The use of glucagon-like peptide-1 (GLP-1) receptor agonists has rapidly expanded over the past decade, marking a significant advancement in the treatment of type 2 diabetes and obesity. This class of drugs has gained traction primarily due to its proven benefits in managing blood glucose levels and achieving substantial weight reduction. For example, medications like semaglutide and tirzepatide have been shown to reduce body weight by 10-20%, making them an attractive option for individuals with obesity, regardless of whether they have diabetes.

These drugs work by mimicking the effects of the GLP-1 hormone, which enhances insulin secretion, suppresses glucagon release, and delays gastric emptying. While these mechanisms are beneficial for glycaemic control and weight management, the delay in gastric emptying has raised concerns in specific medical scenarios. For instance, it could lead to retained gastric contents, posing risks in procedures requiring sedation or anaesthesia. This dual nature, beneficial for chronic conditions but potentially risky in procedural settings, has sparked significant discussion and research within the medical community.

Mechanism of Action and Associated Risks

GLP-1 receptor agonists exert their therapeutic effects by targeting multiple pathways. One of their key mechanisms is delaying gastric emptying, which prolongs the feeling of fullness and contributes to weight loss. However, this delayed gastric emptying can result in retained stomach contents, which may not empty properly before certain medical procedures. Retained gastric contents are a recognised risk factor for pulmonary aspiration, a serious complication that can occur during procedures involving sedation or anaesthesia.

Pulmonary aspiration happens when gastric contents are inhaled into the lungs, potentially leading to respiratory complications such as aspiration pneumonia. Reports have emerged documenting cases of pulmonary aspiration in patients taking semaglutide, despite adherence to fasting protocols. This has drawn attention to the potential procedural risks associated with GLP-1 receptor agonists, particularly during upper gastrointestinal endoscopy and other elective procedures.

Small observational studies have also reported an increased likelihood of retained gastric contents in GLP-1 receptor agonist users compared to non-users. This raises questions about whether standard fasting guidelines are sufficient for this patient population. Given the increasing prevalence of GLP-1 receptor agonist use, these findings have prompted new clinical guidelines to mitigate the risks.

Safety Guidelines and the Ongoing Debate

In response to these safety concerns, the American Society of Anaesthesiologists (ASA) published consensus-based guidance recommending that GLP-1 receptor agonists be withheld before elective procedures. For drugs administered daily, they recommend skipping one dose, while for weekly medications, they advise discontinuation one week prior to the procedure. This guidance aims to reduce the risk of pulmonary aspiration by allowing sufficient time for gastric emptying.

However, these recommendations have not been universally accepted. Some medical professionals argue that withholding GLP-1 receptor agonists could pose risks for patients with diabetes who rely on these medications for glycaemic control. The American Gastroenterological Association has highlighted the need for more robust studies to evaluate the actual risks of pulmonary aspiration associated with GLP-1 receptor agonists. Additionally, a multi-society statement recently questioned the necessity of discontinuing these drugs before elective endoscopic procedures, citing a lack of conclusive evidence to support such practices.

Real-World Evidence

To address the growing concerns, a cohort study was conducted to evaluate the risks associated with GLP-1 receptor agonists in the context of upper gastrointestinal endoscopy. This study compared GLP-1 receptor agonist users with those taking sodium-glucose co-transporter-2 (SGLT-2) inhibitors, another class of antidiabetic drugs with similar indications. By using SGLT-2 inhibitors as a comparator, the researchers aimed to minimise confounding factors related to disease severity and treatment stage.

The findings indicated no significant increase in the risk of pulmonary aspiration among GLP-1 receptor agonist users compared to SGLT-2 inhibitor users. Pulmonary aspiration events were rare in both groups, aligning with previous studies that reported a low incidence of this complication in the general population. This data provides reassurance that the procedural risks associated with GLP-1 receptor agonists may be lower than initially feared.

However, the study did identify an increased rate of endoscopy discontinuation among GLP-1 receptor agonist users. Procedures were more likely to be cancelled or rescheduled due to suspected retained gastric contents. This highlights a potential administrative and clinical burden, as delays in procedures can lead to increased healthcare costs and prolonged diagnostic timelines.

Risk of Endoscopy Discontinuation

The increased risk of endoscopy discontinuation among GLP-1 receptor agonist users accentuates the importance of adapting pre-procedural care for these patients. The study noted a higher likelihood of procedure cancellation in patients with a body mass index (BMI) of 30 or higher, suggesting that obesity may amplify the risks associated with delayed gastric emptying. Additionally, the use of higher-potency GLP-1 receptor agonists, such as semaglutide and tirzepatide, appeared to contribute to this elevated risk.

