Spotlight on digestive risks of newer diabetes drugs

Recent studies focused on the association between newer diabetes drugs and the development of digestive diseases, including acute cholecystitis.

A systematic review and meta-analysis found that glucagon-like peptide-1 (GLP-1) receptor agonists are associated with higher risks of four kinds of digestive diseases, whereas no association was seen with sodium-glucose cotransporter-2 (SGLT-2) inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors. Researchers included 21 randomized trials of SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, and the outcomes of interest were 91 different digestive diseases (75 GI disorders and 16 kinds of hepatobiliary disorders). Results were published Aug. 26 by Medicine.

Compared with placebo, GLP-1 receptor agonists were associated with higher risks of gastric ulcer hemorrhage (risk ratio [RR], 2.68 [95% CI, 1.07 to 6.68]; P=0.035), pancreatitis (RR, 1.48 [95% CI, 1.02 to 2.15]; P=0.41), acute cholangitis (RR, 5.96 [95% CI, 1.04 to 34.08]; P=0.045), and acute cholecystitis (RR, 1.52 [95% CI, 1.08 to 2.15]; P=0.017). The drug class was not significantly associated with the occurrence of the other 87 kinds of digestive diseases (range for P values, 0.064 to 0.999). SGLT-2 inhibitors and DPP-4 inhibitors were not significantly associated with the occurrence of 91 kinds of digestive diseases versus placebo (range for P values, 0.077 to 0.995 and 0.085 to 0.999, respectively).

The main limitation of the meta-analysis was the limited numbers of occurrences of various digestive diseases, which attenuated its power, the authors noted. “These findings seem to suggest that GLP1 [receptor agonists] are not applicable for patients at high risk of 4 specific digestive diseases whereas SGLT2 [inhibitors] and DPP4 [inhibitors] are safe for patients susceptible to digestive diseases,” they wrote. “However, our findings require to be further verified by future studies with sufficient statistical power.”

The second study, a case series, identified cases of acute cholecystitis associated with use of GLP-1 receptor agonists that did not have warnings and precautions regarding acute gallbladder disease. Researchers from the FDA reviewed the FDA Adverse Event Reporting System (FAERS) from April 28, 2005, the FDA approval date for exenatide (the first approved GLP-1 receptor agonist), through Sept. 16, 2021, to identify the cases. Criteria for acute cholecystitis included compatible signs and symptoms treated with cholecystectomy, a confirmatory pathology report, or diagnosis by a health care practitioner. The researchers excluded cases if there was history of either cholelithiasis or cholecystitis preceding GLP-1 receptor agonist use, if there was insufficient information to confirm the diagnosis of acute cholecystitis or to determine the temporal association with use of a GLP-1 receptor agonist, or if an alternative cause was considered likely. Results were published as a research letter on Aug. 29 by JAMA Internal Medicine.

The case series included 36 cases of acute cholecystitis associated with exenatide (n=21), dulaglutide (n=7), semaglutide (n=7), and lixisenatide (n=1). Patients had a median age of 55 years (range, 14 to 85 years), and 19 (53.1%) were female. Comorbidities included diabetes (n=33), overweight or obesity (n=21), hyperlipidemia (n=19), nonalcoholic fatty liver disease (n=6), and periportal fibrosis (n=1). Cholecystectomy occurred in 30 cases. Two cases resolved with ursodeoxycholic acid treatment and GLP-1 receptor agonist discontinuation, one patient had an unrelated cerebrovascular accident and therefore no cholecystectomy was scheduled, and one patient died within 24 hours of cholecystitis presentation, prior to undergoing surgery (an autopsy reported coronary artery disease, cholelithiasis, and hemorrhagic pancreatitis). Surgical status was unknown in two cases. All cases reported a serious outcome, including pancreatitis (n=7, including two deaths) and fatal liver necrosis (n=1, although there was confounding with prior fatty liver disease and possible thalassemia minor). Time from GLP-1 receptor agonist initiation to onset of acute cholecystitis was less than 90 days in 47% of cases. Acute cholecystitis occurred in 14 patients taking the recommended starting dose of the GLP-1 receptor agonist and in 14 patients taking the maximum recommended dose, with time to onset tending to be shorter for patients in the former group (mean, 49 d [range, 4 to 150 d] vs. 16 mo [range, 2 wk to 4 y), as nearly all patients on the higher dose were titrated up from the recommended starting dose.

Potential mechanisms of the association of cholecystitis with GLP-1 receptor agonists include weight loss, suppression of cholecystokinin secretion, and reduced gallbladder emptying, the study authors noted. Limitations of the study include the fact that the data were possibly influenced by underreporting, the time a drug product was marketed, and differences in market share, they said.

“Based on the mechanistic plausibility, small but consistent imbalances in clinical trials in acute gallbladder events in GLP-1 [receptor agonist]– vs placebo-treated groups, and cases reported in FAERS, the US Prescribing Information regarding GLP-1 [receptor agonist] products indicated for glycemic control has recently been revised to include warnings and precautions about this risk and also include product-specific data on acute gallbladder disease event rates compared with placebo from clinical studies,” the authors wrote.