying, and intraoperative pulmonary aspiration: a case report. Can J Anaesth. 2023 Aug;70(8):1394-1396. English. doi: 10.1007/s12630-023-02440-3. Epub 2023 Mar 28.

2. Gulak MA, Murphy P. Regurgitation under anesthesia in a fasted patient prescribed semaglutide for weight loss: a case report. Can J Anaesth. 2023 Aug;70(8):1397-1400. English. doi: 10.1007/s12630-023-02521-3. Epub 2023 Jun 6.

3. Beam WB, Hunter Guevara LR. Are serious anesthesia risks of semaglutide and other GLP-1 agonists under-recognized? Case reports of retained solid gastric contents in patients undergoing anesthesia. ASPF. 2023 Jun.

4. Jones PM, Hobai IA, Murphy PM. Anesthesia and glucagon-like peptide-1 receptor agonists: proceed with caution! Can J Anaesth. 2023 Aug;70(8):1281-1286. English. doi: 10.1007/s12630-023-02550-y. Epub 2023 Jul 19.

Addendum

Summary of Glucagon-like Peptide-1 Receptor Agonists for Adults^*

Generic Drug	Brand Name	Indications/ Administration/ Frequency	Gastric Emptying/ Half-life (t_1/2)	Mechanism of Action^*	Add-on Therapy	Adverse Effects
Dulaglutide	Trulicity	T2D SQ Injection x1 weekly	Delayed by ~120 min, where the effect is largest after the first dose and diminishes with subsequent doses. 4.5-4.7 days (t_1/2)	↑ intracellular cyclic AMP in pancreatic β cells leading to glucose-dependent insulin release. ↓ glucagon secretion and slows gastric emptying	Optional as monotherapy, or as add-on to OADs +/ insulin	Mild to moderate: Nausea, vomiting, diarrhea Hypoglycemia Acute pancreatitis (rare)
Exenatide (ER)	Bydureon BCise	T2D SQ Injection x1 weekly	2.4 h/Sustained release (t_1/2)	Binding of the drug to pancreatic GLP-1 receptors mediates: ↑ glucose-dependent insulin secretion from pancreatic β cells Suppresses glucagon secretion and delays gastric emptying Reduces food intake	None	Nausea (less occurrence compared to twice daily dose) Injection-site nodule
Exenatide (IR)	Byetta	T2D/Obesity SQ Injection x2 daily	100-120 min 2.4 h/Sustained release (t_1/2)	Same as ER version	None	nausea irritation at injection site
Liraglutide (3 mg)	Saxenda	Obesity (BMI ≥30 kg/m2 or ≥27 kg/m2 with obesity-related comorbidities) SQ Injection x1 daily	70 min (median) 13 h (t_1/2)	Delays gastric emptying of solids Effects to relevant phenotype and genotypic biomarkers of gastrointestinal functions (variants GLP1R and TCFL2 genes)	None	nausea diarrhea abdominal pain/discomfort constipation
Liraglutide (1.2 mg \|1.8 mg)	Victoza	T2D SQ Injection x1 daily	13 h (t_1/2)	Induced weight loss ↑ glucose-dependent insulin release Improved insulin secretion/β-cell function Reduced liver fat content	+/- long-acting insulin	hypoglycemia GI-tract events increased pulse rate
Lixisenatide	Adlyxin	T2D SQ Injection x1 daily	3 h (t_1/2)	Weight loss Delays gastric emptying Delays intestinal glucose absorption Reduces postprandial insulin secretion May indirectly suppress glucagon secretion	+/- long-acting insulin	hypoglycemia nausea (moderate) vomiting injection site reaction headache dizziness
Semaglutide	Ozempic, Wegovy, others	T2D/Obesity SQ Injection x1 weekly	60 minutes ~1 week (t_1/2)	↓ glucagon secretion Delays gastric emptying	+/- long-acting insulin	nausea diarrhea constipation
Semaglutide	Rybelsus	T2D Oral x1 daily	60 minutes ~1 week (t_1/2)	Delays gastric emptying ↓ in HbA1c Weight loss ↓ systolic blood pressure	+/- long-acting insulin	nausea diarrhea

Sunnybrook Health Sciences Centre Perioperative Protocol for Patients on GLP-1 Receptor Agonists

By Dr. J Huang & Dr. M Gulak - October 2023

Background:

- Glucagon-like peptide 1 receptor agonists (GLP-1 RAs or GLP-1 agonists) such as Ozempic (semaglutide) are prescribed for type 2 diabetes and more recently weight loss, with a large surge in prescribing in the last year

