A nationwide cohort study found that patients with type 2 diabetes who take incretin-based drugs had a significantly increased risk of gallbladder and biliary tract diseases compared with those using sodium-glucose cotransporter 2 inhibitors.
In their study published in The Lancet Regional Health – Western Pacific, the researchers analyzed more than 1.8 million patients using South Korea's National Health Insurance Service data and found that the increased risk remained significant across body mass index (BMI) categories.
The investigators employed a target trial emulation design with 1:1 propensity score matching to balance baseline characteristics. The study stratified patients by BMI into normal-weight (18.5 kg/m² to less than 23 kg/m²), overweight (23 kg/m² to less than 25 kg/m²), and obese (at least 25 kg/m²) categories. Follow-ups averaged 1.3 years for glucagon-like peptide-1 receptor agonists (GLP-1 RA) users and 2 years for dipeptidyl peptidase-4 inhibitors (DPP4i) users.
Compared with sodium-glucose cotransporter 2 inhibitors, DPP4is were associated with an increased gallbladder or biliary tract disease (GBD) risk in the total cohort (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 1.14–1.28), particularly among patients with overweight (HR = 1.26; 95% CI = 1.09–1.47) and obesity (HR = 1.20; 95% CI = 1.13–1.29). Similarly, GLP-1 RAs were linked to elevated risk in the total cohort (HR = 1.27; 95% CI = 1.07–1.50) and the obese subgroup (HR = 1.24; 95% CI = 1.01–1.54). The number needed to harm over 5 years was 198 for obese, 248 for overweight, and 141 for normal-weight patients on GLP-1 RAs.
The researchers noted that while obesity is a known risk factor for gallstone formation, the data suggest that the increased GBD risk associated with incretin-based drugs is not significantly modified by BMI. Potential biological mechanisms include delayed gallbladder emptying and inhibition of cholecystokinin secretion. They emphasized the importance of considering comorbid conditions, such as hypertension and liver disease, when prescribing these therapies.
Despite efforts to minimize bias, the study acknowledged limitations, including potential residual confounding and outcome misclassification.
"Given the increasing usage of incretin-based drugs in routine clinical practice, further studies, including randomized controlled trials that consider the heterogenous nature of individuals with T2D, on the association between the risk of GBD and drugs, would be beneficial," Hwa Yeon Ko of the School of Pharmacy at Sungkyunkwan University in Suwon-si, South Korea and colleagues concluded.
A full list of disclosures can be found in the published study.