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/Aim: 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 (MASLD). Approaches and Results: Using TriNetX, a nationwide database, we identified all patients with MASLD from 01/01/2011 to 12/31/2019. 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 regression was used to determine the risk of mortality, major adverse liver outcomes (MALO), major adverse cardiac events (MACE), and incident cancers. Of the 35988 eligible patients, 28423 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 (Hazard Ratio (HR) 0.59, 95% confidence interval [CI]: 0.51–0.68). ACEi/ARB was associated with a significantly reduced risk of developing MALO (HR 0.70, 95% CI: 0.61–0.80), including ascites (HR 0.78, 95% CI: 0.63–0.98) and hepatic encephalopathy (HR 0.67, 95% CI: 0.57–0.78). ACEi/ARB use was also associated with a lower risk of MACE (HR 0.82, 95% CI: 0.76–0.90) but not incident cancer (HR 0.97, 95% CI: 0.86-1.10) compared to CCB. Conclusions: ACEi/ARB use in patients with MASLD was associated with a reduced risk of mortality, MALO, and MACE compared to CCB use. A large prospective study is needed for external validation.