The prognostic impact of statin exposure in metabolic dysfunction-associated steatotic liver disease: a cohort study

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a major global health issue, reflecting the rising prevalence of metabolic syndromes such as obesity, type 2 diabetes, and dyslipidemia. The previous term, non-alcoholic fatty liver disease (NAFLD), had a global prevalence of 32% among adults. The condition was more prevalent in males than in females, with its prevalence increasing over time from 26% in studies prior to 2005 to 38% in studies from 2016 onwards. This upward trend is expected to continue, particularly in regions like the Americas and South-East Asia, where prevalence already exceeds 40% (1-3).

MASLD encompasses a spectrum of liver conditions characterized by excessive fat accumulation in the liver, occurring without significant alcohol consumption (4). Although many patients with MASLD may be asymptomatic, a significant number may progress to more severe liver diseases such as steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) (5-7). This progression to advanced stages is associated with substantial morbidity and mortality, emphasizing the importance of identifying factors that can mitigate these risks.

One area of growing interest in the management of MASLD involves the use of statins, which are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Statins are primarily prescribed to manage hypercholesterolemia and to reduce the risk of cardiovascular and cerebrovascular diseases (8-10). Beyond their lipid-lowering effects, statins exhibit a range of pleiotropic properties, including anti-inflammatory, antifibrotic, and anticancer benefits (11-14). These properties support the hypothesis that statins may not only benefit cardiovascular and cerebrovascular health but also protect against the progression of chronic liver diseases, including MASLD.

Several observational studies and meta-analyses have supported the potential benefits of statin therapy in liver diseases, suggesting that statin use is correlated with a reduced risk of liver-related events, such as the development of HCC, and enhanced overall survival in patients with chronic liver diseases (15,16). A nationwide population-based study further demonstrated that statin use was linked to a notable decrease in the risk of HCC in patients with chronic hepatitis B, independent of aspirin use (17). Despite these promising findings, the specific effects of statins on outcomes in MASLD, particularly regarding all-cause mortality, liver-related mortality, and the incidence of hepatic decompensation, remain underexplored. Moreover, comprehensive studies investigating the effects of different types of statins and gender differences are lacking.

This study aims to fill these gaps by conducting an in-depth analysis of the potential prognostic impact of statin use on a large cohort of patients with MASLD. In light of the complex interplay between metabolic dysfunction and liver disease progression, along with the crucial role statins play in managing major vascular events, the results of this study could be significant for enhancing management strategies for MASLD. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-54/rc).

Methods

Study design and participants

This population-based cohort analysis uses data from the UK Biobank (application ID: 117214), a large-scale biomedical database encompassing comprehensive health information from approximately 500,000 participants aged 40–69 years, recruited from 2006–2010 until May 2021. Diagnoses were coded according to the International Statistical Classification of Disease and Related Health Problems, Tenth Revision (ICD-10). ICD-10 codes registration was based on hospital admission code and was transmitted to the UK Biobank (18,19).

Initially, all participants (n=502,370) were considered. Exclusions were made for participants lacking clinical information (n=25,895). Participants with other chronic liver diseases such as autoimmune hepatitis (K754 for ICD-10 code, n=353), chronic hepatitis B (B181 for ICD-10 code, n=315), chronic hepatitis C (B182 for ICD-10 code, n=448), primary biliary cirrhosis (K753 for ICD-10 code, n=45), and cryptogenic steatotic liver disease (SLD) (n=966) were also excluded to specifically focus on MASLD. Cryptogenic SLD was defined as hepatic steatosis in individuals who did not meet criteria for MASLD, alcohol-related liver disease (ARLD), or metabolic dysfunction and alcohol-associated liver disease (MetALD), based on the absence of both metabolic risk factors and significant alcohol use or relevant ICD-10 codes. To exclude ARLD, we applied both clinical alcohol consumption thresholds (≥350 g/week for females, ≥420 g/week for males) and relevant ICD-10 codes (K700, K701, K702, K703, K704, and K709). MetALD was defined as steatosis in individuals with both metabolic dysfunction and moderate alcohol intake not meeting ARLD criteria (20). Specifically, participants with ARLD, including MetALD (n=63,649) and solely alcohol-associated liver disease (n=8,223), were excluded. After these exclusions, the final study cohort included 402,476 participants, of which 67,160 were identified as statin users and 335,316 as non-users (Figure 1).

