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A certain class of antidiabetic agent was linked with gallbladder and biliary diseases, researchers reported.

According to a systematic review and meta-analysis of 76 randomized clinical trials, use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were linked with a higher risk of gallbladder or biliary diseases (pooled RR 1.37, 95% CI 1.23-1.52), namely:

• Cholelithiasis: RR 1.27 (95% CI 1.10-1.47)
• Cholecystitis: RR 1.36 (95% CI 1.14-1.62)
• Biliary disease: RR 1.55 (95% CI 1.08-2.22)
• Cholecystectomy: RR 1.70 (95% CI 1.25-2.32)

Although this elevated risk was significant, study authors said to keep in mind that the overall absolute risk increase was rather small, at only an additional 27 cases per 10,000 persons treated per year. "This absolute risk increase should be weighed against the benefits of treatment with GLP-1 RA drugs," Huabing Zhang, MD, of Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, and colleagues wrote in .

The extent of this risk also seemed to vary widely with regards to whether the GLP-1 RA trial was aimed at weight loss versus type 2 diabetes. For example, in the 63 trials where the agent was primarily used for type 2 diabetes or other diseases, there was a 27% higher risk for gallbladder or biliary diseases (RR 1.27, 95% CI 1.14-1.43).

On the other hand, in the 13 trials that were assessing GLP-1 RAs for weight loss -- where the dosage is typically higher -- there was an over two-fold higher risk for these outcomes (RR 2.29, 95% CI 1.64-3.18).

Delving into this further, Zhang's group did confirm that GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR 1.56, 95% CI 1.36-1.78) but not lower doses (RR 0.99, 95% CI 0.73-1.33).

Duration of use also appeared to play a role, as patients who were on a GLP-1 RA for longer stretches of time -- more than 26 weeks -- saw a 40% higher risk for gallbladder or biliary disease (RR 1.40, 95% CI 1.26-1.56). Meanwhile, this relationship was significant for shorter durations of use lasting 26 weeks or fewer (RR 0.79, 95% CI 0.48-1.31).

"Use of GLP-1 RAs may be associated with increased risk of gallbladder or biliary diseases because GLP-1 inhibits gallbladder motility and delays gallbladder emptying by suppressing the secretion of cholecystokinin," the researchers suggested. "In addition, marked weight loss, which occurs in some patients using GLP-1 RAs, has been associated with a high risk of gallbladder disorders."

Zhang's group went on to say that many of these drugs have reported gallbladder disease as a known adverse event, although biliary disease "have seldom been reported."

Shanzay Haider, MD, and Kasia Lipska, MD, MHS, both of Yale School of Medicine in New Haven, agreed that its entirely possible that this risk may actually be attributable to the weight loss associated with GLP-1 RA use.

"The higher-risk signal in GLP-1 RA trials for weight loss indications may be attributable to more weight loss achieved in those trials and/or to the higher doses of GLP-1 RAs typically used for weight loss," they said in an , adding how its also still unclear exactly which patients are most at risk for these complications.

Haider and Lipska added that while slow titration of these agents can help mitigate other unpleasant side effects, like nausea, it should also be tested if that strategy may reduce this risk of gallbladder or biliary disease.

"Ultimately, the decision to start, continue, or change the dose of a GLP-1 RA should be reached through a collaborative and individualized discussion between a clinician and a patient," they recommended.

Zhang and colleagues reported no increased risk of biliary cancer with GLP-1 RA use in their meta-analysis.

The 76 randomized trials included data on 103,371 patients with an average age of 57.8 years.

Risk of gallbladder or biliary disease appeared highest for liraglutide (Saxenda, Victoza), which also made up the largest number of trials. This was followed by dulaglutide (Trulicity) and exenatide (Byetta, Bydureon). Subcutaneous semaglutide (Ozempic, Wegovy), oral semaglutide (Rybelsus), lixisenatide (Adlyxin), and albiglutide (Tanzeum) weren't significantly linked with this outcome.

High doses of GLP-1 RAs were defined as equal to or greater than albiglutide 50 mg once weekly, dulaglutide 1.5 mg once weekly, liraglutide 1.8 mg once daily, subcutaneous semaglutide 1.0 mg once weekly, and oral semaglutide 7 mg once daily.

Low doses were as follows: albiglutide 30 mg (<50 mg) once weekly, dulaglutide 0.75mg (<1.5mg) once weekly, liraglutide 0.6 to 1.2mg (<1.8mg) once daily, subcutaneous semaglutide 0.5mg (<1.0 mg) once weekly, and oral semaglutide 3.0mg (<7.0mg) once daily.

Because exenatide and lixisenatide only have single doses, they were not included in the sub-analysis by dose.

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