Research needed to create ‘robust, conclusive’ evidence to manage preprocedural GLP-1 use
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The use of glucagon-like peptide-1 receptor agonists exponentially increased in recent years for treating diabetes and obesity, with benefits also observed in other cardiometabolic syndromes.
However, digestive adverse effects such as nausea and vomiting are commonly reported. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an incretin hormone mimetic and contribute to gastrointestinal dysmotility, including delayed gastric emptying. Consequently, this has raised concerns regarding the potential increase in risk for respiratory complications for GLP-1RA users undergoing procedural sedation.
Early case reports and anecdotes appeared to corroborate these concerns, with instances of retained foods found in the stomach of GLP-1RA users during upper endoscopy after standard fasting.
New Research May ‘Provide Some Clarity’
Despite limited empirical data at the time, the American Society of Anesthesiologists issued consensus-based guidance in June 2023 suggesting holding these medications before procedural sedation or proceeding with “full-stomach” precaution vs. canceling procedures if they were not withheld.
On the other hand, the AGA advised a more conservative approach that includes a 24-hour preprocedural liquid-only diet without universal withholding of GLP-1RAs. These divergent recommendations led to considerable challenges and debates in endoscopy centers, as procedures were delayed/canceled or performed under higher levels of sedation than would otherwise be needed. This resulted in substantial and lasting impact on a health care system already strained to meet the vast societal needs for screening, diagnostic and therapeutic endoscopy.
Moreover, withholding GLP-1RAs may have consequences in the conditions for which they were prescribed, such as worsened glycemic control. It is, therefore, important to critically examine the empirical evidence available to more accurately assess the procedure-related aspiration risk with GLP-1RA use.
While current data remain far from conclusive, a growing body of research has emerged to provide some clarity. Both laboratory and clinical data have consistently shown evidence of altered gastric motility with GLP-1RA, although the severity and clinical relevance of the observed delays appear less clear. Retrospective studies have found increased retained gastric contents (RGC) on endoscopy among GLP-1RA users. However, these studies mostly relied on descriptions or images on procedure reports to assess RGC, which may range from scattered small particulates to more substantial food contents.
Since aspiration risk is influenced by the volume and consistency of gastric content, whether the observed increase in RGC among GLP-1RA users was of clinically relevant volume or constituted any significant respiratory complication risk is unclear. Indeed, the few aspiration events reported in these studies did not correlate with the presence of RGC. Published data on endoscopic RGC with GLP-1RAs should be interpreted through the lens of these study limitations and clinical relevance.
‘Inconsistent Results’ May Be Due to Underlying Condition
The degree of gastric emptying delay is another important factor that may be distinct between solids and liquids. A meta-analysis of randomized control trials found a mild delay in solid emptying with GLP-1RAs and no significant difference in liquid emptying. Real-world observational studies appeared to support these findings, as GLP-1RA users undergoing both upper endoscopy and colonoscopy did not show significant increase in RGC, likely due to the preprocedural clear liquid diet and bowel preparation.
These collective findings suggest that prolonged liquid diet together with standard preprocedural fasting may be adequate in modulating the potential risk for significant RGC with GLP-1RAs.
The incidence of periprocedural aspiration with GLP1-RA has also been examined. However, these retrospective, nonrandomized, observational studies comparing GLP1-RA users with nonusers are prone to significant confounding by indication, given the conditions for which these medications are used.
This means that any relationship observed between GLP-1RAs and aspiration may be the consequence of the underlying conditions for which a GLP-1RA was prescribed, rather than GLP-1RA use itself. This was evident by the higher frequency and severity of diabetes consistently observed among the GLP-1RA cohorts compared with nonusers in these studies.
Common statistical maneuvers such as regression modeling or propensity score matching are often inadequate in addressing confounding by indication, without the use of more rigorous active comparator designs such as comparing diabetic GLP1-RA users vs. diabetic nonusers. This may explain the inconsistent results reported, with most studies that included active comparator groups showing no increase in aspiration.
Reassuringly, a recent meta-analysis of published studies to date also found no increase in periprocedural respiratory complication risk with GLP1-RA use.
‘Rational Approach’ Needed for GLP-1RA Management
As a breakthrough treatment for common cardiometabolic syndromes, GLP1-RA use will continue to rise.
Therefore, it is imperative to establish a rational approach to preprocedural GLP-1RA management based on high-quality evidence. Overall, the data published to date can be summarized as: increased incidence of RGC of unclear significance/magnitude; some delay in emptying of solids, although maybe mild relative to pre-endoscopy fasting and modulated by concurrent colonoscopy with prolonged clear liquid diet and bowel preparation; no/minimal delay in liquid emptying; and no clear evidence of increased respiratory complications.
The approach suggested by AGA appears to be most sensible for the majority of patients, focusing on prolonged liquid-only diet coupled with standard fasting prior to procedures. Importantly, a collaborative, multidisciplinary approach with the anesthesiology team remains paramount in caring for these patients. More data is also vitally needed to address knowledge gaps, including the impact and risks of different subgroups based on GLP-1RA formulations, duration of therapy and comorbidities.
The introduction of any novel therapy is associated with initial periods of uncertainty, with understandable hypervigilance and caution for any potential adverse effects. The debate on the management of GLP-1RA before procedural sedation is no different, with the challenge of balancing the theoretical risk for aspiration against the impact of withholding therapy and/or delaying procedures.
Nonetheless, the importance of providing evidence-based care cannot be overstated. While finding food contents in the stomach during an endoscopy may be unnerving and memorable, one must not mistake anecdotes for high-quality evidence from optimally designed studies.
For investigators, there remains a critical need for more rigorous research with clinically meaningful endpoints and subgroups to generate robust, conclusive and precise evidence to direct preprocedural GLP-1RA management.
- References:
- American Society of Anesthesiologists consensus-based guidance on preoperative management of patients (adults and children) on glucagon-like peptide-1 (GLP-1) receptor agonists. https://www.asahq.org/about-asa/newsroom/news-releases/2023/06/american-society-of-anesthesiologists-consensus-based-guidance-on-preoperative. Published June 29, 2023. Accessed August 26, 2024.
- Facciorusso A, et al. Clin Gastroenterol Hepatol. 2024;doi:10.1016/j.cgh.2024.07.021.
- Garza K, et al. Am J Gastroenterol. 2024;doi:10.14309/ajg.0000000000002777.
- Hashash JG, et al. Clin Gastroenterol Hepatol. 2023;doi:10.1016/j.cgh.2023.11.002.
- Hiramoto B, et al. Am J Gastroenterol. 2024;doi:10.14309/ajg.0000000000002820.
- Silveira SQ, et al. J Clin Anesth. 2023;doi: 10.1016/j.jclinane.2023.111091.
- Yoshida K, et al. Nat Rev Rheumatol. 2015;doi:10.1038/nrrheum.2015.30.
- For more information:
- Walter W. Chan, MD, MPH, AGAF, FACG, is director of the Center for Gastrointestinal Motility at Brigham and Women’s Hospital and associate professor at Harvard Medical School. He can be reached at wwchan@bwh.harvard.edu.
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