INTRODUCTION

Bariatric surgery has long been considered the gold standard treatment for obesity that is refractory to lifestyle and medical management. However, new antiobesity medications (AOMs) are increasingly being tested as a less-invasive treatment option. New gastrointestinal incretin receptor agonist medications are becoming more prevalent due to their effectiveness and popularity as a weight loss intervention and their apparent benefits in the management of multiple weight-related comorbidities, including diabetes as well as hepatic and cardiovascular disease.¹ As these medications are new to modern practice and their use in weight loss is still novel for some patients, they are commonly omitted from being reported during routine preoperative medication screening despite their potential association with perioperative adverse events, such as pulmonary aspiration of gastric contents. The increasing use of these agents, their evolving pharmacodynamic and side effect profiles, and the relevance of these physiologic changes to perioperative anaesthetic management merit increased awareness and vigilance. This article will help familiarise practitioners with these new medications, their uses, benefits, side effects, and, finally, what anaesthetists can do to maintain patient safety in the perioperative period.

THE NOVEL AOMS AND THEIR EFFECTS

Mechanism of Action and Indications

Incretins are peptide hormones secreted, under neural control, by the gastrointestinal tract (GIT) lumen following nutrient intake.² The incretins most implicated in glucose control and satiety are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).² GLP-1 is secreted by ileocolonic L cells, and GIP is secreted by duodenojejunal K cells; both are endocrine cells lining the GIT.² GIP and GLP-1 are secreted 15 to 30 minutes after ingestion of food, in parallel to increases in blood glucose, but are rapidly enzymatically inactivated by dipeptidyl peptidase-4 (DPP-4) 2 minutes after secretion.² Although both incretins affect pancreatic β cells, stimulating insulin production, GLP-1 receptors are also widely distributed throughout the body, including the GIT, cardiac, adipose, and neural tissues.¹ It is via these extrapancreatic receptors that GLP-1 suppresses neural appetite centres, decreases hepatic glucagon release, and delays gastric emptying, enhancing satiety.² Type 2 diabetes mellitus (T2DM) can be associated with reduced secretion of GLP-1 and decreased sensitivity to GIP, a pathology that the GLP-1 analogue agents can reverse.² A compendium of these effects is depicted in Figure.

At the time of publication, there are several incretin analogue and receptor agonist medications approved internationally for glucose control and/or weight loss.¹ The usual indication, for weight loss alone is a body mass index (BMI) of ≥30 kg/m² or a BMI of ≥27 kg/m² with associated weight-related comorbidities.¹ There are a variety of medications that target different aspects of this physiologic pathway. Liraglutide (Saxenda, Victoza) and semaglutide (Ozempic, Wegovy) are GLP-1 receptor agonists (RAs).¹ Tirzepatide (Mounjaro, Zepbound) is a dual GLP-1/GIP RA.² The US Food and Drug Administration has approved Victoza, Ozempic, and Mounjaro for the treatment of T2DM, whereas Saxenda, Wegovy, and Zepbound are approved for weight management. All of these drugs exert their actions by working directly at their respective receptors but, importantly, also by an engineered resistance to inactivation by DPP-4. Combined with a low renal clearance, this resistance to inactivation prolongs their effects.^2,3 Liraglutide has a half-life of 8 to 12 hours, semaglutide has a half-life of 7 days, and tirzepatide has a half-life of 5 days.³ A summary table of these agents is presented in Table 1.

Due to their different half-lives, liraglutide is dosed once daily, whereas the other agents are dosed weekly. Other GLP-1 RAs are on the market, such as exenatide (Byetta), lixisenatide (Adlyxine), and dulaglutide (Trulicity), which are currently approved only for glycaemic control in T2DM.³

Efficacy in Weight-Related Comorbidities

These new AOMs are surprisingly efficacious in relation to weight loss and glycaemic control.¹ Weight loss of >5% at 3 months defines an “AOM responder,”⁴ and this amount of weight loss can potentially prevent or slow progression of multiple diseases, such as T2DM, hypertension, polycystic ovary syndrome, hepatic steatosis, and osteoarthritis.⁵ Weight loss of >10% has been shown to potentially have even greater health benefits in relation to cardiovascular events, heart failure, sleep apnoea, asthma, and remission of T2DM.⁵

Figure. Effects of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist medications on various organ systems (images from iStock by Getty Images 2024).

