Effects of GLP-1 and Other Gut Hormone Receptors on the Gastrointestinal Tract and Implications in Clinical Practice

Abstract

Agonists targeting the receptors of incretin hormones, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, have been well established for the treatment of type 2 diabetes mellitus. There is increasing awareness that gastroenterologists and hepatologists should be treating obesity when patients present to their clinics. In addition, gastroenterologists and hepatologists should be aware of the effects of these classes of medications prescribed by other providers. Therefore, given the widespread use of incretin agonists for obesity treatment and weight loss, it is important to recognize their effects in the gastrointestinal tract, which could constitute significant benefits in weight loss and cardiometabolic benefits, but can be associated with adverse effects that constitute a potential barrier to their use, particularly at higher doses. Multiple studies reviewed in this article document the diverse effects of these drugs on the GLP-1 receptors that are widely expressed in the human body, including the nervous system modulating appetite, the gastrointestinal tract modifying gastric emptying, and lipid metabolism regulation leading to reduction in fat deposition. The objective of this review is to summarize the mechanism of action of incretin receptor agonists, their effects in the gastrointestinal tract, and implications in clinical practice, particularly in the practice of gastroenterology, endoscopy, and surgery.

Introduction

Gastroenterologists and hepatologists should be aware of the opportunities to treat obesity when patients present to their clinics (1) and of the adverse effects of obesity medications. The objectives of this review are to summarize the mechanisms of action of incretin receptor agonists (RAs), their effects in the gastrointestinal tract, and the clinical practice implications associated with their use in the practice of gastroenterology, endoscopy, and surgery. While gastrointestinal adverse events are reported with these classes of medications, it is important to note that these are generally based on self-reports, rather than prospective collection using validated measures.

Pathophysiology and Phenotypes of Obesity

Apart from rare monogenetic disorders causing obesity such as pro-opiomelanocortin (POMC) deficiency or leptin receptor (LEPR) deficiency that cause early-onset obesity due to deficiencies in the melanocortin-4 receptor (MC4R) and pathway and that respond to an MC4R agonist setmelanotide (2), obesity results from the imbalance between energy intake and expenditure. In a study involving 507 overweight, obese, or normal weight participants (3), obesity was associated with larger fasting gastric volume, accelerated gastric emptying of solids and liquids, lower postprandial levels of one of the satiation-associated hormones, PYY, and higher volume of liquid calories ingested to achieve comfortable postprandial fullness and larger calorie intake in a buffet meal. Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese participants, including satiety or satiation (21%), gastric motility (14%), behavioral factors leading to hedonic rather than homeostatic obesity (13%), and gastric sensorimotor factors (11%) (Figure 1). Based on these different phenotypes, therapeutic approaches may take the form of pharmacological agents as well as bariatric interventions, as illustrated in Figure 2. For example, abnormalities of satiety and satiation may respond to centrally-acting medications such as the combination of phentermine and topiramate, whereas abnormalities of gastric motor function could be targeted with single, dual, or triple gut hormone agonists, and large gastric reservoir capacity may be treated with either intragastric space-occupying balloons, or vertical sleeve gastrectomy, or more complex bariatric procedures such as Roux-en-Y gastric bypass or biliopancreatic diversion with duodenal switch with or without vertical sleeve gastrectomy. Hyperglycemia typically responds to these procedures, and treatments and can be enhanced with the addition of an SGLT2 blocker that prevents reabsorption of glucose in the renal tubules (4).

Figure 1.

Latent dimensions identified in phenotypes of obesity illustrating importance of satiation, satiety, psychological behavior, gastric functions and peak incretins levels (from ref. 3, Acosta et al. 2015).

Figure 2.

