Appendicitis: A Hidden Danger of GLP-1 Receptor Agonists?

Abstract

Introduction: While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become increasingly prescribed, use is often inhibited by the gastrointestinal adverse effects that patients must endure. Nausea, vomiting, and cholelithiasis are most commonly associated with use, with little to no data or labeling reflecting risk of appendicitis or associated symptoms. Appendicitis etiology is theorized to develop secondary to obstruction of the vermiform via infection or fecalith causing an increase in intraluminal pressure. It is hypothesized that given the aforementioned gastrointestinal effects associated with GLP-1 RAs, patients taking such agents may be more at risk for developing this acute condition. Patient Case: We describe a case of a 48-year-old woman who presented to the emergency department several months after being initiated on Ozempic (semaglutide). This report aims to analyze the potential secondary adverse effects that may result from GLP-1 RA use. Her examination was positive for focal abdominal tenderness and leukocytosis along with imaging suggestive of appendicitis. Her acute condition ultimately required an appendectomy. Discussion: While minimal data are available to suggest significant causation between GLP-1 RAs and appendicitis, a literature and database search revealed that instances may be more common than previously thought. Conclusion: Trial results and adverse event reporting systems report an infrequent incidence in patients using these medications, but this report aims to contribute to the literature describing this potential adverse event.

Introduction

Over the last several years, there has been a rise in the prescribing and use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for type 2 diabetes (T2DM) and weight management.^1,2 The logic behind utilization of GLP-1 RAs (eg, liraglutide, semaglutide, dulaglutide, exenatide, lixisenatide, albiglutide) and combined GLP-1 RA/glucose-dependent insulinotropic polypeptides such as tirzepatide is to mimic the action of the natural hormonal peptide that is secreted in the human body when food is ingested, leading to an increase in insulin and somatostatin secretion while simultaneously reducing the secretion of glucagon. ³ These effects promote weight loss and glycemic control through delaying gastric emptying and subsequently promoting satiety.^4,5

While these agents have become increasingly popular, use may be limited by the gastrointestinal adverse effects that patients may experience, such as nausea, vomiting, constipation, and cholelithiasis. ⁶ As of current, appendicitis or associated rupture is not a highly noted concern with these agents, though is included in the Wegovy package insert. ⁷ While the specific etiology of appendicitis is not entirely clear, it is theorized that obstruction of the vermiform via infection or fecalith could cause the acute condition. ⁸ Intraluminal pressure may increase as a result of inflammation or injury that causes said obstruction, leading to small vessel occlusion and inhibited lymphatic drainage which can thereby cause an infectious process. ⁸ It may be hypothesized that given the gastrointestinal effects secondary to delayed gastric emptying associated with GLP-1 RAs, patients taking such agents may be more at risk for developing appendicitis due to increased risk of developing fecalith.

We present the case of a 48-year-old woman who presented to the emergency department with acute appendicitis after being initiated on Ozempic (semaglutide) 6 months prior. This report aims to analyze the potential secondary adverse effects that may result from GLP-1 RA use.

Case Presentation

A 48-year-old woman presented to the emergency department for evaluation of acute abdominal pain. She reported her symptoms began earlier that day, mostly in the epigastric region, and described a burning sensation followed by right lower quadrant abdominal pain. Her symptoms were associated with nonbilious vomiting but improved with single doses of morphine and ketorolac. Her past medical history is significant for T2DM, hypothyroidism, hypertension, and gastroparesis. She did not have a prior medical history significant for constipation, nor new complaints of such symptoms that she was being treated for. Her most recent colonoscopy and endoscopy were conducted in 2021 and unremarkable. She has no relevant family history, and her social history is absent of any alcohol or illicit drug use. Prior to admission, her home medications included glimepiride 2 mg by mouth daily; hydrochlorothiazide 50 mg daily; levothyroxine 100 μg by mouth daily; metformin 1000 mg by mouth 2 times a day; montelukast 10 mg by mouth every evening; naproxen 500 mg by mouth every 12 hours as needed for mild pain; omega-3 acid ethyl esters 1 g by mouth daily; omeprazole 40 mg by mouth nightly; Ozempic (semaglutide) 0.5 mg subcutaneously once weekly; Sunosi (solriamfetol) 75 mg by mouth every morning. All medications were taken chronically long term except for the GLP-1 RA, semaglutide, which was initiated most recently about 6 months prior.

A physical examination was performed at the bedside and only noted focal tenderness at McBurney point. Laboratory data were significant for leukocytosis (23.6 × 10³/μL). All other laboratory markers were within normal limits. The patient’s abdomen was scanned via computed tomography with contrast and notable for stool-filled colon and cecum and inflammation of the appendix.

The patient was ultimately brought to the operating room for a total appendectomy completed without complications.

