Abstract
Real-world evidence assessing dipeptidyl peptidase-4 inhibitors (DPP4i)'s risk of inflammatory bowel disease (IBD) is conflicting. One study modeling DPP4i as a time varying exposure (TVE) observed a harmful effect in a UK population, while an active comparator new-user (ACNU) study observed a null effect in a US population. To assess the impact of study design in estimating treatment effect, we implemented both designs in the UK Clinical Practice Research Datalink population from 2007 to 2022. We conducted three ACNU analyses: DPP4i vs sulfonylureas (SU) (43 204 vs 86 411), DPP4i vs thiazolidinediones (TZD) (67 288 vs 22 474), and DPP4i vs sodium-glucose transport protein 2 inhibitors (SGLT2i) (54 253 vs 30 993). The propensity score adjusted hazard ratios (aHRs) for DPP4i were 1.12 (95% CI, 0.83-1.50) vs SU, 1.15 (0.66-2.01) vs TZD, and 1.43 (0.83-2.48) vs SGLT2i, over a median follow-up of 2.2 to 6.1 years. In TVE analyses, patients who switched from the comparator to DPP4i were censored at switching and accrued person-time on DPP4i thereafter. We observed similar or higher aHRs for DPP4i vs SU 1.06 (0.80-1.41), TZD 1.76 (0.84-3.78), and SGLT2i 1.62 (0.91-2.90). Our findings suggest DPP4i does not increase IBD risk and emphasize the crucial role of study design in assessing treatment effect.