GLP-1 RAs: How to Manage Real-World GI Complications

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are revolutionizing blood sugar control in diabetes, and their popularity as a weight loss treatment in the general population has skyrocketed in recent years. But the medications can cause a range of gastrointestinal (GI) side effects, and gastroenterologists increasingly will be called upon to manage them in their patient populations.

Michael Camilleri, MD, DSc

"We can't lose sight of the fact that these medications are having significant beneficial effects, not only on diabetes and weight loss but also on cardiometabolic parameters," Michael Camilleri, MD, DSc, a consultant in the division of gastroenterology and hepatology at Mayo Clinic in Rochester, Minnesota, told Medscape Medical News. Camilleri is also involved in clinical enteric neuroscience translational and epidemiologic research.

"We need to keep that in perspective and learn how best to manage the GI side effects so patients can continue to reap the medications' benefits," he added.

Camilleri, who is an associate editor of Gut, coauthored an invited article about the effects of GLP-1 and other gut hormone receptors on the GI tract that was published online in the American Journal of Gastroenterology. He shares insight here on the implications of their use in clinical practice.

GLP-1 Receptor Agonists in Brief

GLP-1 and glucose-dependent insulinotropic peptide (GIP) are incretin hormones. These gut peptides modulate glucose metabolism by stimulating insulin release after eating and by inhibiting the release of glucagon by pancreatic cells. Agonists targeting their receptors are well established for the treatment of type 2 diabetes.

The US Food and Drug Administration (FDA) approved the first GLP-1 RA, exenatide (Byetta), in 2005 for the treatment of type 2 diabetes. In addition to exenatide, six other GLP-1 RAs are currently available in the United States: exenatide extended-release (Bydureon), dulaglutide (Trulicity), liraglutide (Victoza), lixisenatide (Adlyxin), semaglutide injection (Ozempic), and semaglutide tablets (Rybelsus).

One dual GLP-1/GIP receptor agonist, tirzepatide (Mounjaro), is also approved.

More recently, GLP-1 RAs have gained traction in treating obesity with or without diabetes. They appear to cause weight loss by slowing stomach emptying, stimulating centers in the brain that control appetite, and increasing the feeling of being full after a meal.

"It is becoming clearer that in addition to benefits derived from reduced appetite and improved glucose control, a significant component of the weight loss is attributable to the effects on the GI tract, particularly delayed gastric emptying," Camilleri said.

Although GI effects may contribute to weight loss, "they were not the dominant determinant of weight loss," he added. "Rather, most of the lost weight is

secondary to the effect of the medication on appetite suppression."

Thus far, only injectable semaglutide (Wegovy), high-dose liraglutide (Saxenda), and tirzepatide (Zepbound) are approved for weight loss. Tirzepatide was most recently approved in 2023, with semaglutide and liraglutide being first approved in 2021 and 2014, respectively. Other agents are being used off-label for weight loss.

Dosing schedules vary among the GLP-1 RAs, and their half-lives also are different. All but semaglutide tablets are given by injection.

The dose amount, dosing frequency, drug delivery method, and specific approved indications can affect the benefits conferred, as well as potential side effects, Camilleri noted.

Key Side Effects

The most commonly reported GI side effects with GLP-1 RAs are nausea, vomiting, diarrhea, and constipation. They are prevalent with both subcutaneous and oral versions.

In the SUSTAIN 10 trial of subcutaneous (SC) semaglutide, for example, 52% of patients reported these GI side effects, as well as abdominal pain, compared with 35% of those on placebo. The side effects sometimes led to premature discontinuation of the drug.

A longitudinal assessment of once-weekly SC semaglutide in adults who were overweight or obese documented the development of GI side effects at any time after randomization up to 68 weeks, with median durations of 8 days for nausea and 2 days for vomiting. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (4.5% vs 0.8%, respectively).

These common side effects were also found in a randomized, double-blind, placebo-controlled phase 3 trial assessing the weight-loss efficacy of 50 mg oral semaglutide in patients with overweight or obesity but without diabetes. Of the participants reporting adverse events, 52% developed nausea, 24% vomiting, 28% constipation, and 27% diarrhea.

Intestinal motility has also taken center stage recently.

With GLP-1 RAs, "we see a reduction in the motility index. This means there is an inhibition of the contractions of the intestine, as well as the stomach, which is something we've known about since 2009," Camilleri said. "So, it's not surprising that some people are more susceptible to developing an exaggerated and negative response to this class of medications."

After more than a dozen recent reports of ileus among people taking SC semaglutide, the FDA changed the label to reflect this side effect. The same warning is already listed on the labels for Mounjaro and Wegovy.