Strategies directed at the management of obesity including approaches for central disturbances of appetite, and alterations of gastrointestinal structure and function with bariatric procedures or pharmacological agents (adapted from ref. 4, Camilleri M, Acosta A. Metab Syndr Relat Disord 2018;16:390-39)

Incretin Hormones and their Actions on Satiety and Glycemic Control

Nutrients provided by meal ingestion, particularly those that are rich in fats and carbohydrates, result in the stimulation of peptide hormones that are involved in the digestive process, regulation of appetite and blood glucose (5). The incretin hormones, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are metabolic hormones secreted from the epithelial intestinal L-cells, (located in the ileum and colon) and K-cells (located in the proximal small intestine), respectively. These hormones are released into the bloodstream after meal ingestion, stimulating insulin secretion from β-cells in a glucose-dependent manner (6).

The insulinotropic effects of GLP-1 are mediated by the GLP-1 receptors located in the pancreatic β-cells. However, GLP-1 receptors are widely distributed and expressed by the gut, pancreas, brainstem, hypothalamus, and vagal afferent nerves (5). The latter effects are also involved in mediating satiety (7). Additionally, GLP-1 inhibits glucagon secretion from α-cells in pancreatic islets during the fasting state, thereby maintaining normoglycemia in patients with type 2 diabetes mellitus (T2DM). Weight loss in response to GLP-1 receptor activation is multifactorial and includes stimulation of centers controlling appetite in the brain, as well as slowing of gastric emptying (8) and enhancing postprandial fullness to reduce food intake via its synergistic effect on central regulation of feeding (9).

Endogenous GLP-1 has a very short half-life of approximately 2 minutes; however, chemical modification of its structure, such as removal of the site of degradation of GLP-1 by dipeptidyl-peptidase IV (DPP-4) enzyme and structural alterations such as amino acid substitutions in the N-terminal sequence, led to the development of agents with far longer half-lives. These modifications led to better glycemic control and increased postprandial satiation, thereby promoting weight loss. These initial modifications led to short-acting agents (half-lives of approximately 3 hours) such as exenatide and lixisenatide (latter no longer available in the USA). Subsequently, other modifications of the molecular structure of GLP-1 were implemented, leading to longer half-lives that allow for subcutaneous (SQ) daily or weekly administration. These molecular modifications included microsphere encapsulation of a biodegradable polymer, poly [lactic-co-glycolic acid] (PLG), for exenatide, covalent conjugation with human albumin for albiglutide, covalent conjugation to human IgG4-Fc heavy chain for dulaglutide, addition of a fatty acid side chain allowing binding to circulating albumin for liraglutide, and addition of a hydrophilic spacer and fatty acid side chain linked to albumin for semaglutide (10).

The actions of GIP on the pancreatic β-cells are analogous to those of GLP-1 (11), as their primary role is that of an incretin hormone that enhances glucose-dependant insulin secretion in response to nutrient ingestion. However, in contrast to GLP-1 which suppresses glucagon secretion, GIP increases glucagon secretion (12). GIP also exhibits extrapancreatic effects such as increased lipogenesis, increased bone formation, and decreased bone resorption, and, at the level of the central nervous system, GIP plays a role in neural progenitor cell proliferation and behavior modification. Additionally, since there is no clear evidence of GLP-1 or GIP receptors in the liver, it is thought that, through a multifactorial, incompletely understood mechanisms, GIP increases insulin and glucagon secretion in the pancreas and indirectly inhibits glycogenolysis in the liver (11,13). It is worth noting that this hypothesis has only been tested in animal studies (12). However, there is evidence that a naturally occurring GIP antagonist, GIP(3–30)NH2, reduced GIP-induced insulin secretion without affecting other hormones such as plasma glucagon, GLP-1, or somatostatin (14).

Incretin Agonists

To date, there are 7 FDA approved incretin hormone RAs available for clinical use (Table 1). The effects on the gastrointestinal tract and liver are substantial and of relevance in clinical gastroenterology and hepatology.

Table 1.

