Trust the Gold Standard: All Glucagon-like Peptide-1 Receptor Agonists Can Delay Gastric Emptying

The recent release of the “American Society of Anesthesiologists Consensus-Based Guidance on Preoperative Management of Patients (Adults and Children) on Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists” was timely and relevant.  These medications delay gastric emptying and have resulted in significant complications for patients undergoing anesthesia.  These effects on gastric emptying have consistently been demonstrated in studies using the gold standard examination, scintigraphy. However, the continued use of an inferior test instead of scintigraphy coupled with uncertainty around the concept of tachyphylaxis has created the potential for confusion that must be firmly contradicted. The evidence is clear, all GLP-1 receptor agonists can delay gastric emptying.

The gold standard examination for measuring gastric emptying, nuclear scintigraphy, has consistently found that all GLP-1 receptor agonists delay emptying (table 1).  However, not all studies in the GLP-1 receptor agonists have used scintigraphy. Instead, the cheaper acetaminophen absorption test has increasingly and detrimentally been used to studying emptying in the GLP-1 receptor agonists. In fact, all but one study evaluating gastric emptying in the newest and most popular GLP-1 receptor agonists, semaglutide and tirzepatide, have been performed using the acetaminophen test. The continued and inappropriate use of this test is not justified and has been questioned by experts who have stated that the “literature supports the need to avoid the acetaminophen absorption test to estimate gastric emptying.” 

The acetaminophen test is problematic for several reasons. Nuclear scintigraphy directly measures emptying, whereas the acetaminophen test instead indirectly measures medication absorption as a surrogate for emptying.  In addition, the test routinely uses liquid acetaminophen, which even when given with a solid meal will follow the gastric-emptying pattern of liquids not solids.  Liquids empty exponentially; solids triturate before emptying at a constant rate.  Last, the acetaminophen test underestimates emptying by measuring the drug absorption at the end of the 4- to 6-h period, thus undermining its use in delayed emptying states.  For these reasons, experts have concluded that the continued use of the acetaminophen absorption test compromises knowledge of the effects of the GLP-1 receptor agonists on gastric emptying. 

The concept of tachyphylaxis has created the potential for further confusion as well. The hypothesis that patients develop tachyphylaxis to the effects of the long-acting GLP-1 receptor agonists was introduced in a 2011 article assessing gastric emptying in healthy subjects receiving GLP-1 infusions.  The study demonstrated that those receiving continuous GLP-1 infusions developed gastric slowing after two consecutive meals, but the degree of slowing was reduced after the second meal compared with the first.  However, even with this attenuation, patients still exhibited significant delays after the second meal compared with the placebo.  This is extremely relevant because any degree of gastric slowing, even if somewhat decreased over time, can prove clinically significant for patients undergoing anesthesia. A similar study from 2014 evaluating the concept of tachyphylaxis also found attenuation not abolishment of the effect of prolonged GLP-1 receptor agonist stimulation on gastric retention in subjects exposed to 24 h of exogenous GLP-1 infusions compared with those receiving placebo.  Although these studies are valuable and provide important insight about the effects of prolonged receptor stimulation, they have been inappropriately applied to suggest that patients on long-acting versions of these medications are not at risk for delayed gastric emptying.

The GLP-1 receptor agonists are more popular than ever with impressive evidence supporting their use. But as these patients present for anesthetic care, it is critical that anesthesiologists recognize the risks these medications pose and disregard evidence from studies using inferior examinations. Further studies are required to assess risk in the intraoperative period, but in the meantime, we must believe the gold standard, all GLP-1 receptor agonist users are at risk from the effects of delayed gastric emptying.