Perioperative Use of Semaglutides: More Questions than Answers

Global prevalence for obesity and type 2 diabetes are continuing to rise, with special concerns for the very high prevalence of obesity (>25% of adults) and Type 2 diabetes (>13% of adults) in several regions of the Americas, Middle East and amongst Pacific Island communities. [1,2]  Both obesity and Type 2 diabetes are associated with high susceptibility to development of several co-morbidities, including non-alcoholic fatty liver disease, cardiovascular and renal diseases, which are all major contributors to the premature mortality [3] Although weight loss can substantially reduce the risks and comorbidities associated with type 2 diabetes, it is notoriously difficult to achieve and maintain by changes in lifestyle alone [4]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have now proved to be particularly effective as glucose-lowering and weight reducing agents in the management of overweight or obese type 2 diabetes, and are now widely available in most countries as once-daily and once-weekly injectable formulations.[5] Furthermore, recent evidence for their beneficial cardiovascular effects has elevated their importance in the treatment guidelines, especially for obese diabetic patients with atherosclerotic cardiovascular disease. [1] 

There are currently three FDA-approved GLP-1RA agonists (semaglutides). Ozempic®ᓀ injection and Rybelsus®ฐ tablets are approved to lower blood sugar levels in adults with type 2 diabetes mellitus, in addition to diet and exercise. Ozempic®ഀ is also approved to reduce the risk of heart attack, stroke, or death in adults with type 2 diabetes mellitus and known heart disease. Wegovy®ഀ injection is approved to help adults and children aged 12 years and older with obesity or some overweight adults, who also have weight-related medical problems. All three medications are only available with a prescription, and there are no approved generic versions as of now.

Mechanism of Action 

Semaglutides are long-acting GLP-1 RAs with 94 percent homology with native human GLP-1. GLP-1 is an endogenous hormone released from the proglucagon gene in L-cells of the distal small intestine and colon in response to oral nutrient intake. It then binds to GLP-1 receptors expressed in tissues such as the pancreatic beta cells, gastric mucosa, kidney, heart, and hypothalamus. This stimulates the secretion and release of insulin in hyperglycemic states, inhibits glucagon release in hyperglycemic or euglycemic states, slows gastric emptying, and reduces food intake. Semaglutides, like GLP1, further promotes insulin secretion from beta cells in the pancreas and decreases glucagon secretion in a glucose-dependent manner. Unlike GLP1, which has a half-life of 1-2 minutes, the half-life of Semaglutide is 155-184 hours. Therefore, it leads to weight loss via reduced energy intake with minimal effects on energy expenditure. [2]

Several gastrointestinal side effects have been reported with the use of Semaglutides, such as nausea, vomiting, diarrhea, constipation, and decreased GI motility, Although the mechanisms behind these side effects are not fully understood.[3] Although long-acting GLP-1RAs slow gastric emptying, this effect is less pronounced than in short-acting GLP-1Ras [4,5]. In addition, the effect on gastric emptying depends on the dose and duration of medication use. Delay in gastric emptying is attenuated with dose escalation and with duration, which suggests possible tachyphylaxis, since delayed emptying occurs within 12 weeks of semaglutide use and then tends to subside or resolve after 20 weeks. [6]  

Semaglutides in the perioperative period

Current American Society of Anesthesiologists (ASA) recommendations call for holding GLP-1 agonists on day of the procedure for patients taking them daily, or one week before surgery for patients on weekly dosing. [7] On the day of the procedure, if the GLP1 agonists have been held appropriately and there are no gastrointestinal (GI) symptoms, then the patient can proceed with surgery. If the GLP1 agonists have not been stopped as instructed, but the patient has no GI symptoms, then they recommend considering the patient having a “full stomach” and performing a gastric point-of-care ultrasound (POCUS) (if feasible) to evaluate for gastric contents. If the stomach is empty, then the recommendations are to proceed as usual, but if the stomach shows gastric contents on POCUS or if the POCUS exam is inconclusive, the recommendations are to consider delaying the procedure or proceeding with full stomach precautions. [7] If the patient has GI symptoms, such as severe nausea/vomiting/retching, abdominal bloating or abdominal pain, the recommendations are to consider delaying the procedure. If unable to, the ASA recommends proceeding with full stomach precautions and discussing the risk of regurgitation and aspiration with the patient and the surgical team.[7] These current guidelines allow patients to take their semaglutides with minimal disruption before surgery which leads to less hyperglycemic episodes and negates the need for bridging therapy. Furthermore, there are less reasons for cancellation of surgery, which can be disruptive to both patients and surgeons. 

