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An analysis of FDA's reporting system for adverse events turned up three dozen cases of acute gallbladder disease in patients taking glucagon-like peptide-1 (GLP-1) receptor agonists for diabetes or weight loss, including three deaths.

From 2005 to 2016, postmarketing cases of acute cholecystitis were identified in 21 patients taking exenatide (Byetta), in seven taking dulaglutide (Trulicity), in seven on semaglutide (Ozempic), and in one patient taking lixisenatide (Adlyxin), reported Daniel Woronow, MD, and colleagues from the FDA in Silver Spring, Maryland.

Thirty of the cases were treated with cholecystectomy and two resolved with ursodeoxycholic acid treatment and discontinuation of the GLP-1 receptor agonist. Of the three patients who died, two had pancreatitis and one died from fatal liver necrosis.

In 42% of the cases, patients experienced disease onset within 90 days from the time of treatment initiation, according to the findings in .

The case series complements results of a recent meta-analysis of 76 randomized trials that detected an association between cholecystitis and GLP-1 receptor agonists, the group said, explaining that "potential mechanisms include weight loss, suppression of cholecystokinin secretion, and reduced gallbladder emptying."

Prescribing information in the U.S. for these products "has recently been revised to include warnings and precautions about this risk," the group noted, based on the "mechanistic plausibility," along with the small-yet-consistent imbalances of acute gallbladder events in placebo-controlled trials of GLP-1 receptor agonists and the current series from the .

Woronow's group explained that at the time of initial approval, only some GLP-1 receptor agonists for glycemic control in type 2 diabetes carried warnings about the risk for acute gallbladder disease, while others did not. To assess the risk in the latter group of agents in the class, staff at the agency conducted an analysis of FAERS to look for cases of acute cholecystitis linked to GLP-1 receptor agonists starting from the time of the first approval in 2005 through 2016.

In total, 36 cases of acute cholecystitis were identified based on pathology reports, diagnosis by a healthcare provider, or compatible signs and symptoms treated with cholecystectomy. Excluded from the analysis were patients with cholelithiasis or cholecystitis prior to use of a GLP-1 receptor agonist, or cases where an alternative cause of cholecystitis was suspected.

Nine patients had weight loss before their diagnosis (mean 7.6 kg [16.8 lb] in cases where the weight loss was recorded). Two patients were also receiving fenofibrate, which comes with a labeled warning of cholelithiasis.

Median patient age was 55, and 53.1% of the cases involved women. Thirty-three of the patients were taking the drugs for type I or II diabetes, with the remaining taking the drug for weight loss. Overall, 21 patients were overweight or obese, 19 had hyperlipidemia, six had non-alcoholic fatty liver disease, and one had periportal fibrosis.

Fourteen of the cases were in patients who received the recommended starting dose of GLP-1 receptor agonist, another 14 were in those on the maximum recommended dose, four were receiving a dose somewhere in between, and the dose was unknown in the other cases.

Time to disease onset was shorter in those on the starting dose compared to patients on the maximum recommended dose (mean 49 days vs 16 months, respectively).

Woronow and co-authors acknowledged limitations to the analysis, including the potential for underreporting in FAERS, along with differences in product marketing times and market shares.

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