Dyslipidemia in liver cirrhosis: Pathophysiology and emerging therapeutic approaches

Abstract

Dyslipidemia in liver cirrhosis represents a dynamic consequence of progressive hepatocellular failure rather than a conventional metabolic disorder, arising from coordinated disruptions in lipoprotein synthesis, remodeling, and clearance. Cirrhotic liver remodeling is associated with reduced apolipoprotein production, impaired very low-density lipoprotein export, downregulation of low-density lipoprotein receptor-mediated uptake, and cholestasis-driven accumulation of atypical lipoproteins, including lipoprotein X and lipoprotein Z, which distort standard lipid metrics and contribute to oxidative and inflammatory signaling. These molecular perturbations are further shaped by disease etiology, insulin resistance, and cytokine-mediated inhibition of lipid-processing pathways, generating stage-specific lipid phenotypes that correlate with prognosis and systemic complications. Given the altered hepatic handling of lipid-modifying drugs and the limited applicability of statins in advanced disease, this review synthesizes current mechanistic and translational evidence on non-statin lipid-lowering therapies in cirrhosis. Available data indicate that ezetimibe and fibrates modulate intestinal cholesterol flux and peroxisome proliferator-activated receptor-α signaling, respectively, but their effects on cirrhotic lipid networks remain incompletely defined. In contrast, proprotein convertase subtilisin/kexin type 9 inhibitors and RNA-based therapies such as inclisiran reduce circulating atherogenic lipoproteins through receptor-dependent pathways with minimal hepatic biotransformation, although clinical and molecular data are largely restricted to compensated cirrhosis. Emerging agents targeting upstream cholesterol synthesis and intrahepatic thyroid hormone receptor-β signaling further highlight the potential to influence hepatic lipid oxidation and fibrogenic signaling, yet evidence in cirrhosis is sparse. Collectively, the data underscore dyslipidemia as an integrated molecular feature of cirrhosis and identify non-statin therapies as tools to interrogate, rather than simply correct, disrupted hepatic lipid biology, emphasizing the need for stage- and mechanism-specific investigation.

Key Words: Liver cirrhosis; Dyslipidemia; Hepatic lipid metabolism; Lipoprotein dysfunction; Cholestasis; Cardiometabolic risk

Core Tip: Dyslipidemia in liver cirrhosis reflects fundamental alterations in hepatic lipid biology, including impaired apolipoprotein synthesis, defective lipoprotein export, receptor downregulation, and cholestasis-driven accumulation of atypical particles such as lipoprotein X and lipoprotein Z. These molecular disturbances generate stage-specific lipid phenotypes that challenge conventional cardiovascular risk assessment and drug targeting. Non-statin lipid-lowering agents provide mechanistically informative tools to probe these disrupted pathways; however, their effects in cirrhosis remain largely defined by pharmacologic rationale rather than direct clinical evidence. Understanding how disease stage and etiology reshape hepatic lipid handling is essential for rational application and future development of lipid-modifying strategies in cirrhotic populations.

INTRODUCTION

Liver cirrhosis represents the advanced stage of chronic liver injury and is defined by progressive fibrosis, nodular regeneration, and irreversible distortion of hepatic architecture[1]. It arises from heterogeneous etiologies, including viral infections, toxic exposures, metabolic causes, hereditary disorders, and immune-mediated liver diseases[2]. Given the liver’s central role in lipid synthesis, lipoprotein assembly, and metabolic regulation, cirrhosis is consistently accompanied by systemic metabolic disturbances, among which dyslipidemia is prominent[3]. Dyslipidemia - defined as quantitative and qualitative abnormalities in lipid and lipoprotein fractions[4-6] - is highly prevalent in chronic liver disease and has been associated with accelerated disease progression and adverse clinical outcomes[7].

Statins remain the reference therapy for dyslipidemia; however, their applicability in cirrhosis, particularly in decompensated disease, is constrained by altered pharmacokinetics, limited representation of advanced liver disease in clinical trials, and safety considerations. Muscle toxicity and hepatocellular injury constitute the principal adverse effects of concern in this setting[8]. Reduced hepatic metabolism in cirrhosis increases systemic statin exposure, thereby amplifying the risk of myotoxicity, which ranges from myalgia to rhabdomyolysis[9]. Statin-associated liver injury is infrequent and typically manifests as transient aminotransferase elevations consistent with hepatocellular rather than cholestatic patterns[10,11].

These limitations have renewed interest in non-statin lipid-lowering therapies for patients with cirrhosis. Although statins confer well-established cardiovascular benefit, treatment discontinuation or dose reduction occurs in a substantial proportion of patients due to intolerance, prompting guideline-supported use of non-statin agents when additional low-density lipoprotein (LDL) cholesterol (LDL-C) reduction is required in high-risk populations[12]. Moreover, several non-statin therapies, particularly inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), target discrete molecular pathways involved in lipoprotein turnover, inflammatory signaling, and hepatic lipid handling, raising important mechanistic and translational questions in cirrhotic liver disease[13].

