GLP-1 Receptor Agonists: Perioperative Management - Recent Advances

1. Introduction and Clinical Relevance

2. Mechanisms of Action Relevant to Perioperative Medicine

• Incretin effect: Stimulate glucose-dependent insulin secretion and suppress glucagon
• Gastric emptying inhibition: Delay gastric emptying, especially for solids - the most anesthesiologically significant effect
• Hypothalamic appetite suppression: Reduce appetite via hypothalamic signaling, contributing to weight loss
• Tachyphylaxis: Gastric emptying effects partially attenuate (tachyphylaxis) after 12-20 weeks on a stable dose, but gastric stasis can persist even with long-term stable dosing

3. The Core Perioperative Concern: Delayed Gastric Emptying and Aspiration Risk

Pathophysiology

• Increased residual gastric volume at the time of anesthesia induction
• Risk of regurgitation and pulmonary aspiration of gastric contents
• Aspiration pneumonitis (Mendelson syndrome) if acidic gastric fluid (pH <2.5) is aspirated
• Risk is heightened during dose initiation and escalation phases

Key Clinical Evidence (2024-2025)

• Multiple studies confirm that patients on GLP-1 RAs have higher incidence of residual gastric contents even after standard fasting
• A meta-analysis (April 2025) found no statistically significant difference in actual aspiration incidence (OR 1.04, 95% CI 0.87-1.25), but noted low certainty of evidence
• A second meta-analysis (July 2025) focused specifically on endoscopy patients found a doubled aspiration risk (OR 2.29, 95% CI 1.36-3.87) in GLP-1 RA users
• The SPAQI 2025 consensus (Society for Perioperative Assessment and Quality Improvement, published in the British Journal of Anaesthesia, July 2025) reviewed 112 studies and represents the most comprehensive synthesis to date

4. Evolution of Guidelines (2023-2025)

4a. ASA 2023 Initial Guidance

• Hold daily (oral) GLP-1 RAs for 1 day before surgery
• Hold weekly injectable GLP-1 RAs for 1 week before surgery
• If medication was NOT held: apply full-stomach precautions
• Criticism: No differentiation by dose, phase of therapy, or symptom status

4b. ASA 2024 Updated Guidance

• Allowed continuation in low-risk, asymptomatic patients
• Advised a 24-hour liquid diet for higher-risk groups
• Criticized for relying on symptom-based stratification - studies show GI symptoms poorly predict gastric content volume
• Still left decisions to shared clinical decision-making

4c. British Association of Anaesthetists (BAA) - January 2025

• Recommended continuing GLP-1 RAs perioperatively without exception
• Explicitly stated: "upper gastrointestinal symptoms alone should not be used to determine gastric content"
• Focus on modified fasting rather than drug cessation

4d. ADS/ANZCA/GESA/NACOS Joint Clinical Practice Recommendations - 2025

1. All patients must be asked about GLP-1 RA and dual GLP-1/GIP RA use before anesthesia
2. Elective preprocedural cessation is NOT recommended (withholding for 1-2 weeks is unlikely to restore normal gastric emptying and risks hyperglycemia and loss of cardioprotective/renoprotective benefits)
3. Diet modification: 24-hour clear fluid diet followed by standard 6-hour fast for solids
4. If 24-hour liquid diet was not completed: use gastric ultrasound or minimally sedated gastroscopy to assess gastric contents
5. Erythromycin is reasonable as a prokinetic to counteract GLP-1 RA-induced gastric emptying inhibition
6. Weight stigma may cause patients to underreport GLP-1 RA use or not consider weight-loss drugs as "medications" - proactive questioning is essential

4e. SPAQI 2025 Multidisciplinary Consensus (Endorsed by AACE)

• Based on 112-study review with expert Delphi process
• Recommends continuing GLP-1 RAs (no discontinuation)
• Extended fasting protocol for asymptomatic patients:
  • Solid food: stop ≥24 hours before anesthesia
  • Low-glucose clear liquids: permitted until 4 hours pre-op
  • High-glucose clear liquids (≥10% glucose): avoid for 8 hours pre-op
  • Acceptable: water, black coffee, broth, sugar-free electrolyte drinks
  • Avoid: juice, soda, sweetened beverages, milk/cream
• Delay surgery when: significant nausea/vomiting, poor oral intake, active GI symptoms, or suspected gastric stasis

5. Preoperative Assessment and Stratification

What to elicit in history

• Specific agent and formulation (daily vs. weekly)
• Duration of therapy and recent dose changes
• Presence of GI symptoms (nausea, vomiting, bloating, early satiety)
• Indication (diabetes vs. obesity vs. heart failure)
• Concomitant medications that further delay gastric emptying (opioids, anticholinergics, tricyclic antidepressants)
• Co-existing diabetic autonomic neuropathy (independently increases gastric stasis risk)

Risk stratification

6. Anesthetic Management

Preoperative

• Gastric ultrasound (antral cross-sectional area in the right lateral decubitus position) is emerging as a valuable bedside tool to assess residual gastric contents - allows individualized risk stratification
• Pharmacological prokinetics: Erythromycin IV (3 mg/kg) approximately 30-60 minutes before induction can accelerate gastric emptying; metoclopramide has limited evidence but is commonly used
• Aspiration prophylaxis: H2-receptor antagonists (ranitidine/famotidine) or proton pump inhibitors reduce gastric acidity in high-risk patients, though none are fully reliable alone

