What We Know About Semaglutide Adverse Events and Gastroparesis: Part I

Semaglutide-containing medications sold under the brand names Ozempic^® and Wegovy^® have made headlines after being linked to gastroparesis. Both medications belong to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 is a regulator of appetite and caloric intake and is known to have various drug interactions due to delayed gastric emptying as a result of therapy.

In a 2-year study (ClinicalTrials.gov Identifier: NCT03693430) of semaglutide use in patients with overweight or obesity, researchers found that 82.2% of patients taking semaglutide experienced mild to moderate gastrointestinal (GI) adverse events compared with 53.9% in the placebo group. There were no reports of gastroparesis in the study.¹ 

While semaglutide and other GLP-1 agonists cause adverse events, such as nausea, vomiting, diarrhea, and a range of other GI symptoms, these effects of delayed gastric emptying are reported to be reduced after 20 weeks of use. ²  

What Are Other Causes of Gastroparesis? 

Diabetes is the most common underlying cause of gastroparesis and can damage the vagus nerve, leading to impaired muscular function in the stomach and small intestine.³ Studies show that the 10-year cumulative incidence of diabetic gastroparesis is estimated to be 5.2% among patients with type 1 diabetes and 1% in patients with type 2 diabetes.⁴ 

Other known causes of gastroparesis include celiac disease, neurological disorders such as Parkinson disease and central nervous system tumors, collagen vascular disorders such as scleroderma and systemic lupus erythematosus, hypothyroidism, and medications.⁵

Medications that can result in delayed gastric emptying leading to gastroparesis include proton pump inhibitors, tricyclic antidepressants, calcium channel blockers, opioid analgesics, progesterone, lithium, cyclosporin, and levodopa.⁵

Research on semaglutide-induced gastroparesis is limited, but patient reports have been increasing.

Case Studies of GLP-1-Induced Gastroparesis

1. A 52-year-old woman with a 10-year history of diabetes presented with a 7-month history of postprandial epigastric pain with concomitant fullness, bloating, and nausea that was unrelieved after proton pump inhibitors and antispasmodics. She was initiated on weekly semaglutide subcutaneous injection 1 month prior to symptom onset, and her diabetes is currently well-managed (A1c, 5.7%). A 4-hour scintigraphic gastric emptying (SGE) test indicated delayed gastric emptying. Semaglutide was held for 6 weeks, leading to symptom resolution.⁶

2. A 57-year-old woman with a 16-year history of diabetes presented with a year history of abdominal bloating, nausea, and vomiting. The patient was initiated on dulaglutide subcutaneous weekly injection 15 months prior and has an A1c of 8.2%. A SGE confirmed delayed gastric emptying. Dulaglutide was held for 4 weeks, resulting in a gradual resolution of symptoms.⁶

3. A 52-year-old man with a history of diabetes, hypertension, and hyperlipidemia presented with a 1-week history of nausea, abdominal distension, and pain. The patient was receiving daily liraglutide for glycemic control (A1c, 7%). After temporary discontinuation of liraglutide, dietary modification, and a short course of antiemetics and metoclopramide, the man’s symptoms resolved.⁷

Semaglutide and Gastroparesis in the News

In July 2023, 3 women told CNN that they developed severe GI symptoms after receiving treatment with semaglutide injections. Two of the women were diagnosed with severe gastroparesis.⁸

Then, in early August 2023, a woman sued Novo Nordisk and Eli Lilly, the manufacturers of semaglutide and tirzepatide injections, alleging that the companies failed to warn patients of severe GI symptoms. The woman reported stomach pain, severe vomiting, GI burning, hospitalization due to stomach issues, and a loss of teeth due to excessive vomiting.⁹ 

While both medication package inserts state that delayed gastric emptying is possible with the medication and may affect drug absorption, they do not specifically state that gastroparesis is a potential risk.¹⁰ The GI adverse events listed on the semaglutide package inserts appear to be mild to moderate, including nausea, stomach pain, bloating, constipation, diarrhea, and vomiting.^10-12 

As the popularity of these medications increases, experts expect an increase in GI adverse event reports in the future. The US Food and Drug Administration (FDA) told CNN in a statement that they have “received reports of gastroparesis with semaglutide and liraglutide, some of which documented the adverse event as not recovered after discontinuation of the respective product at the time of the report.”⁸ 

However, the FDA also told CNN that they are unable to confirm if the medications directly caused gastroparesis or an alternative etiology.⁸

Active Ingredient	Brand Name	FDA-Approved Indication10-15	Formulation10-15
Semaglutide	Wegovy; Ozempic	Diabetes: Adjunct to diet and exercise to improve glycemic control in adults   Chronic Weight Management: Adjunct to a reduced caloric diet and increased exercise in adults	Subcutaneous injection
Semaglutide	Rybelsus	Diabetes: Adjunct to diet and exercise to improve glycemic control in adults	Oral tablet
Dulaglutide	Trulicity	Diabetes: Adjunct to diet and exercise to improve glycemic control in patients 10 years and older and reduce risk for major adverse cardiovascular events	Subcutaneous injection
Liraglutide	Saxenda; Victoza	Diabetes: Adjunct to diet and exercise to improve glycemic control in adults   Chronic Weight Management: Adjunct to a reduced caloric diet and increased exercise in children and adults	Subcutaneous injection

Clinician Guidelines for Managing Gastroparesis

Clinicians do not recommend semaglutide for patients who experience symptoms of gastroparesis.⁴ An SGE over a duration of 3 hours is recommended when evaluating for gastroparesis in patients with upper GI symptoms. If an SGE assessment is not feasible, wireless motility capsule or a stable isotope breath test is a reasonable alternative.¹⁶

Dietary modifications with small-particle, low-fat, nondigestible food are recommended to provide symptom relief and enhance gastric emptying. Metoclopramide, domperidone, or 5-HT4 agonists are recommended to improve gastric emptying. Antiemetics are suggested for symptom control but do not improve gastric emptying. Central neuromodulators, ghrelin agonists, and haloperidol are not recommended in therapy.¹⁹

There is limited research on the management of medication- or drug-induced gastroparesis. Based on current case studies, management includes discontinuation of the medication, symptom control with antiemetics and prokinetic agents per guidelines, nutritional support, and dietary modification.⁷ Further research is warranted to identify next steps for patients who develop gastroparesis after semaglutide use, and whether reinitiation of therapy is possible after discussion of benefit vs risk with their health care provider.

This is the first article in a 2-part series on gastroparesis. The second article Clinician Insights on How to Manage Semaglutide-Induced Gastroparesis: Part II is available here.

This article originally appeared on Gastroenterology Advisor