Currently approved incretin agonists for treatment of type 2 diabetes mellitus and weight loss

Drug name (brand name)	Dosages/routes of administration	Mechanisms of action	Indications	Elimination half-life	Common GI-related adverse effects	Package insert recommendation on drug titration
Short-acting GLP-1 RA
Exenatide (Byetta®)	Twice-daily SQ injection	↑ glucose-dependent insulin secretion from pancreatic β cells Suppress glucagon secretion Delays gastric emptying	Glycemic control in T2DM	2.4hr	nausea, diarrhea, vomiting	Start: 5mg BID Week 4: 10mg BID
Long-acting SQ GLP-1 RA
Liraglutide (Victoza®)	Once-daily SQ injection	↑ glucose-dependent insulin secretion from pancreatic β cells Suppression of glucagon secretion Delay gastric emptying	Glycemic control in T2DM Weight management in adults with BMI >30 or BMI >27 + 1 weight related comorbidity (HTN, T2DM, HLD)	13hr	nausea, vomiting, diarrhea, decreased appetite, constipation, dyspepsia and abdominal pain, eructation	Start: 0.6mg daily; increase dose by 0.6mg/week until full maintenance dose of 3mg)
Semaglutide SQ (Ozempic® or Wegovy®)	Once-weekly SQ injection			7 days	nausea, vomiting, diarrhea, abdominal pain, and constipation	Start: 0.25mg/week; Week 4: 0.50mg/week; Week 8: 1 mg/week
Dulaglutide (Trulicity®)			Glycemic control in T2DM	5 days	nausea, diarrhea, vomiting, dyspepsia	1.5mg q. week
Exenatide ER (Bydureon®)				8-16hrs	nausea, diarrhea, vomiting	2mg weekly (no dose adjustment)
Long-acting Oral GLP-1 RA
Semaglutide PO (Rybelsus®)	Once-daily per oral	↑ glucose-dependent insulin secretion from pancreatic β cells; suppresses glucagon secretion; delays gastric emptying	Glycemic control in T2DM	7 days	nausea, abdominal pain, diarrhea, decreased appetite, vomiting, constipation	Start: 3mg daily; Week 4: 7mg daily; Week 8: 14mg daily
Long-acting Dual Incretin GIP/GLP-1 RA
Tirzepatide (Mounjaro®)	Once-weekly SQ injection	↑ insulin response; suppresses glucagon secretion; promotes satiety; improves insulin sensitivity	Glycemic control in T2DM Currently on “fast-track” FDA review for obesity	5 days	nausea, vomiting, diarrhea, decreased appetite, constipation, dyspepsia, and abdominal pain	Start 2.5mg weekly; increase dose by 2.5mg/4 weeks until full maintenance dose of 15mg at week 20

Abbreviations: BID=twice a day; GLP-1 RA=Glucagon-like peptide-1 receptor agonists; GIP=gastric inhibitory polypeptide; SQ=subcutaneous; T2DM=type 2 diabetes mellitus; BMI=body mass index; FDA=Food and Drug Administration; q.=every; HLD=hypersensitivity lung disease; HTN=hypertension

Effects of GLP-1 and GLP-1 Receptor Agonists in the Gastrointestinal Tract

Pharmacological effects:

GLP-1 increases gastric accommodation (9) through activation of vagal afferents, an effect lost in the presence of vagal denervation in diabetic patients (15). Additionally, GLP-1 causes delay in gastric emptying, and increased gastric accommodation; the latter is associated with greater retention of food in the proximal stomach and overall delay in gastric emptying (16). Indeed, GLP-1 (1.2 pmol/kg/min) reduces the acceleration of gastric emptying induced by hypoglycemia (17), and there is evidence that slowing of gastric emptying by pharmacological doses of GLP-1 may even outweigh its insulinotropic effects (18). The slowing of gastric emptying has been demonstrated using radioscintigraphic emptying of a solid meal in response to treatment with the short-acting GLP-1 agonist, exenatide, 5μg SQ twice daily for 30 days (19). Liraglutide titrated up to 3mg/day administered over 16 weeks resulted in marked retardation of gastric emptying (20) (Figure 3). It is hypothesized that, with long-acting GLP-1 RAs, there is a decreasing effect on slowing gastric emptying over time, and this is suspected to be due to tachyphylaxis which has been documented with several agents including GLP-1 itself, liraglutide, semaglutide, and weekly exenatide formulation (12,20,21–24). However, in T2DM, comparison of effects of lixisenatide and liraglutide (respectively short- and long-acting GLP-1 RAs) on gastric emptying of a 280kcal, 60% fat meal labeled with ¹³C-octanoate showed numerically slower emptying with lixisenatide. However, the overlap of the data’s 95% confidence interval (CI) suggests no significant differences between the two treatments (25).