- GLP-1 agonists delay gastric emptying and can have very long half-lives (i.e., 7 days for semaglutide)

- There is increasing concern for patients presenting for elective procedures with full stomachs and experiencing regurgitation/pulmonary aspiration despite appropriately fasting (up to 20h)1-3

Scope:

- Elective and planned surgeries and procedures requiring anesthesia

Aim:

- To minimize the risk of regurgitation/pulmonary aspiration under anesthesia in patients taking GLP-1 agonists while accounting for the practical challenges of a prolonged medication hold

Preoperative Recommendations:

1. Patients taking GLP-1 agonists for weight loss

Recommendation: Hold GLP-1 agonist for ≥3 half-lives prior to surgery, i.e., 3 weeks for Ozempic (semaglutide)

2. Patients taking GLP-1 agonists for type 2 diabetes

Consider:

- How recently has the GLP-1 agonist been started?

- What is the risk of hyperglycemia if the GLP-1 agonist is held?

- Does the patient take insulin and can they self-regulate their glycemic control if the GLP-1 agonist is held?

Recommendations (to be adjusted based on above considerations):

- If Hb1AC <7%: Hold GLP-1 agonist for ≥3 half-lives prior to surgery, i.e., 3 weeks for Ozempic (semaglutide)

- If HbA1C ≥7% and taking insulin:

~ Hold GLP-1 agonist for ≥3 half-lives AND instruct patient to self-regulate glycemic control

- If HbA1C ≥7% and NOT taking insulin:

~ Refer to RADAR clinic (rapid referral endocrinology clinic) preoperatively

- If no HbA1C available, draw one in PAC, refer to RADAR if necessary. If not enough time before surgery, treat as per perioperative diabetic protocol. Hold GLP-1 agonist.

Day of Procedure Recommendations:

3. GLP-1 agonist appropriately held

Recommendation: Proceed as usual

4. GLP-1 agonist NOT appropriately held

Recommendation: Anesthesiologist should use clinical judgement regarding proceeding vs. delaying

- Consider treating patient as a full stomach if proceeding

- Consider delaying if any GI symptoms (nausea, vomiting, bloating, abdominal pain)

- Consider use of gastric ultrasound to determine stomach contents

Additional Considerations:

- Currently, no evidence to guide modification of fasting duration/regimens for these patients

- Avoid increasing the dose of GLP-1 agonist prior to elective surgery as this tends to precipitate side effects

- Although Ozempic (semaglutide) is most likely to be encountered, other GLP-1 agonists have varying half-lives which should be accounted for (see algorithm below)

Proposed Algorithm for Patients Presenting to Preassessment Clinic on GLP-1 agonists:

* The recommendation for 3 half-lives is adapted from Jones et al. (CJA 2023)4 and is based on balancing pharmacokinetic principles (87.5% drug elimination) with the practicality of a prolonged medication hold. It should be determined based on the following:

- Semaglutide (Ozempic, Wegovy) – weekly injection, half-life = 7 days

- Semaglutide (Rybelsus) – daily oral tablet, half-life = 7 days

- Tirzepatide (Mounjaro) – weekly injection, half-life = 5 days

- Dulaglutide (Trulicity) – weekly injection, half-life = 4.5 days

- Liraglutide (Victoza, Saxenda) – daily injection, half-life = 12.5 hours

- Lixisenatide (Adylxin) – daily injection, half-life = 3 hours

** RADAR clinic is the rapid referral endocrinology clinic at Sunnybrook

Addendum

Summary of Glucagon-like Peptide-1 Receptor Agonists for Adults*

*GLP-1 RAs share the same underlying mechanism of action, but they differ in terms of formulations, administration, injection devices and dosages.

Abbreviations: ER=extended release; IR=immediate release; OAD=oral antihyperglycemic drugs; SQ=subcutaneous; T2D=type 2 diabetes; BMI=body mass index.

- There is increasing concern for patients presenting for elective procedures with full stomachs and experiencing regurgitation/pulmonary aspiration despite appropriately fasting (up to 20h)^1-3

* The recommendation for 3 half-lives is adapted from Jones et al. (CJA 2023)⁴ and is based on balancing pharmacokinetic principles (87.5% drug elimination) with the practicality of a prolonged medication hold. It should be determined based on the following:

Summary of Glucagon-like Peptide-1 Receptor Agonists for Adults^*

^*GLP-1 RAs share the same underlying mechanism of action, but they differ in terms of formulations, administration, injection devices and dosages.