Dear Editor,

Alcohol-associated liver disease (ALD) continues to be a major public health challenge, affecting millions of individuals worldwide [1,2]. It ranks as the second most common cause of liver-related mortality globally and remains the leading cause across Europe [2]. Cardiovascular risk factors are common in the general population and are also prevalent among patients with ALD. While statins are widely recognized for their role in both primary and secondary cardiovascular prevention, not all statins are the same [3,4]. Based on solubility, statins are classified as either lipophilic or hydrophilic, and several studies have compared their cardiovascular effects accordingly [3,5]. Beyond lipid-lowering, statins are increasingly acknowledged for their pleiotropic effects, particularly their anti-inflammatory and antifibrotic properties, which are highly relevant in chronic liver diseases [6]. However, no study to date has specifically examined whether the lipophilicity of statins influences liver-related outcomes, particularly in patients with ALD.

This population-based study aimed to assess the association between statin use and the risk of death, major adverse liver outcomes (MALO), major adverse cardiac events (MACE), other cardiovascular outcomes, alcoholassociated hepatitis (AH), and acute pancreatitis among individuals with alcohol-associated liver disease (ALD). The analysis utilized multicenter data from the TriNetX database, which reflects a broad and diverse patient population across various insurance types, socioeconomic backgrounds, ethnicities, and geographic regions [7]. We accessed data through the TriNetX research platform, a federated network providing real-time, anonymized electronic health records. The data were sourced from the Collaborative Network of a U.S.-based healthcare organization (HCO), which includes hospitals, primary care centers, and specialty clinics. These HCOs contribute data from both insured and uninsured patients. TriNetX is a global health-collaborative platform that supports clinical research by aggregating real-time medical data from a wide range of HCOs [8]. Patients with a history of other liver diseases, cancer, or end-stage renal disease were excluded. To minimize confounding, we performed 1:1 propensity score matching (PSM) using nearest-neighbor greedy matching. Matching accounted for demographic variables, comorbidities, pre-index medication use, and relevant laboratory values. Additionally, we matched patients based on their receipt of alcohol use disorder treatment.

The main exposure in this study was statin type, categorized by lipophilicity: atorvastatin, simvastatin, pitavastatin, and fluvastatin were considered lipophilic, while rosuvastatin and pravastatin were classified as hydrophilic [9]. To account for variations in statin types and dosages, equivalent doses were standardized to atorvastatin 10 mg (e.g., rosuvastatin 5 mg, simvastatin 20 mg, pravastatin 40 mg, fluvastatin 80 mg, and pitavastatin 1 mg) [9]. Use of hydrophilic statins was compared to lipophilic statins, which served as the reference group. The index date was defined as the initial prescription date of a statin. Time-to-event outcomes were analyzed using Kaplan–Meier estimates, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. A two-sided P-value <0.05 was considered statistically significant. Patients with prior events of MALO, MACE, or acute pancreatitis were excluded from the analysis, while those with a history of AH were retained. The outcomes were assessed over a 5-year follow-up period.

After propensity score matching, a total of 992 individuals with ALD receiving statin therapy were included in the analysis, with 496 patients each in the lipophilic and hydrophilic statin groups. Baseline demographic, clinical, medication-related, and laboratory characteristics were well balanced between the two groups (Supplementary Table 1). The prevalence of comorbidities, use of concomitant medications (including acamprosate and naltrexone), and key laboratory values were comparable across groups. Propensity scores were also well matched (Supplementary Fig. 1).

Use of hydrophilic statins was not associated with a significantly different risk of MALO compared to lipophilic statins (HR 1.14, 95% CI 0.86–1.49; P=0.134). No significant differences were observed in the risk of AH (HR 1.01, 95% CI 0.73–1.39, P=0.964) or acute pancreatitis (HR 0.69, 95% CI 0.38–1.26; P=0.548) (Fig. 1 and Supplementary Table 2).

All-cause mortality did not differ significantly between the lipophilic and hydrophilic statin groups (HR 1.00, 95% CI 0.75–1.32, P=0.257) (Fig. 1). Similarly, rates of major adverse cardiac events (MACE) were comparable between groups (HR 0.95, 95% CI 0.70–1.29, P=0.615). No significant differences were observed in the risk of ischemic heart disease (HR 1.03, 95% CI 0.61–1.74, P=0.758), or stroke (HR 1.30, 95% CI 0.87–1.95; P=0.066). Additionally, the risk of arrhythmia (HR 0.87, 95% CI 0.65–1.17; P=0.260) and heart failure (HR 0.92, 95% CI 0.67–1.27; P=0.825) did not differ significantly between the two groups (Fig. 1 and Supplementary Table 2).

Our study found that lipophilic statins were associated with a non-significantly different risk of developing MALO after PSM in patients with ALD. This finding contrast with the biological properties of statins, as the superior ability of lipophilic statins to penetrate hepatocytes may allow for more substantial local pleiotropic effects, such as anti-inflammatory and antioxidant actions, that directly impact liver health [8].

Similarly, overall 5-year mortality, MACE, and other cardiovascular outcomes were comparable between ALD patients receiving lipophilic versus hydrophilic statins. Prior studies in populations beyond ALD have reported better cardiovascular outcomes associated with lipophilic statins [9,10], while others have shown more favorable results with hydrophilic statins [11]. The lack of significant differences in our cohort may be attributable to the complex pathophysiology of ALD, which involves pronounced systemic inflammation, oxidative stress, and endothelial dysfunction, often in the context of comorbidities such as malnutrition and metabolic risk factors [12,13]. These factors contribute to a markedly elevated baseline cardiovascular risk in this population. It is plausible that the profound systemic effects of ALD overshadow more modest differences in cardiovascular protection potentially linked to statin hydrophilicity or li-pophilicity [9]. Therefore, the selection of statin therapy in ALD patients may be guided more by considerations of hepatic tolerability and safety rather than by optimization of cardiovascular benefit based on physicochemical properties. Nevertheless, statins are considered safe in liver disease, including compensated cirrhosis, and have been associated with lower mortality and risk of decompensation [14]. Furthermore, patients with ALD face a high risk of mortality from non-cardiovascular causes, including MALO. This substantial competing risk may reduce the likelihood of detecting statistically significant differences in cardiovascular outcomes, as many patients may succumb to liver-related complications, particularly MALO, before experiencing cardiovascular events. Consequently, any true differential effect of statin type on cardiovascular endpoints may be attenuated or obscured in this high-risk population. Further research is warranted to clarify these effects specifically within the ALD population.

Several limitations should be acknowledged. First, reliance on diagnostic codes may have resulted in underestimation or misclassification of ALD despite the use of standardized coding systems. Second, residual differences in alcohol consumption, some laboratory markers, and cirrhosis severity between groups could not be fully accounted for due to limitations in available data and propensity score matching [10]. Third, changes in statin dosage over time were not captured, and thus, a dose-dependent effect could not be assessed. Additionally, alcohol consumption itself was not accounted for, which may influence outcomes and introduce residual confounding. Fourth, our cohort was predominantly composed of White individuals, potentially limiting the generalizability of findings to more diverse populations. Fifth, some ALD cases may have been misclassified as MetALD, which could affect the accuracy of cohort definitions [13].

In conclusion, this study found that among patients with ALD, the overall 5-year mortality, cardiovascular outcomes, MALO, AH, and acute pancreatitis were similar between the two statin groups. Future research should investigate whether patient-specific factors modify the comparative effectiveness of hydrophilic versus lipophilic statins in individuals with ALD.