Figure 3.

Left panel: Comparison of the effects of liraglutide, 3.0 mg per day, and placebo on gastric emptying T_1/2 in obesity. Note the increase in gastric emptying T_1/2 at 5 weeks in the liraglutide treatment group, with persistent retardation at 16 weeks in contrast to the absence of effects of placebo at 5 or 16 weeks. Right panel: Data show the gastric emptying T_1/2 median and interquartile range and outliers at 5 and 16 weeks in the 64 patients treated with liraglutide. The change in gastric emptying T_1/2 is significant, consistent with tachyphylaxis to the effects of liraglutide (from reference 20, Maselli et al. Obesity 2022).

Short-acting exenatide also inhibits small intestinal motility, flow and transit (26).

Adverse effects:

The most common reported adverse effects (AEs) with these incretin RAs are gastrointestinal symptoms that include nausea, vomiting, diarrhea, and constipation. To date, a comparison between all the available GLP-1 RAs regarding gastrointestinal AEs and gastric emptying as primary outcomes has not been performed.

Below are examples of gastrointestinal AEs that have been documented with GLP-1 RAs. In the SUSTAIN 10 trial with SQ semaglutide, 52% patients reported gastrointestinal AEs compared to 35% in the placebo group, and these gastrointestinal AEs sometimes led to premature discontinuation of the medication (27). Gastrointestinal AEs are also highly prevalent with oral GLP-1 RAs (28). Oral semaglutide (approved for treatment of T2DM), 25mg and 50mg per day, was associated with nausea in 27% and vomiting in 18% of patients. Moreover, in patients with obesity without T2DM treated with 50mg oral semaglutide, 52% developed nausea, 24% vomiting, 28% constipation, and 27% diarrhea (29). The experimental oral, non-peptide GLP-1 RAs, danuglipron and orforglipron, also induced significant gastrointestinal AEs, primarily nausea (30–32).

A longitudinal assessment of gastrointestinal adverse effects during a 68-week trial with once-weekly SQ semaglutide in adults with overweight or obesity documented gastrointestinal AEs developing at any time after randomization up to 68 weeks, with the median duration of nausea occurring for 8 days and vomiting for 2 days (33). These gastrointestinal AEs led to discontinuation of medication at any time after randomization, up to 68 weeks (33).

Relationship of gastrointestinal AEs to weight loss:

Gastrointestinal AEs contributed to, but were not the dominant determinant, of weight loss; rather, most of the lost weight was secondary to the effect of the medication itself (25). Oral semaglutide trials (PIONEER 1, 4 and 5) that used 7mg and 14mg doses in T2DM documented association of weight loss relative to comparator treatment with significant gastrointestinal AEs, though this was not the predominant contributor to weight loss (34). A meta-analysis of almost 25,000 patients included in 60 trials of GLP-1 RAs showed association of risk difference of nausea with absolute excess weight loss over placebo (29).

The significance of gastrointestinal AEs is also illustrated by 2 systematic reviews and meta-analyses. Htike et al. found that exenatide ER had lower reports of nausea and vomiting compared to liraglutide and dulaglutide (35). Vosoughi et al. showed in an analysis including 64 randomized, controlled trials and 27,018 patients that overall, GLP-1 RAs were associated with increased numbers of patients with nausea [RR, 2.75 (95% CI, 2.44 to 3.09)] and vomiting [RR, 3.22 (95% CI, 2.74 to 3.78)] compared to placebo (36).

