Letter: Statins for Cirrhosis: Are We Ready to Move From Cardiovascular Prophylaxis to Portal Pressure Management?

I read with great interest the recent systematic review and meta-analysis by Moraes et al. regarding the role of statin therapy in patients with liver cirrhosis [1]. This comprehensive analysis of 25 studies and over 80,000 patients provides timely evidence on a long-debated topic in hepatology: the transition of statins from “contraindicated” agents to potentially disease-modifying therapies in advanced liver disease. The authors' findings, specifically the significant reduction in all-cause mortality (OR 0.59 [95% CI: 0.48–0.71]) and the mechanistic support of hepatic venous pressure gradient (HVPG) reduction in RCTs, align with an evolving paradigm shift [1]. However, as summarised in Table 1, a notable discrepancy remains between these robust findings and the conservative stances maintained by major international societies [2-4]. The discrepancy between the robust mortality benefits observed in this meta-analysis and the cautious recommendations in current guidelines likely stems from the heterogeneity of the cirrhotic population. While the pleiotropic effects of statins on the hepatic microcirculation, particularly their role in ameliorating sinusoidal endothelial dysfunction via the Krüppel-like factor 2 (KLF2) pathway, offer a compelling rationale for disease modification, defining the precise clinical ‘sweet spot’ remains a challenge [5]. Furthermore, the significant survival benefit must be interpreted through the lens of ‘competitive risk’. In observational cohorts, patients prescribed statins often have lower MELD scores or more stable profiles. This ‘healthy user bias’ might overstate the liver-specific benefit. It is telling that the effect on clinical decompensation in this meta-analysis did not reach significance in the RCT subgroup (OR 0.75; 95% CI: 0.52–1.09) [1]. Safety remains the final hurdle. The LIVERHOPE-SAFETY trial demonstrated that high-dose simvastatin (40 mg) in decompensated patients was associated with increased rhabdomyolysis [6]. Current society perspectives thus suggest a ‘start low, go slow’ approach, typically capping simvastatin at 20 mg/day. In conclusion, Moraes et al. provide compelling evidence that statins may reduce mortality and portal pressure. However, until we have large-scale RCT evidence that accounts for competitive risks and defines safety thresholds in decompensated patients, statins will likely remain an ‘adjunctive’ rather than ‘primary’ therapy in our guidelines. Abdulrahman Ismaiel: conceptualization, investigation, writing – original draft, visualization, writing – review and editing, data curation, supervision. The author has nothing to report. This article is linked to Moraes et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70526 and https://doi.org/10.1111/apt.70599. The author has nothing to report.