Figure 1 Participant selection flowchart. The selection process of participants from the UK Biobank cohort began with 502,370 participants. After excluding individuals with missing clinical information, viral liver diseases, and alcohol-related liver diseases, a final cohort of 402,476 participants was included in the analysis. This group consisted of 67,160 statin users and 335,316 non-users.

The fatty liver index was utilized to identify SLD (21). Additionally, for a MASLD diagnosis in the absence of other causes of liver fat accumulation, the presence of at least one cardiometabolic risk factor (CMRF) with SLD was required. These CMRFs include obesity, type 2 diabetes, hypertension, dyslipidemia, and metabolic syndrome. Definitions were based on the consensus criteria. Obesity was defined as body mass index ≥30 kg/m². Type 2 diabetes was determined by history of diagnosis, or antidiabetic medication use. Hypertension was defined as a history of diagnosis, use of antihypertensive medications, or systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg. Dyslipidemia was defined as total cholesterol ≥240 mg/dL, low density lipoprotein cholesterol (LDL-C) ≥160 mg/dL, or use of lipid-lowering medications. Metabolic syndrome was defined as the presence of at least three of the following: elevated waist circumference (≥102 cm in men or ≥88 cm in women), elevated triglycerides (≥150 mg/dL), reduced HDL cholesterol (<40 mg/dL in men or <50 mg/dL in women), elevated fasting glucose (≥100 mg/dL), or elevated blood pressure (≥130/85 mmHg or on treatment) (20).

These other causes, including ARLD, MetALD, and cryptogenic steatosis, were excluded based on clinical alcohol intake thresholds and relevant ICD-10 codes, as outlined above. Excessive alcohol intake with ARLD was defined as a consumption of 350 grams per week for females, and 420 grams per week for males, as described earlier (20).

Statin exposures

Statin exposure was defined as either self-reported statin use or the presence of a statin prescription record, identified using relevant UK Biobank Field IDs. The medication was defined to focus on consistent use with exclusion of single or transient statin prescriptions. Healthcare providers conducted interview for registration of medications. The definition was based on data from two UK Biobank fields: self-reported use of cholesterol-lowering medication (Field IDs: 6177 and 6153) and confirmed prescription history using the Treatment/Medication Code (Field ID: 20003). In the analysis of the MASLD cohort, specific statin types were identified using codes from the UK Biobank’s Treatment/Medication Code (Field ID: 20003), including simvastatin (1140861958), pravastatin (1140888648), atorvastatin (1141146234), and rosuvastatin (1141192410).

Ethical approval of the UK Biobank cohort

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was conducted under the ethical guidelines provided by the UK Biobank which has received approval from the North West Multi-Centre Research Ethics Committee (Ref: 11/NW/0382). All participants in UK Biobank provided informed consent at the time of enrollment.

The primary and secondary outcomes

The primary outcomes were all-cause mortality and liver-related mortality. All-cause mortality was defined as the time from baseline to death from any cause, while liver-related mortality was defined as death specifically attributable to liver disease. The incidence of hepatic decompensation, which included complications such as varices with or without bleeding (I85.0, I85.9, I98.2, and I98.3 for ICD-10 code), portal hypertension (K76.6 for ICD-10 code), hepatorenal syndrome (K76.7 for ICD-10 code) and ascites (R18 for ICD-10 code), and the occurrence of HCC identified through cancer registries within the UK Biobank dataset were also investigated for secondary outcomes.

Statistical analysis

The statistical analysis was performed using R version 4.4.0 (Bell Laboratories, USA). Baseline characteristics of the study population were summarized using descriptive statistics. In addition, continuous variables were presented as means with standard deviations and categorical variables as frequencies with percentages. Standardized mean differences (SMDs) were calculated to assess the balance of covariates between statin users and non-users. To adjust for potential confounders and ensure comparability between the groups, inverse probability of treatment weighting (IPTW) was utilized based on propensity scores derived from baseline covariates including age, sex, body mass index, physical activity, and comorbidities like diabetes mellitus and hypertension.