Effects of GIP in the Gastrointestinal Tract

The insulinotropic effect of GIP (whose plasma half-life is approximately 7 minutes) (37) is impaired in patients with T2DM. Infusion of GIP over 6 hours that resulted in an approximate 3-fold increase in postprandial GIP levels showed no significant effects on gastric emptying, based on a stable isotope breath test with a 250-kilocalorie egg meal (38). Therefore, effects of GIP receptor stimulation have been tested in combination with other incretin agonists. The SURPASS and SURMOUNT trials showed that dual GLP-1/GIP RAs (also known as “twincretins”) demonstrated better efficacy in diabetes control and weight reduction of up to 25% of body weight in 72-week trials (39,40). These results are attributed to synergistic effects of the dual incretin agonists.

Urva et al. (41) studied the effect on gastric emptying of the dual GLP-1/GIP RA tirzepatide (the only dual agonist approved by FDA to date) compared to the selective GLP-1RA dulaglutide and placebo in healthy humans, based on acetaminophen absorption (reflecting liquid emptying, and therefore a suboptimal test for emptying of solids). In fact, Urva et al. documented delay in the initial emptying of acetaminophen. The study documented comparable effects on gastric emptying with tirzepatide and dulaglutide following the first dose. However, repeated dosing of tirzepatide, 5mg over several weeks, was associated with tachyphylaxis. Additionally, the same authors found that long-acting GIP RA had no effect on semi-liquid gastric emptying in contrast to GLP-1 RA in mice. The authors suggested that this effect might reflect potential benefits in reduction in weight and less gastrointestinal side-effects observed with tirzepatide (41). However, nausea with 10mg and 15mg doses of tirzepatide was 20% and 22% in the phase 3 SURMOUNT-2 trial in patients with obesity and T2DM (42).

Effects of Incretin Agonists on Liver Disease

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising worldwide and, in the USA, it has become the leading cause of end-stage liver disease and the main indication for liver transplantation. The exact pathologic mechanisms are still under investigation; however, it has been suggested that insulin resistance contributes to the development of fatty liver disease, and progression occurs through hepatic lipogenesis and lipolysis from peripheral adipose tissues and increased free fatty acid delivery to the liver (43).

Currently, there is no definitive treatment for MASLD, and lifestyle modifications with diet and exercise are the basis of management. However, treatment with incretin receptor agonists has shown significant weight loss which is beneficial for reduction of hepatic fat and an important objective in the treatment of MASLD. It is believed that GLP-1 effects on the liver are indirect, since it is hypothesized that there are no GLP-1 receptors in the liver, as demonstrated in a study on primate livers (44). However, its indirect effects on other organs can influence MASLD comorbidities such as cardiovascular disease. Table 2 summarizes the literature on the effects of incretin RAs on liver structure and function (45–53). Thus, recent studies have shown that reduced visceral fat improved liver enzymes [alanine transaminase (ALT) and aspartate transaminase (AST)] and reduced nonalcoholic fatty liver disease activity score with exenatide, liraglutide, and dulaglutide (54). Histological improvement of liver disease has been shown with semaglutide (47); however, in the same trial, there was no significant between-group difference in the percentage of patients with fibrosis stage. There is ongoing research on other drugs that target multiple incretin and incretin-like receptors, and a new range of therapeutic approaches for MASLD are in development.

Table 2.

