Glucagon-like peptide 1 receptor agonists (GLP-1RAs) were first developed to treat diabetes but are now a popular weight-loss drug—and a media lightning rod. Despite exhibiting impressive weight loss, users of GLP-1RAs, such as semaglutide and liraglutide, are at increased risk for gastrointestinal adverse events, including gastroparesis, biliary disease, pancreatitis, and bowel obstruction. 

 

Risks quantified

 

Researchers publishing in JAMA reported on a study of GI adverse effects with GLP-1RAs taken for weight loss.

Sodhi M, Rezaeianzadeh R, Kezouh A, et al. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA. 2023;330(18):1795–1797.

The study cohort consisted of 4,144 liraglutide users, 613 semaglutide users, and 654 bupropion-naltrexone users (the active comparator).

 

Adjusted HRs for increased risk of pancreatitis, bowel obstruction, and gastroparesis were 9.09, 4.22, and 3.67, respectively. That for biliary disease was 1.50. Excluding hyperlipidemia did not change the results, and BMI was not a confounding variable.

 

Gastroparesis

 

This condition can be caused by prolonged diabetes and in these cases is irreversible. Drugs including proton pump inhibitors, anti-Parkinson medications, opioids, and GLP-1RAs can cause reversible cases of gastroparesis. Specialists should distinguish reversible from irreversible causes of gastroparesis based on etiology. 

Authors writing in the Journal of Investigative Medicine High-Impact Case Reports note the difficulty in making this distinction.

Kalas MA, Galura GM, McCallum RW. Medication-induced gastroparesis: a case report. J Investig Med High Impact Case Rep. 2021 Jan-Dec;9:23247096211051919.

 

“However, in diabetics, it can be tricky owing to the fact that both diabetes and GLP-1 receptor agonists (an agent for diabetes management) can cause delayed GE [gastric emptying]; hence, the timeline of drug initiation and symptom onset becomes of the utmost importance. Glucagon-like peptide-1 receptor agonists act through the incretin receptors, which results in glucose-dependent insulin secretion and a decrease in glucagon release."

Furthermore, GLP-1 receptor agonists inhibit the motility of the stomach antrum and the duodenum in addition to pyloric contraction which slows GE.

Although GLP-1RAs can cause delayed GE, experts suggest that long-acting forms (ie, weekly dosing) are not linked with delayed GE because of tachyphylaxis and improvement of GE with continued use. Moreover, GLP-1 agonists depend on the baseline rate of GE; they have little or no effect on diabetes patients with pre-existing gastroparesis. 

 

Pancreatitis

 

Randomized clinical trials have identified a small increased risk of acute pancreatitis in patients taking GLP-1RAs, which is why these drugs are generally avoided in patients with a history of the disease.

The overall rate of recurrent acute pancreatitis among these patients was 9.9%, which is similar to the general overall rate of recurrent acute pancreatitis in the literature of 12.7%.

“While caution needs to be exercised, our data would support the use of GLP-1RA in patients with a history of acute pancreatitis, on an individualized basis, where the benefits are considered to outweigh the risks,” the authors stated.

Johns Hopkins investigators identified a causal link between hospitalization for acute pancreatitis and the use of GLP-1RAs, confirming results from earlier studies.

Singh S, Chang HY, Richards TM, et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173(7):534–539.

They theorized that the link could be due to  increased levels of serum lipase and serum amylase elicited by the drug, although more research is needed to flesh out such a hypothesis.

 

 

Bowel obstruction

 

An increased risk of intestinal obstruction has been noted in diabetic patients taking GLP-1RAs long-term. These patients are at a 4.5 times higher risk of this adverse event vs patients taking other types of medications for glucose control. The risk of intestinal obstruction increases over time, with the highest rates of occurrence at 1.6 years following the initiation of GLP-1RAs. Clinical trials of these drugs, however, usually do not last for more than 1 year.

Chinese researchers called attention to the problem of intestinal obstruction in a letter to the editor of Acta Pharmaceutica Sinica B.

Lu J, Liu H, Zhou Q, et al. A potentially serious adverse effect of GLP-1 receptor agonists [letter]. Acta Pharm Sin B. 2023;13(5):2291–2293.

 

Long-term upper-intestinal obstruction could result from several factors, such as the use of doses in excess of physiological levels of GLP-1, or the use of GLP-1RA agents with longer half-lives (ie, 6–24 hours) than native GLP-1 (ie, 1–2 minutes). The simultaneous secretion of GLP-1 and glucagon-like peptide-2 (GLP-2) in equal amounts under normal conditions could also play a role. 

“Long-term application of GLP-1RAs may also elevate the release of endogenous GLP-2, which is a cell-specific growth hormone regulating the growth of the small intestine, colonic villi and crypts, increasing the length and weight of the small intestine, and reducing antral motility,” they stated.