Survival analysis was conducted using Kaplan-Meier survival curves to compare survival probabilities between statin users and non-users. Cox proportional hazards models were employed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between statin use and the outcomes of interest. Subgroup analyses were performed to evaluate the effects of specific statin types, such as atorvastatin, pravastatin, rosuvastatin, and simvastatin, and to explore potential differences in outcomes between male and female participants. Throughout the analyses, a P value of less than 0.05 was considered statistically significant.

Results

Distribution of population and SMD reduction after IPTW

In the entire cohort, baseline characteristics showed significant differences before IPTW (Figure S1 and Table S1). Statin users were generally older and exhibited higher rates of comorbidities including dyslipidemia and type 2 diabetes. These differences were reflected in high SMDs, particularly for age and dyslipidemia. After IPTW, the SMDs were substantially reduced, demonstrating that the IPTW method effectively balanced the groups (Table S2 and Figure S2).

The differences in the No SLD cohort were minimized after IPTW, allowing for more accurate comparisons between statin users and non-users (Figure S2, Table S3, and Table 1). The MASLD cohort also exhibited substantial baseline imbalances particularly in age and dyslipidemia. After IPTW, these imbalances were significantly reduced, ensuring a balanced comparison between the groups for subsequent analyses (Figure S2, Table S3, and Table 1).

All-cause mortality and liver-related mortality between statin users and non-users

Within the entire cohort, Kaplan-Meier survival curves demonstrated that statin users exhibited a significantly higher survival probability than non-users, both before and after IPTW adjustment, achieving a 23% reduction in all-cause mortality. Liver-related mortality was also significantly lower among statin users (Figures S3-S5 and Table 2). In the no SLD cohort, the Kaplan-Meier analysis showed a non-significant difference in all-cause mortality between statin users and non-users (Figure 2A,2B, Figure S5, and Table 2). In the MASLD cohort, statin users experienced a 19% reduction in all-cause mortality and a 37% reduction in liver-related mortality compared to non-users, as indicated by Kaplan-Meier curves (Figure 2C,2D, Figure S5, and Table 2).

Figure 2 Kaplan-Meier survival curves for both all-cause and liver-related mortality among statin users and non-users within the no SLD and MASLD cohorts after IPTW. (A) All-cause mortality in the no SLD cohort. (B) Liver-related mortality in the no SLD cohort. (C) All-cause mortality within the MASLD cohort. (D) Liver-related mortality within the MASLD cohort. IPTW, inverse probability of treatment weighting; MASLD, metabolic dysfunction-associated steatotic liver disease; OS, overall survival; SLD, steatotic liver disease.

Incidence of HCC with or without statin use in SLD

The HR for HCC incidence in the entire cohort was 0.60, indicating a significant reduction in HCC risk, as visualized by Kaplan-Meier analysis (Figures S4C,S6A and Table S4). The no SLD cohort also demonstrated inverse association of statins against HCC, with an HR of 0.24 (Figure 3A, Figure S6A, and Table S4). In the MASLD cohort, the HR for HCC incidence was 0.57, addressing the significant inverse association of statins against liver cancer in this population (Figure 3, Figure S6A, and Table S4).

Figure 3 Incidence of HCC and hepatic decompensation in both no SLD and MASLD cohorts. (A) HCC incidence in the no SLD cohort. (B) Hepatic decompensation in the no SLD cohort. (C) HCC incidence in the MASLD cohort. (D) Hepatic decompensation in the MASLD cohort. HCC, hepatocellular carcinoma; IPTW, inverse probability of treatment weighting; MASLD, metabolic dysfunction-associated steatotic liver disease; SLD, steatotic liver disease.

Incidence of liver cirrhosis and hepatic decompensation including ascites with statin use

Initially, we analyzed the HR for liver cirrhosis incidence considering the effect of statins after IPTW adjustment. Multivariate analysis revealed no significant impact in the entire and MASLD cohorts (Table S5).