Effects of GLP-1 receptor agonists on liver structure and function

GLP-1 Receptor Agonist	Patient Group	Outcome Findings: Improvements in				Type of Study	Study Ref.
		Histological NASH	Histological Fibrosis	Liver enzymes	Noninvasive (FIB-4 score, imaging)
Exenatide, liraglutide, or dulaglutide	T2DM with NAFLD	Reduced NAFLD activity score	Not assessed	Seen with exenatide only	Reduced Liver fat content was seen with exenatide by MRI and Spectroscopy in 1 study	SRMA	45,53
Exenatide vs insulin glargine	NAFLD and T2DM	Not assessed	Not assessed	Reduction in AST, ALT and GGT	Improved FIB-4 score, LFC, VAT, and SAT measured by MRS	24-week, multicenter, RCT	40
Semaglutide	Biopsy-confirmed NASH and liver fibrosis F1-3 +/− T2DM	Histological NASH resolution	No Δ in % with improved fibrosis stage	Not assessed	Not assessed	Double-blind, phase 2, placebo-controlled trial	47,48
Semaglutide	NCT02453711 in obese, no T2DM SUSTAIN-6: T2DM with prior CV event or high risk	Not assessed	Not assessed	Dose-related normalization of ALT after 52 weeks in up to 46% on 0.4 mg semaglutide vs. 18% on placebo	Not assessed	NCT02453711 and SUSTAIN-6 (both placebo-controlled) cardiovascular outcomes trials in T2DM	48
Semaglutide, liraglutide, dulaglutide	NAFLD	SUCRA: liraglutide highest ranking in increasing resolution of NASH		SUCRA: Sema-glutide may be most effective to reduce AST and ALT (superior to dulaglutide)	Liraglutide was superior to placebo in decreasing the CAP which evaluates steatosis based on shear-wave propagation	SRMA of RCTs	49
Liraglutide vs insulin glargine	T2DM and NAFLD with metformin	Not assessed	Not Assessed	Not assessed	Reduced intrahepatic lipid, subcutaneous abdominal adiposity and visceral adipose tissue using proton MRS	Single-center, prospective, RCT	50
Semaglutide	BMI >25 with NAFLD	Not assessed	Not assessed	18-28% reduction in ALT, AST and GGT with sema-glutide vs. placebo at weeks 48 and 72	Reductions in liver steatosis by MRI were significantly greater with semaglutide. Change from baseline liver stiffness was not significant	Randomized, double-blind, placebo-controlled trial	51
Liraglutide (LEAN trial)	Overweight with NASH	After 48 weeks of treatment, 39% of liraglutide group vs. 9% of placebo group had resolution (P=0·019), but total NAFLD activity score was p=NS	Fewer patients in liraglutide group vs. placebo had progression of fibrosis	A decreasing trend with liraglutide was not statistically significant	Serum enhanced liver fibrosis test results showed a reduction in fibrosis in patients receiving liraglutide vs. placebo, p=0.05	Multicentre, DB, PC, phase 2, RCT	52

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CAP=controlled attenuation parameter; DB=double-blind; GGT=gamma glutamyl transferase; LFC=liver fat content; MRI=magnetic resonance imaging; MRS=magnetic resonance spectroscopy; NAFLD=nonalcoholic fatty liver disease; NASH=nonalcoholic steatohepatitis; PC=placebo controlled; RCT=randomized, controlled trial; SAT=subcutaneous adipose tissue; SRMA=systematic review and meta-analysis; T2DM=type 2 diabetes mellitus; VAT=visceral adipose tissue;

Another benefit of GLP-1 agonism has been proposed in treatment of alcohol-related liver disease by GLP-1 RAs targeting alcohol use disorder. Preclinical studies have shown that GLP-1 agonism may reduce alcohol craving and intake by attenuating the ability of alcohol to activate the mesolimbic dopamine system in rodents (55,56). In clinical studies, genetic variation in GLP-1 receptor gene is associated with alcohol dependance in humans (57); unfortunately, replication of these results has not been achieved. In one study by Klausen et al., exenatide did not alter alcohol intake in patients who were of normal weight; however, there was a modest reduction in alcohol intake with exenatide in patients with BMI >30kg/m² (58). Use of GLP-1 RAs for this indication has limitations, such as unwanted additional weight loss in patients who might already be malnourished, and the potential risk of pancreatitis for which this population is already at a higher risk.