Table 1. Trade Names and Half-lives of the Commonly used Glucagon-like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Agonist Medications; NA, Not Applicable

In phase 3 trials, these new AOMs were given to study participants and predominantly compared with placebo.¹ In the SCALE study, participants taking Saxenda (liraglutide) demonstrated an average weight decrease of 6 to 8% in the intervention arm compared with 2% in the placebo arm. In the STEP studies, Wegovy (semaglutide approved specifically for weight loss), which is the higher dose of Ozempic, showed even greater degrees of participant weight loss. There was an average weight decrease of 8 to 14% in intervention arm participants compared with the placebo arm, which demonstrated a 2% weight decrease in the 56-week trial. Tirzepatide, the new GLP-1/GIP RA, has shown the most impressive results, especially at its highest dose of 15 mg/week. The average weight decrease was >20% compared with the placebo arm, which only demonstrated a 3% decrease in weight. In the aforementioned trials, all study participants also underwent lifestyle changes, including diet and exercise.

In relation to glucose control, patients with obesity and T2DM who were randomised to the Saxenda (liraglutide) or Wegovy (semaglutide) arm of their respective trials showed significant improvement in haemoglobin A1c (a drop of >1%) compared with placebo.¹ For the trials investigating patients with obesity and prediabetes, there was a statistically significant decrease in haemoglobin A1c in the intervention arms for both Saxenda and Wegovy, but the magnitude of the decrease was very small (<1%), calling into question the clinical relevance of these medications in this population.

With these striking impacts on weight and glycaemic control, anaesthesiologists might find an increasing number of their patients taking these medications. Furthermore, patients requiring weight and diabetic optimisation might represent having newly commenced these medications after referral back to their primary doctor or to an endocrinologist for preoperative optimisation. It is conceivable that we may begin to see patients for elective procedures, such as orthopaedic joint replacement patients, trialling these medications to reduce their weight and ameliorate arthritic symptoms.

Investigation into other positive health benefits of these medications is underway. There is some evidence from small studies, phase 1 and 2 trials, and post hoc analyses of phase 2 and 3 trials that the new AOMs might improve non-alcoholic steatohepatitis, lipid profiles, blood pressure, and cardiovascular outcomes.¹ Further investigation is required, but the relevance to this topic remains the same; with an increased diversity of potential benefits, perioperative patients are more likely to present while taking these medications.

Side Effects

Side effects for these new AOMs are common.¹ In the STEP 8 trial, comparing liraglutide and semaglutide, up to 90% of patients experienced adverse events, which were mostly GI related.¹ Adverse events at a rate of more than 10% seemed to consistently occur in study populations. The side effects are largely GI related, with nausea, dyspepsia, vomiting, diarrhoea, abdominal pain, and constipation being the main complaints.^1,6,7 Neurological side effects included headaches and dizziness.¹ Patients receiving GLP-1 RAs also experience mildly increased heart rates.¹ Heart rates rise between 1 and 10 beats/min and are thought to be due to direct action on the sinus node, but they are not associated with increased risk of arrhythmia.^8,9 Infections such as nasopharyngitis, influenza, and urinary tract infections were also reported.¹ Caution may be required when prescribing these medications to patients with a history of pancreatitis, as episodes of acute pancreatitis are increasingly being noted in case reports,¹ with liraglutide and semaglutide showing a stronger potential association with pancreatitis than the other GLP-1 RAs.⁷ AOMs may exacerbate a current episode of pancreatitis, and discontinuation should be considered, but there is a lack of evidence implicating these medications as an independent risk factor in the development of acute pancreatitis,¹⁰ and emerging studies and analyses continue to challenge this association.¹¹

Using the US Food and Drug Administration retrospective adverse events reporting database, Liu et al. were able to analyse 21,281 reports of GI side effects of the 81,752 adverse events reported between 2018 and 2022.⁷ The authors found that 77% of GI adverse events occurred within the first month of commencing the medication. Liraglutide was implicated with the highest rate of GI side effects, consistent with other studies, along with dulaglutide.^6,7 However, other research shows semaglutide to have a stronger association with nausea, vomiting, diarrhoea, and constipation.⁷ Of the GI side effects, nausea was self-reported by 42% of patients, and diarrhoea and vomiting were both reported by 22% of patients.⁷ The incidence of reported side effects varies between studies and may be due to several factors, including variation in study populations, specific medications tested, and study design. Risk factors associated with higher odds of experiencing side effects were younger age, female sex, chronic kidney disease, and heart failure.⁶ Table 2 demonstrates how commonly these side effects are reported. For anaesthesiologists, this means that a large proportion of patients taking these medications may need further preoperative investigation/optimisation.

