Silver Spring, MD—Prescribing information related to GLP-1 RAs indicated for glycemic control has recently been revised by the FDA to include warnings and precautions about acute gallbladder events.

The information also now includes product-specific data on acute gallbladder disease event rates compared with placebo from clinical studies, according to a research letter published in the Journal of the American Medical Associate Internal Medicine.

Previously, labeling for some products indicated for glycemic control in patients with type 2 diabetes included warnings and precautions regarding acute gallbladder disease, but others did not. The FDA recently reviewed the Adverse Event Reporting System (FAERS) to identify cases of acute cholecystitis (AC) associated with the GLP-1 RA products that did not have warnings and precautions regarding acute gallbladder disease, according to the agency-led study.

The authors said they reviewed FAERS from April 28, 2005 (the initial FDA approval date for exenatide—the first approved GLP-1 RA), through September 16, 2021, looking for any cases of AC associated with GLP-1 RA use.

The review team used the following criteria for AC:

• Compatible signs and symptoms treated with cholecystectomy
• A confirmatory pathology report, or
• AC diagnosed by a healthcare practitioner.

The cases excluded were those with a history of either cholelithiasis or cholecystitis preceding GLP-1 RA use, if there was insufficient information to confirm the diagnosis of AC or to determine the temporal association with the use of a GLP-1 RA, or if an alternative etiology was considered the likely cause of AC.

The FDA team said it identified 36 postmarketing cases of AC with exenatide (n = 21), dulaglutide (n = 7), semaglutide (n = 7), and lixisenatide (n = 1). For those patients, median age was 55 years and 53.1% were female.

Cholecystectomy occurred in most of the cases (30). Of the others, two cases resolved with ursodeoxycholic acid treatment and GLP-1 RA discontinuation; another case had an unrelated cerebrovascular accident, and as a result, no cholecystectomy was scheduled; and a third case died within 24 hours of cholecystitis presentation, prior to undergoing surgery (the autopsy reported coronary artery disease, cholelithiasis, and hemorrhagic pancreatitis). The reviewers did not know the surgical status in two cases.

"All cases reported a serious outcome, including pancreatitis (n = 7, including 2 deaths), and fatal liver necrosis (n = 1, although there was confounding with prior fatty liver disease and possible thalassemia minor)," the study noted.

In 24 of the patients, the median (range) patient weight was 94 (56-201) kg; nine patients reported recent weight loss, with a mean (range) of 7.6 kg (2.3-16.0) kg for seven patients of whom weight loss was recorded.

The reviewers pointed out that the time from GLP-1 RA initiation to onset of AC was fewer than 90 days in 47% of the cases. "Acute cholecystitis occurred in 14 patients taking the GLP-1 RA recommended starting dose and in 14 patients taking the maximum recommended dose (n = 14)," they explained. "Time to onset tended to be shorter for patients taking the recommended starting dose (mean [range], 49 [4-150] days) compared with patients taking the maximum recommended dose (mean [range], 16 months [2 weeks to 4 years]), as almost all patients on the higher dose were titrated up from the recommended starting dose."

In addition, the reviewers noted that two patients reported the use of fenofibrate, which carries a warning of cholelithiasis in the prescribing information of its package insert.

The patients had a range of comorbidities, including 33 patients with diabetes, 21 patients who were overweight or had obesity, 19 patients with hyperlipidemia, six patients with nonalcoholic fatty liver disease, and one patient with periportal fibrosis.

The authors wrote that the case series provided patient-level data to support a Chinese meta-analysis published earlier this year in the same journal. It found that potential mechanisms for the association of cholecystitis with GLP-1 RAs included weight loss, suppression of cholecystokinin secretion, and reduced gallbladder emptying.

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