Discussion

As mentioned previously, appendicitis or rupture is not a widely publicized concern associated with GLP-1 RAs. However, clinical trial reports for the various drug products within the class have recorded varying rates of appendicitis during and following treatment with this class of agents (Table 1). In a study evaluating 1896 tirzepatide users (SURMOUNT-1), 6 cases of appendicitis over the course of 84 weeks were reported and documented. ⁹ Four of these cases occurred at a dose of 5 mg, while 2 cases occurred at a dose of 15 mg; no cases were reported at a dose of 10 mg. This trial data did not include any statistics from post-trial reporting. ⁹ An additional 8 cases (0.17%) of appendicitis were reported in the trial evaluating Liraglutide and Cardiovascular Events in Type 2 Diabetes (LEADER). ¹⁰ Liraglutide was initiated at a dose of 0.6 mg and titrated up to 1.2 mg after 1 week, then titrated up to 1.8 mg after another week for the remainder of the 60-month clinical trial. ¹⁰ In an assessment report of Trulicity (dulaglutide), set forth by the European Medicines Agency (EMA) in 2019, 120 cases of “Serious GI Events” (which includes appendicitis, perforated appendicitis, gastrointestinal obstruction, and gallstone/gallbladder-related disorders) were reported, meaning 2.4% of participants in the dulaglutide arm experienced one of these events over 5.4 years. ¹¹ More specifically, 5 of 1670 patients experienced a form of appendicitis. ¹¹ MacConell and colleagues pooled data revolved around exenatide use and determined an incidence of 2 cases of appendicitis in 1934 subjects in addition to commenting on the increased incidence rate specifically seen in the DURATION-6 trial of 2 in 461 subjects.^12,13 Last, a recent pharmacovigilance study based on the Food and Drug Administration (FDA) adverse event reporting system (FAERS) reports 10 cases of serious (0.56%) and 2 cases of nonserious appendicitis (0.05%) associated with semaglutide over the span of 2018 to 2022. ¹⁴

Table 1.

Appendicitis Frequency Identified in GLP-1 RA Users.

GLP-1 RA	Dulaglutide	Exenatide	Liraglutide	Tirzepatide	Semaglutide
Appendicitis incidence in literature9 -14	0.3%	0.1-0.4%	0.17%	0.32%	ROR a (95% CI) 2.58 (1.46-4.54) 0.56%
FAERS Database Case Countb,15	25	57	31	11	40

Abbreviations: CI, confidence interval; FAERS, FDA adverse event reporting system; GLP-1 RA, glucagon-like peptide-1 receptor agonists.

^aRelative odds ratio.

^bCases as of June 30, 2023; reactions queried include appendicitis, appendicitis perforated, appendiceal abscess, appendix disorder, appendicectomy.

One mentionable limitation of the literature is that there are little to no details on the acuity and outcomes of appendicitis, nor specific mentioning on timing and dosage relative to the adverse event to better gauge a correlation. The treatment method, including whether or not an appendectomy was performed, and type of surgery remain unknown in the bulk of the literature. Notably, the type of appendectomy performed—laparoscopic or open—has differing implications on morbidity and mortality rates, as well as risk of infection, intra-abdominal abscess formation, and small bowel obstruction. ¹⁶ In addition, it is unknown how long after the initiation of the GLP-1 RA that the symptoms of appendicitis started in the subjects identified. In this case presentation, the patient experienced symptoms of appendicitis around 6 months after being initiated on a GLP-1 RA. We used the Naranjo Scale in an attempt to establish causality between GLP-1 RAs and appendicitis based on the information afforded to us at the time. In the context of this case, the scale resulted in a score of 4, signifying a “possible” connection. ¹⁷ Further studies are necessary to determine whether there are any temporal or patient-specific patterns of appendicitis after GLP-1 RA initiation.

The FAERS public dashboard is a tool for patients and their health care providers to report adverse effects they have experienced directly to the FDA. As of June 30, 2023, there have been 169 cases of appendicitis and related conditions or procedures associated with GLP-1 RAs reported, 31 of which were reported in 2023 alone. ¹⁵ This is a notable increase in comparison with 2022, in which 29 cases were reported during the entire calendar year. ¹⁵ Exenatide products made up 57 of the cases, 40 semaglutide products, 31 with liraglutide products, 25 dulaglutide products, and 11 with suspected tirzepatide cause. ¹⁵ The increase in reported appendicitis cases may be attributed to an increase in GLP-1 RA prescribing. Since February 2022, Ozempic prescriptions have increased by 111%. ¹ In addition, the prescription weight loss market surpassed its 2022 forecasted growth by 72% and is expected to be a $1.9 billion market in 2023. ¹

Conclusion

Our patient recently started the GLP-1 RA, semaglutide, as an adjunct therapy for her diabetes management ahead of her appendicitis diagnosis. Her imaging studies were notable for stool mass in the colon as well as the cecum located directly next to the vermiform appendix which was inflamed. As previously mentioned, appendicitis etiology is not fully understood, but fecalith and subsequent increased intraluminal pressure of the surrounding area may result in inflammatory and infectious processes such as the case described herein. Gastrointestinal side effects, particularly constipation, are hallmark adverse reactions associated with this class of medications and it may be hypothesized that chronic suffering from such could ultimately lead to acute appendicitis symptoms. For our particular patient, she also had gastroparesis, which may have further increased her risk.

With the knowledge collected from this case and the associated literature search, we recommend that caution of these agents be used when determining whether patients with gastrointestinal histories such as constipation, gastroparesis are present. In patients who are started and begin to suffer from gastrointestinal side effects, it may be more prudent to either stop the GLP-1 RA or treat the symptoms associated with reduced gastric motility in an effort to prevent acute conditions such as that described today. The many benefits of GLP-1 RAs (ie, weight loss, cardioprotection, renal benefits) make these agents increasingly popular among patients with and without diabetes. This case highlights the importance of providers and pharmacists assessing the risk of drug-induced effects and weighing the risks versus benefits in starting patients on these medications despite the increasing popularity for use.

While the Naranjo score for association does not prove causality, it was interesting to identify that there were in fact incidences of appendicitis occurring in clinical trials but not published in final manuscripts given the small sample affected. Furthermore, nonregulated online forums and forms of social media have indicated an increased commentary around similar adverse events shortly after starting these agents. While the verbiage and details of these cases are less than ideal for investigation, it is an interesting concept to broach as more of society turns to Internet forums for camaraderie surrounding disease states and related experiences. Prescribers and pharmacists are urged to educate patients on the potential side effects of these agents and report adverse events to the FAERS database to establish the potential for causation in the future.