Renin-angiotensin-aldosterone system inhibitor use improves clinical outcomes in patients with metabolic dysfunction–associated steatotic liver diseases: Target trial emulation using real-world data

Background and Aims: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) prevent fibrosis progression in a preclinical model of steatotic liver disease. Our objective was to assess the impact of ACEi/ARB use on clinical outcomes in patients with metabolic dysfunction–associated steatotic liver diseases. Approach and Results: Using TriNetX, a nationwide database, we identified all patients with metabolic dysfunction–associated steatotic liver diseases from January 1, 2011, to December 31, 2019. Using a target trial emulation framework, ACEi/ARB users were matched with calcium channel blocker (CCB) users using propensity score matching (PSM). Patients were followed up to 10 years after the index date. Cox proportional hazards regression was used to determine the risk of mortality, major adverse liver outcomes, major adverse cardiac events, and incident cancers. Of the 35,988 eligible patients, 28,423 were ACEi/ARB users, and 7565 were CCB users. After PSM, 7238 pairs were well-balanced. ACEi/ARB use was associated with a significantly decreased mortality risk (HR: 0.59, 95% CI: 0.51–0.68). ACEi/ARB was associated with a significantly reduced risk of developing major adverse liver outcomes (HR: 0.70, 95% CI: 0.61–0.80), including ascites (HR: 0.78, 95% CI: 0.63–0.98) and HE (HR: 0.67, 95% CI: 0.57–0.78). ACEi/ARB use was also associated with a lower risk of major adverse cardiac events (HR: 0.82, 95% CI: 0.76–0.90) but not incident cancer (HR: 0.97, 95% CI: 0.86-1.10) compared with CCB. Conclusions: ACEi/ARB use in patients with metabolic dysfunction–associated steatotic liver diseases was associated with a reduced risk of mortality, major adverse liver outcomes, and major adverse cardiac events compared with CCB use. A large prospective study is needed for external validation.