(053) Incretin-based drugs and the risk of gallbladder or biliary tract diseases among patients with type 2 diabetes across categories of body mass index: A nationwide cohort study

Background: Despite the growing evidence of risks for gallbladder or biliary tract diseases (GBD) associated with incretin-based drugs (dipeptidyl-peptidase 4 inhibitors [DPP4i] and glucagon-like peptide 1 receptor agonists [GLP1RA]), population-specific safety profile considering obesity is lacking.

Objectives: To assess whether stratification by body mass index (BMI) at baseline modifies the measures of association between each incretin-based drug and the risk of GBD compared to sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients with T2D.

Methods: Pursuing the target trial emulation framework, we used nationwide claims data of Korea (2010.01-2022.12) to construct two active-comparator, new-user cohorts of T2D patients stratified by Asian BMI categories: Normal, 18.5 to <23 kg/m2; Overweight, 23 to <25 kg/m2; Obese, ≥25 kg/m2. Each cohort compared DPP4i and GLP1RA with SGLT2i, respectively (DPP4i vs. SGLT2i; GLP1RA vs. SGLT2i). The primary outcome was a composite of GBD, including cholelithiasis, cholecystitis, obstruction of the gallbladder or bile duct, cholangitis, and cholecystectomy. We used 1:1 propensity score (PS) matching to balance treatment groups and estimated PS-matched hazard ratios (HR) with 95% confidence intervals (CI) using Cox models.

Results: For the first cohort (DPP4i vs. SGLT2i), a total of 1,619,901 and 252,037 new users of DPP4i and SGLT2i were identified, respectively, with a mean age of 59.8 years. In total, 251,420 pairs were 1:1 PS matched; 186,697 obese, 39,974 overweight, and 24,749 normal weight pairs. Over a mean follow-up of 2.0 years, the risk of GBD increased with DPP4i vs. SGLT2i in total cohort (HR 1.21, 95% CI 1.14-1.28), obese (1.20, 1.13-1.29), and overweight groups (1.26, 1.09-1.47), while normal group showed no increased risk (1.17, 0.97-1.42) (p for homogeneity: 0.83). For the second cohort (GLP1RA vs. SGLT2i), a total of 45,457 and 728,047 new users of GLP1RA and SGLT2i were identified, with a mean age of 57.4 years. Of these, 45,443 pairs were 1:1 PS matched; 28,011 obese, 8,948 overweight, and 8,484 normal weight pairs. During a mean follow-up of 1.3 years, the risk of GBD increased with GLP1RA vs. SGLT2i in total cohort (1.27, 1.07-1.50) and obese (1.24, 1.01-1.54) group. The risk was not significant in overweight (1.19, 0.82-1.73) and normal (1.46, 0.98-2.18) groups (p for homogeneity: 0.73).

Conclusions: In this nationwide cohort study, the increased risks of GBD were presented in both cohorts with no evidence of effect heterogeneity by BMI status. Prescribers should be aware of GBD risks when using incretin-based drugs among T2D patients regardless of BMI status.