GLP-1 RAs also slow gastric emptying. While this can cause adverse effects in some patients, many experience a return to normal within weeks of starting the drugs.

In a recent study of liraglutide's effects on gastrointestinal functions, for which Camilleri was a principal investigator, the researchers found that about half of patients who had a delay in gastric emptying returned to normal by 16 weeks.

"We're not sure why there is normalization of stomach emptying," he said. "We found there was no significant impact of two reported genetic variants in a protein (TCF7L2) that impacts GLP-1 synthesis and the GLP-1 receptor."

Results of their further investigation on gastric emptying delay in response to liraglutide were recently published.

"To date, a comparison among all the available GLP-1 RAs regarding GI adverse events, including gastric emptying of solid food, as primary outcomes has not been performed," Camilleri noted.

Perioperative Management Concerns

The impact of these drugs on gastric emptying has generated concerns about perioperative management owing to the risk for aspiration of stomach contents.

In response to these concerns, five professional gastroenterology organizations released a statement on August 11 urging their members to "exercise best practices" when performing endoscopy on patients taking GLP-1 RAs, while acknowledging that there are no "actionable data" to rely on.

The statement was issued in response to guidance released on June 29 by the American Society of Anesthesiologists (ASA), which offers strategies for stopping the drugs in the days prior to and on the day of an elective procedure. The ASA based its guidance on a review of the available literature and also acknowledged that the evidence is "sparse, limited only to several case reports."

The ASA guidance is "a step in the right direction for patient safety," Camilleri said.

But some of the suggested strategies may not be appropriate, he said. For example, the ASA recommends holding GLP-1 RAs the week prior to surgery for someone on a weekly dosing schedule.

"A conservative approach is to wait five times the half-life of a drug before you can assume a drug is no longer working," Camilleri said. "If somebody is taking a medication once a week, you can't just stop the medication a week before. For elective procedures, it may be more appropriate to plan the procedure 3-5 weeks after cessation of the GLP-1 agent administered weekly. Meanwhile, attention should be given to ensuring control of diabetes."

For a patient on a GLP-1 RA who must undergo an emergency procedure, he suggested conducting bedside ultrasound to check for any residual gastric content.

It's also worth considering the use of intravenous erythromycin, which rapidly empties food and nondigestible solids from the stomach, at the standard dose of 3 mg/kg intravenously infused over 45 minutes, he said.

"Incretin agonists are highly effective agents for diabetes and obesity; however, practitioners need to be aware of risks of pulmonary aspiration due to delayed gastric emptying," Camilleri said.

Additional research is necessary to determine the "sweet spot" for withholding each GLP-1 RA prior to elective surgery, and large database studies are needed to establish the prevalence of delayed gastric emptying and other GI consequences, he noted.

The American Gastroenterological Association recently addressed the ASA guidance, stating in its own rapid clinical practice update that it "finds no data to support all patients stopping GLP-1 RAs prior to elective procedures and surgeries" and recommends "a balanced approach and patient individualization."

Individualizing Management

Given the various formulations and dosing regimens, lack of robust comparative studies, and dearth of information on risks or factors that might predispose to adverse events, "management comes down to individualizing the experience of the patient," Camilleri said.

"If the patient is tolerating and benefiting from the drug, with no adverse effects, then I don't think there's any reason to intervene," he said. "If the patient is developing symptoms, we need to ask, 'Do those symptoms reflect an impairment of the stomach or intestinal function?' And if so, then manage accordingly."

Patients should be educated on the expected effect of early satiety and informed that nausea might occur if they continue eat after feeling full, Camilleri said.

When a patient develops nausea, fullness, or vomiting during dose escalation, it may be prudent to slow the escalation and keep the dose at a level that does not produce symptoms, Camilleri said.

"Starting a drug at lower doses and titrating more slowly to ensure medication tolerance before moving to higher doses may also minimize the risk of potential side effects," he added. "In either case, the patient should be monitored to ensure that the risk-benefit ratio is still favoring benefit; that is, ensuring that a lower dose does not affect the drug's efficacy for the specific indication of weight loss or diabetes."

Camilleri also emphasized that gastroenterologists need to do a better job of identifying and treating obesity, given that it is a significant risk factor for GI, pancreatic, and liver diseases, and significantly impacts the treatment and complications of inflammatory bowel diseases.

To do so effectively, gastroenterologists need to understand the effects of GLP-1 RAs and be part of multidisciplinary teams who are helping to manage patients with obesity over the long term, he said.

Camilleri has no relevant conflicts of interest.

Follow Marilynn Larkin on X: @MarilynnL

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