Gastrointestinal Adverse Events and Implications for Clinical Practice

The most common side effects of incretin RAs therapies are gastrointestinal in nature (nauseas, vomiting, diarrhea, constipation). In multiple studies, the AEs are likely dose-dependent, and most are observed during the dose escalation period (59) and tend to improve with ongoing use, though the mechanisms for such improvement are unclear. In the PIONEER 7 trial, individuals were allowed to adjust doses of oral semaglutide based on efficacy and tolerability. It was found that 9% of participants discontinued the drug due to gastrointestinal AEs , some even after first exposure at an initial dose of 3mg/day. This suggests there is variability in timing for patients to develop adverse effects, and that it could be related to the pharmacokinetics such as the Tmax of each drug (60,61). Wilding et al. also showed that gastrointestinal AEs may occur at any time during a 68-week study, long after up-titration had been achieved (34). Therefore, an individualized approach is recommended to achieve a dose that will provide medication benefit with the minimal possible side effects. This can be achieved along the recommendations of regulatory agencies by starting medication at lower doses and titrating at recommended rates, but with slower titration to induce tolerance before being exposed to higher doses and to help minimize the risks of potential side effects. In general, patients should be educated on the expected effect of early satiation, and that nausea might occur if attempting to eat after feeling full. It is also recommended that patients who develop gastrointestinal AEs should also modify their diet by decreasing meal sizes, as well as fat and non-digestible, uncooked fiber content, as is recommended for patients with gastroparesis (62). If a patient continues to experience side effects, dose de-escalation to the lowest dose tolerable might reduce symptoms.

Interestingly, a meta-analysis found that the concomitant use of metformin with GLP-1 RA increased the risk of nausea and vomiting (63). Thus, medication review and reconciliation should also be performed. To our knowledge, no head-to head comparison between the different GLP-1 RAs is currently available. However, in general, long-acting agents were associated with less nausea and vomiting, but with more diarrhea than short-acting agents (63). To improve compliance and adherence, education for patients on side effects should be provided as well as close monitoring and follow up.

It is conceivable that these medications may further potentiate symptoms of diabetic gastroparesis in those patients who had not been previously diagnosed. Thus, in this population, an alternative obesity therapy may need to be considered, such as phentermine topiramate.

When GLP-1 RAs were first introduced, there was an initial concern of acute pancreatitis as an AE. Acute pancreatitis was later surveyed in a larger population for cardiovascular outcome trials, and no increased risk of pancreatitis was found, as reported by hazard ratios of these AEs not significantly different from 1.0 (61,64). It is suspected that the elevated levels of amylase/lipase by GLP-1 RAs, along with non-specific abdominal pain, could have led to the concern of acute pancreatitis, without necessarily being associated with imaging findings that support the diagnosis (21,61). However, it is important to note that, in the SUSTAIN 3 trial, there were 6 cases of cholelithiasis reported in the semaglutide group and 2 in the exenatide ER group (65). In addition, the development of gallstones may occur in the setting of rapid weight loss.

Incretin Agonists and Perioperative Management

Most recent concerns pertain to the risks of GLP-1 RA administration relative to perioperative management, given that the increased residual gastric content in patients receiving GLP-1 RAs (Figure 4) increases the risk of aspiration in these patients. Until recently, the universal recommendation regarding medications for patients with diabetes in the preoperative period was to hold medications on the day of the procedure, given the medications’ short half-lives. However, with the introduction of GLP-1 RAs with longer half-lives and with their different AE profiles including gastric stasis, the preoperative management of these medications has been reconsidered, even though there is limited data on perioperative and postoperative outcomes associated with treatment with GLP-1 RAs. One small study evaluated point-of-care gastric ultrasound in patients on semaglutide for the treatment of obesity after a 10-hour fast. The study assessed if these patients had a “full stomach”, defined as clear fluid contents (1.5 mL/kg, or solids), compared to patients not taking a GLP-1 RA. In the lateral and supine positions, 90% and 70%, respectively, of the semaglutide group had solids identified, compared to 10% of controls (both statistically significant). This led to the conclusion that the semaglutide group was at increased risk of aspiration (66).

Figure 4.

Upper panel: Retention of gastric food seen at endoscopy in a patient with type 2 diabetes mellitus treated with semaglutide. Note the absence of any pyloric stenosis. Lower panel: Comparison of gastric emptying images obtained immediately after ingestion of a 320 kilocalorie, 30% fat egg meal, and at 1, 2, and 4 hours later in a patient on dulaglutide and after stopping that treatment. Note the marked retention of the scintigraphically-labeled meal at 2 and 4 hours which are normalized following cessation of dulaglutide treatment.