While the ASA recommendations provide some clarity on the perioperative use GLP-1 RAs, there are several other factors that influence GLP-1RA-related delayed gastric emptying.  These include the type of drug (i.e., short-acting vs. long-acting), the drug dose and duration of use, and glycemic control (good vs. poor control). Hence, there remains a concern for delayed gastric emptying and possibility of increased preoperative residual gastric volume. In obese women with polycystic ovarian syndrome, those receiving semaglutide retained 37% of solid meal after 4 hours, as compared with no gastric retention in the placebo group after 12 weeks of therapy.[8] Similarly, in a single-center retrospective chart review of patients undergoing esophagogastroduodenoscopy under deep sedation/general anesthesia, perioperative use of semaglutide was associated with increased residual gastric content (24.2% vs. 5.1%).[9] These findings support the hypothesis that semaglutide use is associated with delayed gastric emptying and increased residual gastric content, which can last up to a month after drug discontinuation. Finally, in a prospective randomized controlled trial by Sherwin et al [10], gastric POCUS was used to evaluate the presence of solid gastric contents in both supine and lateral positions after an eight-hour fast in those taking GLP-1RA compared with controls. In the lateral position, 90% of participants receiving semaglutide and 20% of control participants had solids identified on gastric POCUS (RR, 7.36; 95% CI, 1.13 to 47.7; P = 0.005). Two hours after drinking clear liquids, the gastric POCUS findings did not differ in the lateral position in the two groups, but in the supine position, 90% of control group participants were rated as empty compared with only 30% of semaglutide group participants. Therefore, suggesting that GLP-1RAs may affect gastric emptying and residual gastric content following an overnight fast and two hours after consumption of clear liquids, which may have implications for aspiration risk during anesthesia. Given that the half-life of semaglutides is around one-week, longer interruption might be indicated. Perhaps, the timing of the last dose of GLP-1RA should be more than 11 days from surgery, especially in patients who have started the medication less than 20 weeks ago, considering that this is the timeframe when tachyphylaxis is observed. Currently, the ASA guidelines are the standard of care in most institutions, and these guidelines call for holding long acting semaglutides only one week before surgery. However, we make an argument that further studies are needed to further evaluate the appropriate dosing of semaglutides in the perioperative period, and that the ASA guidelines in its current form should be applied on a case-by case basis.

Semaglutides in critical illness

Patients on semaglutides may present to the intensive care unit (ICU) with critical illness, and the implications of chronic use of these drugs on morbidity and mortality in this subgroup of patients is unclear. Furthermore, the impact of long-acting GLP-1 RAs on glycemic control in critically ill patients remains poorly understood. Whether the critical illness induced gastroparesis is accentuated by these drugs is also not clear. While it makes sense to hold these drugs during the acute phase of critical illness, implications of abrupt discontinuation, and the timing of restarting them are also areas that need further exploration. Currently there is limited data, and no specific guidelines or recommendations for managing patients in the ICU that use these medications chronically.  Nonetheless, the ICU team should be aware of their side effects (diabetic neuropathy, hypoglycemia, baseline increased heart rate, gastroparesis, pancreatic disease, acute kidney injury etc.) and how they can adversely affect patient outcomes. Future studies are indeed needed to better guide care for these patients in the intensive care setting. 

References:

Bailey CJ, Flatt PR, Conlon JM. An update on peptide-based therapies for type 2 diabetes and obesity. Peptides. 2023 Mar;161:170939. doi: 10.1016/j.peptides.2023.170939. Epub 2023 Jan 3. PMID: 36608818.

A.M. Chao, J.S. Tronieri, A. Amaro et al. Trends in Cardiovascular Medicine 33 (2023) 159–166

Wadden TA, Bailey TS, Billings LK, et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA. 2021;325(14):1403–1413. doi:10.1001/jama.2021.1831

Jones KL, Huynh LQ, Hatzinikolas S, et al. Exenatide once weekly slows gastric emptying of solids and liquids in healthy, overweight people at steady-state concentrations. Diabetes Obes Metab. 2020;22:788–797.

Halawi H, Khemani D, Eckert D, et al. Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo- controlled pilot trial. Lancet Gastroenterol Hepatol. 2017;2:890–899. 

Nauck MA, Kemmeries G, Holst JJ, Meier JJ. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes. 2011;60:1561–1565.

Girish P. Joshi, M.B.B.S., M.D., Basem B. Abdelmalak, M.D., Wade A. Weigel, M.D., Sulpicio G. Soriano, M.D., Monica W. Harbell, M.D., Catherine I. Kuo, M.D., Paul A. Stricker, M.D., Karen B. Domino, M.D., M.P.H., American Society of Anesthesiologists Consensus-Based Guidance on Preoperative Management of Patients (Adults and Children) on Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists. June 29, 2023

Jensterle M, Ferjan S, Lezaic L, et al. Semaglutide delays 4-hour gastric emptying in women with polycystic ovary syndrome and obesity. Diabetes Obes Metab. 2023;25:975–984

Silveira SQ, da Silva LM, de Campos Vieira Abib A, de Moura DTH, de Moura EGH, Santos LB, Ho AM, Nersessian RSF, Lima FLM, Silva MV, Mizubuti GB. Relationship between perioperative semaglutide use and residual gastric content: A retrospective analysis of patients undergoing elective upper endoscopy. J Clin Anesth. 2023 Aug;87:111091. doi: 10.1016/j.jclinane.2023.111091. Epub 2023 Mar 2. PMID: 36870274.

Sherwin M, Hamburger J, Katz D, DeMaria S Jr. Influence of semaglutide use on the presence of residual gastric solids on gastric ultrasound: a prospective observational study in volunteers without obesity recently started on semaglutide. Can J Anaesth. 2023 Aug;70(8):1300-1306. English. doi: 10.1007/s12630-023-02549-5. Epub 2023 Jul 19. PMID: 37466909.