However, statin users demonstrated a significantly lower incidence of hepatic decompensation and ascites across the entire cohort. The HR for hepatic decompensation was 0.41, and more specifically for ascites, it was 0.35, suggesting that statin usage diminishes the risk of severe hepatic complications in the overall population (Figures S4,S6B,S7 and Tables S6,S7). In the no SLD cohort, statin users also experienced a notable decrease in the incidence of hepatic decompensation and ascites compared to non-users (Figure 3, Figures S6B,S7 and Tables S6,S7). In the MASLD cohort, Kaplan-Meier curves and hazard analysis confirmed that statin users manifested a significantly lower incidence of hepatic decompensation and ascites compared to non-users (Figure 3D, Figures S6B,S7 and Tables S6,S7).

Statin component-specific analysis in MASLD cohort

To investigate more specifically, we analyzed the influence of various statin components on the development of MASLD. In the MASLD cohort, atorvastatin and rosuvastatin significantly reduced all-cause mortality compared to other statins (Figure 4A). The HR for all-cause mortality was 0.43 for atorvastatin and 0.78 for rosuvastatin, while simvastatin increased mortality risk (Table S8). For liver-related mortality, only atorvastatin demonstrated a significant inverse association, with an HR of 0.26, indicating a substantial reduction in liver-related deaths compared to other statins (Figure S8A and Table S8). Atorvastatin also significantly reduced the incidence of HCC, whereas other statins showed no inverse association (Figure 4B and Table S8). In terms of hepatic decompensation, atorvastatin, rosuvastatin, and simvastatin all exhibited significant inverse associations, while pravastatin did not (Figure S8B and Table S8).

Figure 4 Subgroup analysis of all-cause mortality and HCC incidence within the MASLD cohort based on the type of statin used. (A) All-cause mortality. (B) HCC incidence. HCC, hepatocellular carcinoma; IPTW, inverse probability of treatment weighting; MASLD, metabolic dysfunction-associated steatotic liver disease; OS, overall survival.

Gender-specific outcomes in the MASLD cohort

Finally, we examined the impact of statin use on various outcomes within the MASLD cohort, with a particular focus on gender differences. Gender-specific analysis of all-cause mortality within the MASLD cohort revealed that female statin users had the best outcomes, followed by female non-users, male users, and male non-users (Figure S9A). HRs indicated significant improvements in all groups compared to male non-users, with HRs of 0.57 for female users, 0.71 for female non-users, and 0.88 for male users (Table S9). All groups demonstrated a significant reduction in liver-related mortality compared to male non-users (Figure S9B). HRs were 0.61 for male users, 0.38 for female non-users, and 0.31 for female users (Table S9). For HCC incidence, male non-users exhibited the highest incidence, while the other three groups showed significantly lower risks (Figure S10A). The HRs compared to male non-users were 0.50 for male users, 0.26 for female non-users, and 0.26 for female users (Table S9). Regarding hepatic decompensation, male non-users experienced the worst outcomes, with female non-users showing no significant difference. However, both male and female users had significantly lower risks of decompensation (Figure S10B and Table S9).

Discussion

The present study provides comprehensive evidence supporting the protective effects of statins in patients with MASLD, demonstrating significant reductions in all-cause mortality, liver-related mortality, HCC incidence, and hepatic decompensation among statin users. These findings are particularly pertinent given the rising global prevalence of MASLD, a significant public health concern strongly associated with metabolic syndromes such as obesity, type 2 diabetes, and dyslipidemia (4,22,23).

Several studies have examined the role of statins in chronic liver disease, particularly regarding their impact on fibrosis and HCC. For instance, one study showed that statin use was associated with a dose-dependent decrease in cirrhosis and HCC incidence in patients with chronic hepatitis C (24). Another study explored the link between statin usage and a reduced risk of cirrhosis development in individuals infected with the hepatitis C virus (25). Recent data have also demonstrated that MASLD patients with greater metabolic burden are at increased risk for advanced fibrosis, addressing the importance of early risk stratification and targeted interventions in this population (26). Specifically, our study not only investigated overall outcomes but also offered a detailed comparison of specific statin types and their differential effects on outcomes, including variations by gender.

