Be Aware of Gallbladder, Biliary Disease With Newer Obesity Drugs

Marlene Busko

March 28, 2022

Treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist was associated with a 37% increase in the relative risk of gallbladder or biliary disease compared with controls — especially when used at high doses, for a longer time, and for weight loss rather than type 2 diabetes — a new meta-analysis has found.

The results "indicate that physicians and patients should be concerned about the risks of gallbladder or biliary diseases with using GLP-1 agonists," study authors Liyun He and colleagues from Peking Union Medical College, Beijing, China, summarize.

However, "the overall absolute risk increase for gallbladder and biliary disease with use of GLP-1 receptor agonists was small (an additional 27 cases per 10,000 persons treated per year)," they note.

"This absolute risk increase should be weighed against the benefits of treatment with GLP-1 agonists," which include glucose control, decreased cardiovascular risk, and weight loss, they add.

The findings are from a meta-analysis of 76 randomized controlled trials of GLP-1 agonists published online March 28 in JAMA Internal Medicine.

Writing in an accompanying editorial, Shanzay Haider, MD, and Kasia J. Lipska, MD, also characterize the absolute risk of these complications as "modest."

"The highest risk for these complications," they add, "occurred among individuals in the weight loss compared with the type 2 diabetes studies (119 vs 13 more events per 10,000 persons per year)."

"Ultimately, the decision to start, continue, or change the dose of a GLP-1 agonist should be reached through a collaborative and individualized discussion between a clinician and a patient," Haider and Lipska, from Yale School of Medicine, New Haven, Connecticut, summarize.

The study authors also note that few of the trials reported biliary-related events.

"Future trials [of drugs in this class] should prespecify gallbladder and biliary diseases as potential adverse events, and fully test for and report on these outcomes," they urge.   

Certain drugs in this class are now approved by the US Food and Drug Administration for weight loss at higher doses than for type 2 diabetes — subcutaneous liraglutide (3.0 mg) and subcutaneous semaglutide (2.4 mg) — "suggesting that GLP-1 agonist drugs will increasingly be used at high doses for weight control," the authors note.

Controversial Link

The association between GLP-1 agonists and gallbladder or biliary disease is controversial, the authors write.

Several randomized controlled trials reported higher rates of gallbladder disorders in patients who received a GLP-1 agonist versus placebo, but it is not clear if this is a class effect.

Liraglutide "has drawn the most attention" about this risk, and a post-hoc analysis of the LEADER trial found a significantly increased risk of acute biliary obstruction with liraglutide versus placebo.

To investigate this, the researchers identified 76 randomized controlled trials of GLP-1 agonists in 103,371 patients that had data for the following safety outcomes: cholelithiasis (gallstones, 61 trials), cholecystitis (inflamed gallbladder, 53 trials), biliary disease (21 trials), cholecystectomy (surgical removal of the gallbladder, seven trials), and biliary cancer (12 trials).

Sixty trials were for type 2 diabetes, 13 were for weight loss, and three were for nonalcoholic steatohepatitis, polycystic ovary syndrome, and schizophrenia. They were classed as short or long (≤ 26 weeks or > 26 weeks).

The GLP-1 agonists were liraglutide (21 trials), subcutaneous semaglutide (14), dulaglutide (11), exenatide (9), albiglutide (8), oral semaglutide (8), and lixisenatide (6). 

Participants were a mean age of 58 years and 41% were women. They had a mean BMI of 31.6 kg/m2 and 36.9 kg/m2 in trials of GLP-1 agonists for type 2 diabetes and weight loss, respectively.  

Patients who received a GLP-1 agonist versus controls had significantly increased rates of cholelithiasis (RR, 1.27; P = .001), cholecystitis (RR, 1.36; P < .001), biliary disease (RR, 1.55; P = .02), and cholecystectomy (RR, 1.70; P < .001), but a nonsignificant increased rate of biliary cancer (RR, 1.43; P = .22).

Use of GLP-1 agonists was associated with a greater increased risk of gallbladder or biliary diseases in trials for weight loss (RR, 2.29) than in trials for type 2 diabetes or other diseases (RR, 1.27; P < .001 for interaction).

Use of these drugs was also associated with higher risks of these complications at higher doses and when given for a longer duration.     

Limitations of the meta-analysis include that the individual studies were not designed to evaluate the risk of gallbladder or biliary diseases associated with GLP-1 agonists.

Also, biliary-related events may have been under-reported, because this was not a predefined safety outcome in most of the trials. The meta-analysis lacked patient-level data, and it may have been underpowered for subgroup analyses.       

The work was supported by grants from the National Natural Science Foundation of China, the Beijing Municipal Natural Science Foundation, the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences, the CAMS Innovation Fund for Medical Sciences, and the Training Program for Excellent Talents in Dongcheng District. The researchers have no relevant financial disclosures.

JAMA Intern Med. Published online March 28, 2022. Article, Editorial

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