US FDA Study Discovers That Diabetics Taking GLP-1 Receptor Agonists Drugs Have Higher Risk Of Acute Cholecystitis

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Medical researchers from the U.S FDA have discovered that diabetics taking glucagon-like peptide-1 (GLP-1) receptor agonists drugs like exenatide, dulaglutide, semaglutide and lixisenatide have a higher risk of developing acute cholecystitis and even higher risk of death.

The study findings were published as a research letter in the peer reviewed journal: JAMA Internal Medicine.
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2795476

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 JAMA Internal Medicine.

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 FDA Adverse Event Reporting System (FAERS).

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.


Glucagon Like Peptide 1 Receptor Agonists

Glucagon like peptide-1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin release, suppresses glucagon secretion, inhibits gastric emptying, and supresses appetite. Plasma levels of GLP-1 are low in a fasted state and increase rapidly after eating. Circulating levels of intact GLP-1 decrease quickly through dipeptidyl peptidase-4 (DPP-4) enzymatic degradation and renal clearance [1]. GLP-1 plays a crucial role in glucose regulation and acts on GLP-1 receptors expressed in α and β pancreatic islet cells and in peripheral tissue.
GLP-1 based therapies (GLP1-RA and DPP-4 inhibitors) affect glucose control through several mechanisms, including enhancement of glucose-dependent insulin secretion, delayed gastric emptying and reduction of postprandial glucagon and food intake [2].

GLP1-RA are synthetic agents that are less resistant to degradation by DPP-4 and therefore have a space in clinical use for T2DM and obesity. In comparison with placebo, all GLP1-RA reduced glycated haemoglobin (HbA1c) by 0.55-1.38% in patients with T2DM [2]. GLP1-RA are also associated with a reduction in: weight, atherosclerotic cardiovascular events, and progression of diabetic renal disease independent of glycaemic control. When used in T2DM they are less likely to cause hypoglycaemia compared to other classes of glucose lowering medicines [2].

reference

  1. Drucker DJ, Nauck MA. 2006. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368(9548):1696-1705. DOI: 10.1016/S0140- 6736(06)69705-5 (accessed 17 December 2021).
  2. Dungan L, DeSantis A. 2022. Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus. In: UpToDate 18 January 2022. URL: uptodate.com/contents/glucagon-like-peptide- 1-receptor-agonists-for-the-treatment-of-type-2-diabetes-mellitus (accessed 19 January 2022).

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