A study of a random sample of 16 million US patients prescribed either liraglutide or semaglutide compared with bupropion-naltrexone for weight loss demonstrated an association between the use of the GLP-1 RAs and an increased risk of pancreatitis, bowel obstruction, and gastroparesis.¹²

However, despite these side effects, the dropout rate of the semaglutide studies was low, ranging between 0 and 6%.¹ Studies involving liraglutide had higher drop-out rates, 10% of the intervention arm, 20% of the placebo arm, and 65% of participants in the extension study. Dropout is a significant consideration as it seems that patients will need to continue these medications lifelong to maintain the weight loss benefits. Tirzepatide may have an improved side effect profile compared with liraglutide and semaglutide, with reasons for this still unclear.

In real-life practice, clinicians slowly increase the dose of these medications over months to achieve the most efficacious dose whilst also mitigating side effects. With slow dose adjustments, patients appear to experience tachyphylaxis to symptoms over several weeks. The relevance of these medications to perioperative care may then involve not only the type of agent used but also the time period over which a patient has been using the medication.

In animal studies, there has been a link between GLP-1 RAs and medullary thyroid cancer.¹³ Studies in rats showed the development of thyroid C cell tumours; however, rats express GLP-1 receptors in their thyroids, and studies have shown low or absent GLP-1 receptor expression in the human thyroid. Nevertheless, it is advised to avoid these medications in patients with a family history of medullary thyroid cancer or Multiple Endocrine Neoplasia type 2.¹³

Table 2. The Prevalence and Relevance of Several Common Gastrointestinal (GI) Side Effects Associated with the use of Glucagon-like Peptide-1 (GLP-1)/Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Agonist Medications; RAs, Receptor Agonists

Anaesthetic Implications of AOMs

As with many new diabetic and weight loss drugs introduced to the market, their rapid uptake secondary to promising health benefits has meant anaesthetic practitioners have had to familiarise themselves with the indications, side effects, complications, and potential drug interactions. This is a challenge when perioperative guidelines continue to evolve in tandem, alongside an evolving collection of case reports and associated complications.

Current guidelines for the preoperative management of AOMs are developing and will require contemporaneous revision as continued observation as research emerges. For glycaemic control, recommendations include withholding single scheduled doses of once- or twice-daily dosed medications (exenatide, liraglutide) or for 1 week before surgery for weekly dosed medications (semaglutide, dulaglutide).^14,15

However, anaesthesiologists are also beginning to consider perioperative adjustments to dosing to minimise GI symptoms, such as delay in gastric emptying, suggesting that cessation should involve more than 1 half-life (ideally 3 to 4 half-lives) of the agent in question. This has come about because small studies and case reports have raised concerns about delayed gastric emptying and aspiration risk, despite adequate fasting times preceding surgery whilst patients are continuing to take GLP-1 RAs. In 2023, 2 case reports were presented in the Canadian Journal of Anaesthesia, discussing retained gastric contents despite appropriate fasting duration.¹⁶ One patient was taking semaglutide for weight loss and had appropriately fasted for a gastroscopy procedure for 18 hours and, despite this fasting, had a pulmonary aspiration event. Another non-obese, nondiabetic patient taking semaglutide for weight loss underwent elective breast surgery. She had a large regurgitation event without pulmonary aspiration despite fasting from solids for 20 hours and 8 hours from clear fluids. More case reports on this topic continue to be published.

Several small observational studies of gastric ultrasounds and gastroscopies compared the risk of retained gastric contents after fasting between patients on GLP-1 RAs and controls. These small studies demonstrated a 4- to 10-fold increased risk of having retained gastric contents if the patients were taking GLP-1 RAs.¹⁶ A large retrospective study of endoscopy patients demonstrated a statistically significant increased incidence of aspiration pneumonia in patients who underwent upper endoscopy and were taking a GLP-1 RA versus those who were not (0.83% versus 0.63%).¹⁷ It is important to note that despite some association with the use of GLP-1 RAs and retained gastric contents, we cannot yet confidently conclude the clinical relevance of residual gastric contents with respect to regurgitation.