Interestingly, some researchers have speculated that short-term use of GLP-1 receptor agonists may pose a greater risk due to the initial impact on gastric motility. However, this study did not find a higher incidence of pulmonary aspiration among patients who had recently started these medications. This finding suggests that other factors, such as patient-specific characteristics and drug potency, may play a more significant role in determining procedural risks.

Clinical Implications

While the benefits of GLP-1 receptor agonists are well-established, their potential risks in procedural settings necessitate careful consideration. The increased rate of endoscopy discontinuation among GLP-1 receptor agonist users points to the need for enhanced pre-procedural assessments. For example, endoscopists and anaesthesiologists may need to evaluate gastric contents more rigorously in patients taking these medications.

From a broader perspective, clinicians must weigh the risks of withholding GLP-1 receptor agonists against the potential complications of continued use. For patients with diabetes, abrupt discontinuation of these drugs could lead to suboptimal glycaemic control, which carries its own set of risks. Multidisciplinary collaboration among endocrinologists, gastroenterologists, and anaesthesiologists is essential to develop individualised care plans that minimise procedural risks while maintaining the therapeutic benefits of GLP-1 receptor agonists.

Future Research 

Despite the valuable insights provided by this study, several unanswered questions remain. Future research should focus on evaluating the risks of pulmonary aspiration in non-endoscopic procedures that require general anaesthesia. Such studies could provide a more comprehensive understanding of how GLP-1 receptor agonists affect procedural outcomes across various medical settings.

Additionally, research is needed to explore the impact of different GLP-1 receptor agonist doses and treatment durations on procedural risks. High-potency drugs like semaglutide and tirzepatide may warrant special consideration, as their stronger effects on gastric emptying could pose unique challenges. Subgroup analyses based on patient characteristics, such as BMI and comorbid conditions, could further refine clinical guidelines.

Randomised controlled trials would be the gold standard for addressing these questions, but their feasibility is limited by the rarity of pulmonary aspiration events. For example, a trial with adequate statistical power would require tens of thousands of participants, making it logistically challenging. In the absence of such trials, real-world evidence from large observational studies remains a critical resource for guiding clinical decision-making.

Limitations and Strengths

As with any research, the cohort study had limitations that should be considered when interpreting its findings. One notable limitation was the reliance on claims data, which may be prone to misclassification and underreporting. For example, the exact reasons for endoscopy discontinuation were not captured, leaving room for speculation about the role of retained gastric contents. Similarly, drug adherence could not be confirmed, as the study relied on prescription data rather than direct measures of medication use.

Another limitation was the exclusion of patients who used GLP-1 receptor agonists solely for weight loss without diabetes. This restriction limits the generalisability of the findings to the broader population of GLP-1 receptor agonist users. Additionally, the study did not account for certain confounding factors, such as laboratory measures of glycaemic control or renal function, which could influence procedural outcomes.

Despite these limitations, the study had several strengths that enhance its credibility. By using two large national databases, the researchers were able to analyse a substantial sample size, providing robust real-world evidence. The use of an active comparator design and advanced statistical methods, such as propensity score weighting, helped minimise bias and improve the validity of the findings.

Conclusion

GLP-1 receptor agonists have reformed the treatment of type 2 diabetes and obesity, offering significant benefits in glycaemic control and weight reduction. However, their effects on gastric emptying have introduced new challenges in procedural settings, particularly for patients undergoing upper gastrointestinal endoscopy. While the risk of pulmonary aspiration appears to be low, the increased likelihood of endoscopy discontinuation highlights the need for individualised care and meticulous pre-procedural planning.

Moving forward, ongoing research will be essential to refine clinical guidelines and ensure the safe use of GLP-1 receptor agonists in diverse medical contexts. By balancing the benefits of these medications with their potential risks, clinicians can optimise outcomes for patients while addressing the complexities of this developing therapeutic area.

Reference

Alkabbani, W., Suissa, K., Gu, K. D., Cromer, S. J., Paik, J. M., Bykov, K., Hobai, I., Thompson, C. C., Wexler, D. J., & Patorno, E. (2024). Glucagon-like peptide-1 receptor agonists before upper gastrointestinal endoscopy and risk of pulmonary aspiration or discontinuation of procedure: cohort study. BMJ (Clinical Research Ed.), 387, e080340. https://doi.org/10.1136/bmj-2024-080340