Originally published by our sister publication Pharmacy Practice News

By Bruce Buckley and David Bronstein

There’s a challenge posed by the growing use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for weight loss: Although most patients tolerate GLP-1 RAs, the medications may trigger potentially severe gastrointestinal (GI) side effects, including gastroparesis and an increased risk for aspiration pneumonia.

Pharmacists need to heed the heightened risk for aspiration in these patients because it may lead clinicians on the care team to debate whether changes to preoperative GLP-1 RA regimens are warranted, noted Ion Hobai, MD, PhD, an assistant professor of anesthesia at Massachusetts General Hospital, in Boston. Dr. Hobai noted that gastroparesis, which occurs as a result of delayed gastric emptying, can quickly lead to regurgitation and life-threatening pulmonary aspiration for patients who need anesthesia for surgery or other procedures (Can J Anesth 2023;70[8]:1281-1286).

In a more recent study, investigators examined the health records of nearly 1 million adult GI endoscopy patients to determine whether there was a link between GLP-1 RA use and aspiration pneumonia. After factoring in confounders that could affect gut motility, the investigators found that GLP-1 RA use was associated with a significantly higher risk for aspiration (0.83% vs. 0.63%) compared with a nonuser group (hazard ratio [HR], 1.33; 95% CI, 1.02-1.74; P=0.036) (Gastroenterology 2024 Mar 27. doi.org/10.1053/j.gastro.2024.03.015).

“When we apply this risk to the more than 20 million endoscopies that are performed in the U.S. each year, there may actually be a large number of cases where aspiration could be avoided if the patient safely stops their GLP-1RA medication in advance,” the study’s corresponding author, Ali Rezaie, MD, the medical director of the GI Motility Program at Cedars-Sinai Medical Center, in Los Angeles, said in a press release announcing the findings.

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However, given the “complex pharmacokinetics of GLP-1 RAs [and] uncertain timelines for gastric emptying normalization,” further investigations are warranted “to establish optimal drug withholding periods before endoscopies,” Dr. Rezaie and his colleagues wrote. (For more data on GLP-1 RA GI effects, see sidebar.)

In his own research, Dr. Hobai has found that the risk for having a full stomach even after fasting was about six times greater in patients taking a GLP-1 agonist than for a matched group eligible for GLP-1 therapy but who had not yet begun treatment. The retrospective study accounted for other factors that can cause gastroparesis, including diabetes, body weight, fasting duration and other medications (Can J Anaesth 2024 Mar 14. doi: 10.1007/s12630-024-02719-z). “What’s important is that many of these patients are unaware that food is still in their stomachs,” he said. “They are completely asymptomatic. So we can’t judge their aspiration risk based on whether they feel nauseated or have the sensation of abdominal fullness or pain.” (For more details, see Dr. Hobai’s article, “The Incretin Effect.”)

Dr. Hobai suggested several measures to mitigate the risk for pulmonary aspiration. One would be to withhold the GLP-1 for the time required to eliminate or nearly eliminate it from the blood. In the case of patients with diabetes, that would mean stopping therapy with semaglutide for three weeks prior to endoscopy and other surgeries and replacing it with another medication to keep blood glucose levels under control.

Another possibility, he said, would be to substitute a GLP-1 RA with a much shorter half-life than semaglutide during the three weeks prior to surgery, much in the same way that low-molecular-weight heparin often is used as a warfarin bridge therapy before a surgical or other procedure. He noted, however, that neither suggestion has much support from clinicians who manage diabetes.

Medical Societies Weigh In

On Aug. 11, 2023, five organizations, including the American Gastroenterological Association (AGA), issued a joint guidance stating there were “no data to support stopping GLP-1 agonists prior to elective endoscopy.” The group noted that “while there is anecdotal experience that increased gastroparesis risk may be dose dependent or related to whether [the GLP-1 agonist] is being used for diabetes control versus weight management, we also acknowledge that there is little or no data related to the relative risk of complications from aspiration.”

In the absence of actionable data, the group added, “we encourage our members to exercise best practices when performing endoscopy on patients on GLP-1 receptor agonists.”

The American Society of Anesthesiologists recently took a different stance when it released a consensus-based guidance recommending withholding GLP-1 RAs before an endoscopic or surgical procedure. “For patients on daily dosing, consider holding GLP-1 agonists on the day of the procedure/surgery,” the authors noted. “For patients on weekly dosing, consider holding GLP-1 agonists a week prior to the procedure/surgery.”

The authors added that their recommendations apply whether patients are being treated for type 2 diabetes or weight loss.

Dr. Hobai said there is some room for debate, but that he understands the stance of the AGA joint guidance. “They think the concerns are still unproven and [stopping GLP-1 RAs may] cause more dangers.”

He suggested another potential strategy for navigating these challenges: Using gastric ultrasound to assess asymptomatic gastroparesis in patients about to undergo surgery (Anesth Analg 2021;133[3]:690-697). In such a scenario, the patient would take a GLP-1 medication as usual, hold for one week and then undergo ultrasound imaging before the operation. “If the stomach appears to be empty, we’d proceed with the surgery.”

For patients with a full stomach, Dr. Hobai continued, the procedure can be canceled, or rapid sequence induction and intubation can be taken as a precaution against aspiration.