There is evidence of tachyphylaxis to delayed gastric emptying with short-acting GLP-1 RA infusions.¹⁸ However, a multicentre randomised controlled trial of 142 patients from 2015 described prolonged gastric emptying in both the liraglutide and lixisenatide study arms for the 8-week duration of the study.¹⁹ There is currently no definitive evidence to suggest complete normalisation of gastric emptying time to baseline with long-acting GLP-1 RAs.

Anaesthesiologists must be aware of the indication for a patient being prescribed GLP-1 RAs. Repeated cessation and recommencement for weight control can still result in a delay of gastric emptying.¹⁶ With diabetics, there are additional factors to consider as these patients may have some degree of gastroparesis at baseline, especially with poor blood glucose control, which might compound the effects of GLP-1 RAs.²⁰ Additionally, one must weigh the known risks of poor perioperative glucose control against the emerging but unquantified risk of delayed gastric emptying and retained gastric contents. These considerations highlight the need for accurate history-taking regarding symptoms of incomplete gastric emptying.

It should be noted that other commonly used medications, both prescribed and recreational, can further delay gastric emptying.²¹ Commonly used medications include, but are not limited to, opioids, anticholinergics, calcium channel blockers, tricyclic antidepressants, proton pump inhibitors, histamine-2 receptor blockers, alcohol, tobacco, and cannabinoids.

Last year, the American Society of Anesthesiologists (ASA) published its own set of guidelines to facilitate decision-making around mitigating perioperative risk of pulmonary aspiration secondary to delayed gastric emptying.²² They have suggested the following:

• If a patient has active GI symptoms, such as nausea, vomiting, retching, abdominal pain, or bloating, delay the elective procedure and discuss relevant risks with the surgeon/proceduralist and patient.
• If a patient has appropriately withheld their GLP-1 RA and is not experiencing GI symptoms, surgery can proceed.
• If a patient is asymptomatic but did not withhold their GLP-1 RA appropriately, proceed as if the patient is not appropriately fasted or perform a gastric ultrasound to evaluate for gastric contents. If the ultrasound is negative for retained contents, proceed. If it is positive or equivocal, consider delaying the procedure or proceed as if not appropriately fasted. Again, discuss the relevant risks with the involved parties.
• The ASA could not comment on an alteration to current fasting guidelines.

The Australia and New Zealand College of Anaesthetists (ANZCA), in conjunction with the Australian societies of gastroenterology, diabetes, and obesity, have recently published guidelines regarding periprocedural use of GLP-1 RAs and dual GLP-1 RAs/GIP RAs. They do not consider questions to elicit the presence of active GI symptoms to be a sensitive marker for retained gastric contents. Regarding upper endoscopy procedures, they do not recommend cessation of these medications pre-procedurally, but they do recommend a 24-hour fluid diet before anaesthesia. If there is a clinical concern about retained gastric contents, the guidelines suggest that a procedure with local anaesthetic and minimal to no sedation can be undertaken with an ultrathin gastroscope to assess gastric contents. For nonendoscopic procedures, the guidelines suggest that a patient who has taken 1 of these medications in the last 4 weeks should be considered unfasted. Again, they do not suggest that these medications should be ceased, but cessation can be considered for short-acting agents, such as liraglutide, on the day of surgery. Much like the ASA guidelines, they do suggest gastric ultrasound by a skilled provider and agree that no change to current fasting guidelines can be recommended at this time.

Interestingly, ANZCA has suggested that practitioners consider the administration of a prokinetic agent (such as intravenous erythromycin) 1 to 2 hours before anaesthesia to accelerate gastric emptying. Although there is evidence that intravenous erythromycin can result in rapid gastric emptying, this intervention has been studied in the context of gastrointestinal haemorrhage or diabetic gastroparesis and has not been quantified for efficacy in the setting of GLP1 RA or GLP 1RA/GIP RA use.¹⁷

Current pre-operative medication cessation guidelines do not consider the time needed for therapeutic drug levels to become negligible. Commonly, medication should be withheld for at least 3 half-lives before the surgery/procedure if significant clearance of the drug is desired. Therefore, our current knowledge of the risks of these medications requires further investigation.¹⁵ Endocrinologist input is recommended if prolonged cessation is being considered if a patient is taking the medication as a treatment for diabetes.

Of note, at the time of writing, Tirzepatide is a relatively new GLP-1 RA/GIP RA. Due to its current association with drastic weight loss, it is likely that it will be in high demand. However, only a small amount of evidence currently exists surrounding its peri-operative use.