Renin–angiotensin–aldosterone system inhibitors and risk of pancreatic cancer in older adults: A target trial emulation

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality worldwide. Preclinical studies suggest that the renin-angiotensin-aldosterone system (RAAS) inhibitors may help prevent PDAC by promoting acinar ductal metaplasia reversal, as the RAAS pathway is most inhibited during this process. Our study aims to examine the association between RAAS inhibitor use and the risk of PDAC compared with calcium channel blockers (CCB). Leveraging the target trial emulation framework, we used US Medicare data to emulate a new user, active comparator trial examining the effects of initiating RAAS inhibitors (exposure group) versus CCB (control group), with randomization emulated by propensity score matching with 2:1 ratio. Eligible patients were aged >65 years without malignant cancer or palliative care. Outcomes included PDAC and all-cause mortality. Cox proportional hazards models with inverse probability censoring weight were applied. After propensity score matching, our study included 214,262 patients who initiated RAAS inhibitors and 107,131 patients who initiated CCB, with mean ages of 76.5 and 77.0 years, respectively, and a similar proportion of women (60.9% vs. 61.8%) between two groups. During follow-up, the incidence of PDAC was significantly lower in the RAAS inhibitor group than in the CCB group, corresponding to a 46% reduction in PDAC risk (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.49-0.59). Similarly, all-cause mortality was 22% lower among RAAS inhibitors users compared with CCB users (HR: 0.78, 95% CI: 0.77-0.79). These findings warrant further investigation into RAAS inhibitors' potential benefits, including identification of confounding factors like genetics and biomarkers.