Pharmacists’ Take

To mitigate the risk for aspiration, Jennifer N. Clements, PharmD, BCPS, BCACP, BC-ADM, CDCES, the director of pharmacy education at the University of South Carolina College of Pharmacy, in Greenville, recommended counseling patients who are on GLP-1 RAs “to eat smaller meals throughout the day and avoid certain types of foods, including ones that are fatty or spicy. They also should be cautious about what they’re drinking, avoiding carbonated beverages and substituting plain water.”

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Diana Isaacs, PharmD

Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, a clinical pharmacy specialist in endocrinology at Cleveland Clinic, said the approach “really depends on the magnitude of the GI side effect. If it’s a bowel obstruction or pancreatitis, we’re going to stop the medication.” But if someone is experiencing nausea or diarrhea, she added, “we will consult with the patient, because a lot of people feel that the benefits—like lowering their glucose levels and their weight—are worth some discomfort.”

Next, she added, “we might back off on the dose, or instead of titrating up to the next dose, staying at the lower dose for longer. So it’s very much individualized, but it should be shared decision making with the patient.”

Overall, Dr. Isaacs said, “most people do very well with these agents.”

A Far Less Common Risk

What should clinicians make of another, albeit far less common, side effect that has been associated with GLP-1 RAs: an increased risk for suicidal ideation and actions?

Digging Deeper Into the Data

The debate over how clinicians should respond to data showing that glucagon-like peptide-1 (GLP-1) receptor agonists may cause gastrointestinal (GI) side effects is based in part on a large retrospective study linking the medications to pancreatitis, gastroparesis and bowel obstruction.

In the study, researchers at the University of British Columbia evaluated patients prescribed the GLP-1 agonists semaglutide (Ozempic/Wegovy, Novo Nordisk) and liraglutide (Victoza/Saxenda, Novo Nordisk) for weight loss, comparing their effects with those of naltrexone-bupropion (Contrave, Currax), a weight-loss agent with a different mechanism of action (JAMA 2023 Oct 5. doi:10.1001/jama.2023.19574).

The researchers used a random sample of 16 million patients from the PharMetrics Plus database between 2006 and 2020, a time frame that covers the FDA approvals for weight-loss indication with liraglutide in 2014 and semaglutide in 2021. They ensured every case had an obesity code in the 90 days before or up to 30 days after entry into the study, and excluded patients with a diabetes diagnosis or an antidiabetic drug code.

The results suggested that use of semaglutide and liraglutide for weight loss is associated with an increased risk for pancreatitis (adjusted hazard ratio [aHR], 9.09; 95% CI, 1.25-66.00), gastroparesis (aHR, 3.67; 95% CI, 1.15-11.90) and bowel obstruction (aHR, 4.22; 95% CI, 1.02-17.40) compared with naltrexone-bupropion.

Additional findings showed:

  • the incidence of pancreatitis per 1,000 patients was higher for both GLP-1 agonists relative to naltrexone-bupropion (semaglutide, 4.6/1,000; liraglutide, 7.9/1,000; and naltrexone-bupropion, 1.0/1,000);
  • the incidence of gastroparesis—an adverse effect that can cause nausea and vomiting, among other symptoms, and also could affect endoscopic procedures—was also higher for the GLP-1 agonists (semaglutide, 9.1/1,000; liraglutide, 7.3/1,000; and naltrexone-bupropion, 3.1/1,000); and
  • the incidence of bowel obstruction was higher in patients on liraglutide (8.1/1,000) than semaglutide (zero) or naltrexone-bupropion (1.7/1,000).
—Joe Morreale

In the United States, two GLP-1 agonists already come with a warning about the potential for suicidal behavior and ideation in the branded versions approved for weight loss: semaglutide (Wegovy, Novo Nordisk) and liraglutide (Saxenda, Novo Nordisk). (Both drugs, marketed as Ozempic and Victoza, respectively, are also approved for treatment of type 2 diabetes.) But in 2023, a report from the European Medicines Agency renewed focus on the issue. The agency said that it had “retrieved and [was] analyzing about 150 reports of possible cases of self-injury and suicidal thoughts linked to GLP-1 RAs themselves or to patients’ underlying conditions or other factors.”

In January, the FDA responded by analyzing its Adverse Event Reporting System, and noted that it had “not found evidence” that the use of GLP-1 RAs caused suicidal thoughts or actions. However, the agency stressed that “because of the small number of suicidal thoughts or actions observed in both people using GLP-1 RAs and in the comparative control groups, we cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue.”

Dr. Isaacs told Pharmacy Practice News that she did not believe GLP-1 RAs “are the direct cause of suicide ideation,” but there may be an association, she added, possibly related to the weight loss experienced after taking the medication. Patients with psychological conditions, such as depression, who take the drugs expecting relief from their symptoms may discover that their weight loss was not the solution they envisioned, she explained.

Dr. Clements stressed the need for caution when prescribing GLP-1 agonists for people with uncontrolled or untreated depression. “We may want to treat that condition first and then wait on these products,” she said. “But if someone has active suicidal ideation or previous suicidal attempts, it would be best to err on the side of caution and just not use them, since the risk is mentioned in product labeling.”


Drs. Clements and Isaacs reported that they are speakers for Eli Lilly and Novo Nordisk. Dr. Hobai reported no relevant financial disclosures.