The impact of statins on all-cause mortality in the MASLD cohort was substantial. Both atorvastatin and rosuvastatin provided significant benefits. Furthermore, atorvastatin was the only statin to show a significant inverse association on liver-related mortality. These findings indicate that statins could play a crucial role in managing patients with advanced liver disease, potentially delaying the progression to cirrhosis and reducing the risk of liver-related mortality. These results corroborate a previous study, which found that statins not only reduce cholesterol levels but also possess anti-inflammatory, antifibrotic, and anticancer properties that contribute to enhanced survival outcomes in patients with chronic liver diseases (27). The pleiotropic effects of statins, including the reduction of oxidative stress and inhibition of hepatic stellate cell activation, could account for these protective benefits (28,29).

High-intensity statin therapy includes atorvastatin 80 mg and rosuvastatin 20 mg, while moderate-intensity treatments include simvastatin 20–40 mg and pravastatin 40 mg (30). Numerous studies support high-intensity lipid-lowering agents for enhanced survival in diseases of the circulatory system (31,32). Consistent with prior evidence, our study reinforces the effectiveness of high-intensity statin therapy in reducing LDL-C levels and improving survival outcomes, showing that atorvastatin and rosuvastatin are linked with better liver-related outcomes in MASLD patients.

The inverse associations of statins against HCC is a significant finding of this study. Statins may exert their anticancer effects through the inhibition of cell proliferation, induction of apoptosis, and suppression of angiogenesis in tumor cells (33). Furthermore, these findings align with other studies that have reported a lower incidence of HCC among statin users, especially in populations with chronic hepatitis B or C (34,35).

Gender-specific analyses indicate that female statin users experience the most significant benefits, exhibiting the lowest rates of all-cause mortality, liver-related mortality, and HCC incidence compared to other groups. This discrepancy may reflect gender differences in metabolic responses and disease progression, suggesting that female patients with MASLD may derive greater benefits from statin therapy.

Analysis of hepatic decompensation outcomes further highlights the beneficial effects of statins in MASLD. A study has shown that patients with elevated LDL-C levels have a higher risk of liver fibrosis progression and poorer liver-related outcomes (36). Additional research has highlighted dyslipidemia as a significant risk factor associated with the progression of advanced hepatic fibrosis stages (37). Our research focuses on the efficacy of statins in MASLD patients, particularly demonstrating their ability to reduce hepatic decompensation and improve survival outcomes. Given the observed associations between statin use and improved outcomes, our findings also support the need to improve the frequency of appropriate statin prescribing in patients with MASLD, particularly those with coexisting CMRFs.

The present study has several limitations. First, we did not capture detailed data on the timing, dosage, and duration of statin use. Additionally, although liver-related outcomes were identified from comprehensive registers, the possibility of asymptomatic advanced liver disease still exists. Furthermore, we could not elucidate the specific cellular and molecular mechanisms. In addition, multicollinearity among covariates in the Cox regression models was not formally tested, which might potentially affect the stability of the estimates. Future analyses will incorporate variance inflation factor or similar assessments to address this limitation. And, due to the observational design of this study, causality cannot be established, and the associations observed should be interpreted with caution. Lastly, the UK Biobank population predominantly consists of individuals of European descent, which limits the generalizability of our findings to other ethnic groups. Future research should investigate whether similar benefits of statin therapy are observed in more diverse populations.

Conclusions

In conclusion, the present study provides evidence that statin use, particularly atorvastatin and rosuvastatin, significantly improves survival and reduces liver-related complications in patients with MASLD. These findings suggest the potential for broader application of statins in this patient population, with careful consideration of statin type and patient-specific characteristics such as gender, to enhance therapeutic benefits.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-54/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-54/prf

Funding: This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (No. RS-2023-00238039 to T.R.) and the National Research Foundation of Korea (No. RS-2023-00208767 to S.H.B.). The work was also supported by the Soonchunhyang University Research Fund (to T.R.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-54/coif). T.R. reports this work was supported by the Basic Science Research Program through the National Research Foundation of Korea (No. RS-2023-00238039 to T.R.) and Soonchunhyang University Research Fund. S.H.B. reports this work was supported by the National Research Foundation of Korea (No. RS-2023-00208767 to S.H.B.). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was conducted under the ethical guidelines provided by the UK Biobank which has received approval from the North West Multi-Centre Research Ethics Committee (Ref: 11/NW/0382). All participants in UK Biobank provided informed consent at the time of enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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