Only a few studies have evaluated GLP-1 RAs during cardiac and non-cardiac surgery (67,68), showing effectiveness in glucose control, but with increased reports of preoperative nausea, which also increased their risk of aspiration. However, no studies have been performed in gastrointestinal-related surgeries or procedures. The Society for Perioperative Assessment and Quality Improvement conducted a critical literature review and generated a consensus recommendation suggesting continuing GLP-1 RAs before the day of surgery unless patients experienced gastrointestinal symptoms or were undergoing gastrointestinal-related surgery. If so, it was recommended that the longer-acting GLP-1 RAs should be held from 7 days before surgery with closer monitoring of antidiabetic regimen in patients with T2DM. All other patients were advised to hold GLP-1 RA treatment in the morning of surgery (69).

However, a most recent consensus-based guidance from the American Society of Anesthesiologists (70), in response to concerns of delayed gastric emptying and risks of aspiration, made recommendations for the week prior to and on the day of the elective procedures (Figure 5). Given that the half-life of most long-acting GLP-1 RAs is approximately 5 days, it would be reasonable to recommend that patients receiving such agents who need to undergo elective surgery should stop the medication for a period of approximately 4 weeks (which is 5-6 times the half-life of those medications). In the context of obesity as the indication, that should not be associated with any concern. However, in patients with type 2 diabetes, it will be important to ensure alternative treatments, which patients are often receiving anyway, such as a biguanide (e.g. metformin) or SGLT2 inhibitor (e.g. dapagliflozin), and, if necessary, insulin supplementation with guidance from a diabetologist.

Figure 5.

American Society of Anesthesiologists recommendations for patients scheduled for elective procedures during the week prior to the procedure as well as on the day of the procedure.

Moreover, in patients who need urgent or emergency surgery, it should be assumed that the patient receiving GLP-1 RA has a full stomach and appropriate precautions should be taken. For example, it is important to consider performing a “bedside” ultrasound to check for any gastric residual content (71,72). In addition, intravenous erythromycin rapidly empties food, even non-digestible solids, from the stomach (73,74). The standard erythromycin dose is 3mg/kg IV infused over 45 minutes (75).

Future Research

It is anticipated that many more incretin agonists will be approved and enter the therapeutic armamentarium. For example, the tirzepatide Phase IIb data have established clinical proof-of-concept with combined GIP/GLP-1 receptor agonism, leading to superior efficacy in weight loss and glycemic control, and additional beneficial effects in other organ systems. Similarly, a subcutaneous agent, retatrutide (76), acting on three incretin receptors (GLP-1/GIP/glucagon), as well as oral, non-peptide selective GLP-1 agonists have already been documented as being associated with gastrointestinal AEs. Future research should focus on objective assessment of all these agents and those already approved for gastric emptying of solids using well-validated methods such as scintigraphy (77) or stable isotope breath test (78), both using a 320kcal, 30% fat meal, and including, if possible, comparison head-to-head of these diverse agents.

Another focus for future research should be the validation of an algorithm using ultrasound diagnosis at the point of care to identify gastric retention, followed by intravenous erythromycin which has been proven to be efficacious for upper gut motility disorders (73,74) in patients receiving incretin RAs. This algorithm should be appraised in the perioperative and postoperative periods in the setting of gastrointestinal-related surgeries and procedures that involve bowel manipulation and that can cause postoperative ileus. Further studies should also explore whether the incretin RAs have additional deleterious interactions with anesthetics during deep sedation.

Abbreviations:

AEs

adverse effects

ALT

alanine transaminase

AST

aspartate transaminase

CI

confidence interval

DPP-4

dipeptidyl-peptidase IV

GIP

glucose-dependent insulinotropic peptide

GLP-1

glucagon-like peptide-1

MASLD

metabolic dysfunction-associated steatotic liver disease

PLG

poly [lactic-co-glycolic acid]

RAs

receptor agonists

SQ

subcutaneous

T2DM

type 2 diabetes mellitus