Airway/Induction

• Rapid Sequence Induction (RSI) with cricoid pressure (Sellick's maneuver) for patients with:
  • Suspected full stomach
  • Symptoms suggesting gastric stasis
  • Emergency procedures where GLP-1 RA was not held
• Video laryngoscopy should be immediately available (obesity is a frequent comorbidity)
• Consider awake fiberoptic intubation in patients with predicted difficult airway + high aspiration risk

Intraoperative Glycemic Monitoring

• Goal: glucose 140-180 mg/dL (based on NICE-SUGAR trial evidence)
• Monitor every 1-2 hours in patients receiving insulin perioperatively
• GLP-1 RAs alone carry low hypoglycemia risk (glucose-dependent mechanism), but combination with insulin or sulfonylureas increases risk
• Subcutaneous rapid-acting insulin preferred for short outpatient procedures; IV insulin for major surgeries with fluid shifts

Postoperative

• Resume GLP-1 RA once patient is tolerating oral intake
• In patients with postoperative nausea/vomiting (PONV), consider delay before restarting, as GLP-1 RAs compound nausea
• Adequate PONV prophylaxis is important (e.g., ondansetron, dexamethasone, scopolamine patch)

7. Beyond Aspiration: Other Perioperative Considerations

Glycemic Benefits

• GLP-1 RAs are associated with improved perioperative glycemic control and lower intraoperative insulin requirements (Ihnat et al., Am J Surg, 2025 - systematic review of 21 studies)
• May reduce rates of surgical site infections via improved glucose control

Preoperative Weight Optimization

• GLP-1 RAs can help patients achieve BMI thresholds required for elective surgery (e.g., joint replacement, bariatric surgery)
• Reduce obesity-related comorbidities preoperatively

Cardioprotective and Renoprotective Effects

• Abrupt perioperative discontinuation risks losing cardiovascular and renal protective benefits
• GLP-1 RAs reduce MACE in T2DM (LEADER, SUSTAIN-6 trials)
• This is a key reason modern 2025 guidelines favor continuation over cessation

Surgical Site Infection and Wound Healing

• A 2025 systematic review and meta-analysis (Cureus, PMID 41438726) found GLP-1 RAs associated with reduced periprosthetic joint infection in obese orthopedic surgery patients

Orthopedic Surgery - Specific Considerations

• GLP-1 RAs improve obesity and metabolic comorbidities preoperatively, potentially reducing complications
• Ongoing debate about optimal timing of perioperative cessation vs. continuation
• Current orthopedic literature (Ramanathan et al., JBJS, 2025) endorses the shift toward continued use with modified fasting

Gastrointestinal Endoscopy

• Strongest aspiration signal comes from endoscopy literature (OR 2.29 in July 2025 meta-analysis)
• Endoscopy societies increasingly recommend modified fasting protocols over drug cessation
• The 2025 ADS/ANZCA/GESA joint guideline specifically addresses endoscopic procedures alongside surgical ones

8. SGLT2 Inhibitors: A Comparison (Parallel Concern)

• Euglycemic diabetic ketoacidosis (euDKA) - hold for 3-4 days before surgery
• Unlike GLP-1 RAs (hold 1 week in older guidance, now controversial), SGLT2 inhibitor cessation has a clear safety basis

9. Areas of Ongoing Research and Controversy

1. Adequate washout period - No study has determined what duration of cessation reliably restores normal gastric emptying. Semaglutide's 7-day half-life means even a 1-week hold may be insufficient for full pharmacodynamic recovery.
2. Symptom-based vs. objective stratification - GI symptoms poorly predict gastric content; gastric ultrasound is more reliable but not yet universally available or standardized.
3. Tirzepatide and dual GLP-1/GIP agonists - These newer agents may have different gastric emptying profiles than pure GLP-1 RAs; specific data are limited.
4. Pediatric and obstetric populations - No current guidelines exist for these groups.
5. Optimal prokinetic protocol - Erythromycin dose, timing, and reliability in the GLP-1 RA context requires further study.
6. Postoperative restarting timing - No consensus on optimal timing to restart after major GI surgery.

10. Summary: Practical Recommendations (2025 State of the Art)

Key References

• Sabiston Textbook of Surgery, 21e, pp. 445-446 (Aspiration Pneumonitis; Diabetes Mellitus - Perioperative Management)
• Miller's Anesthesia, 10e, pp. 3999-4000, 4228-4229 (GLP-1 RAs, Perioperative Glycemic Management)
• Ihnat JMH et al. (2025). A systematic review of the use of GLP-1 receptor agonists in surgery. Am J Surg. PMID: 39615284
• Li XY et al. (2025). Perioperative management of patients on GLP-1 receptor agonists: Risks, recommendations, and future directions. J Clin Anesth. PMID: 40378603
• VanderWielen BA, Brian Beam W. (2024). Perioperative Considerations for Patients on GLP1 Agonists. Advances in Anesthesia. PMID: 39443044
• Ramanathan R et al. (2025). GLP-1 Receptor Agonists in Orthopaedic Surgery. JBJS Am. PMID: 40833394
• 2025 ADS/ANZCA/GESA/NACOS Joint Clinical Practice Recommendations (PMC12420935)
• ASA Consensus-based Guidance on Preoperative Management of GLP-1 Receptor Agonists. Anesthesiology. 2024;140(2):346-348.