LITERATURE REVIEW

This narrative mini-review was conducted to synthesize current evidence on the prevalence, pathophysiology, and management of dyslipidemia in patients with liver cirrhosis, with a specific focus on non-statin lipid-lowering therapies. A comprehensive literature search was performed in PubMed/MEDLINE, EMBASE, Scopus, and Web of Science databases, covering publications from January 2000 to August 2025. Search terms included combinations of “liver cirrhosis”, “dyslipidemia”, “non-statin therapy”, “ezetimibe”, “fibrates”, “PCSK9 inhibitors”, “bempedoic acid”, “omega-3 fatty acids”, “thyroid hormone receptor agonists”, and “RNA-based lipid-lowering therapies”. Additional relevant studies were identified through manual screening of reference lists from key reviews and original articles.

Eligible studies included clinical trials, observational cohort studies, systematic reviews, meta-analyses, and selected translational or mechanistic studies evaluating lipid abnormalities or non-statin lipid-lowering interventions in adults with cirrhosis or chronic liver disease. Editorials, case reports, and studies without liver-specific data were excluded. Two reviewers independently screened titles and abstracts, extracted relevant data, and resolved discrepancies by consensus. Owing to heterogeneity in study designs, patient populations, and therapeutic exposures, findings were synthesized narratively and organized by therapeutic class and disease stage (compensated vs decompensated cirrhosis), emphasizing pharmacological mechanisms, hepatic handling, safety considerations, and clinical applicability. In total, 93 studies were included in the qualitative synthesis.

EPIDEMIOLOGY OF DYSLIPIDEMIA IN CIRRHOSIS

Liver cirrhosis remains a major global health burden, ranking among the leading causes of chronic disease-related mortality and accounting for approximately 1 million deaths annually worldwide, with a substantial contribution to disability-adjusted life years[14,15]. The epidemiologic framework of cirrhosis-associated dyslipidemia has been refined by the recent reclassification of non-alcoholic fatty liver disease into steatotic liver disease, encompassing metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease, and the overlapping metabolic dysfunction and alcohol-related liver disease phenotype[16]. In population-based cohorts, MASLD affects up to 18.5% of men and 10.3% of women, and now represents the most prevalent etiologic context in which dyslipidemia coexists with cirrhosis, cardiometabolic disease, and systemic complications, while metabolic dysfunction and alcohol-related liver disease and alcohol-associated liver disease remain less prevalent but disproportionately affect male populations[17-21]. Beyond prevalence, contemporary studies consistently demonstrate that dyslipidemia in cirrhosis is primarily linked to disease severity rather than lipid excess: As hepatic function deteriorates, patients with advanced chronic liver disease or higher Child-Pugh class exhibit marked reductions in total cholesterol, LDL-C, and high-density lipoprotein (HDL) cholesterol (HDL-C), whereas triglyceride and very LDL (VLDL) levels show weaker or inconsistent associations with fibrosis severity[22]. These patterns are reproducible across viral, metabolic, and alcohol-related etiologies, supporting a paradigm in which hypocholesterolemia and hypolipidemia serve as epidemiologic signatures of impaired hepatic metabolic capacity and clinically relevant markers of disease stage and prognosis, rather than conventional indicators of cardiovascular risk[14,22].

ETIOLOGY AND RISK FACTORS OF DYSLIPIDEMIA IN CIRRHOSIS

Cirrhosis encompasses heterogeneous etiologies that converge on a common endpoint: Progressive disruption of hepatic lipid handling. Viral hepatitis exemplifies this interaction, as hepatitis B virus promotes hepatic fatty acid synthesis, whereas hepatitis C virus directly alters intracellular cholesterol trafficking and lipoprotein assembly[23]. Similarly, alcohol-related liver disease evolves from steatosis to cirrhosis primarily as a function of cumulative alcohol exposure, with female sex, obesity, and high-fat diets amplifying metabolic injury[24]. In parallel, MASLD, defined by hepatic steatosis in the presence of cardiometabolic risk factors, has emerged as a dominant cause of cirrhosis and hepatocellular carcinoma, while cardiovascular disease remains the leading cause of death in this population[25]. Autoimmune and cholestatic liver diseases further contribute to end-stage liver disease, in which impaired bile flow profoundly distorts cholesterol excretion and lipoprotein composition[26,27].

However, beyond etiology, cardiometabolic comorbidities and hepatic failure jointly shape the dyslipidemia phenotype of cirrhosis. Insulin resistance and diabetes enhance hepatic VLDL-triglyceride production and reduce HDL concentrations[28-30], whereas obesity and hypertension exacerbate dyslipidemia through visceral adiposity, adipokine imbalance, and chronic inflammation[31-34]. In contrast, progressive hepatocellular dysfunction ultimately lowers total cholesterol, LDL, and HDL levels, while cholestasis may paradoxically elevate triglycerides and total cholesterol[35,36]. In this context, accumulation of lipoprotein X can falsely mimic severe hypercholesterolemia and obscure true atherogenic risk[37-39]. Consistent with this dissociation, studies in hepatitis B virus-related cirrhosis demonstrate inverse relationships between disease severity and cholesterol levels[40]. Finally, chronic systemic inflammation amplifies lipid abnormalities through cytokine-mediated inhibition of lipoprotein lipase and oxidative lipoprotein modification, with elevated C-reactive protein and tumor necrosis factor-α correlating with low HDL and increased small dense LDL particles[36,41-44]. Collectively, these interacting mechanisms define a distinct, stage-dependent dyslipidemia milieu in cirrhosis with direct implications for prognosis and therapeutic decision-making.

PATHOPHYSIOLOGICAL MECHANISMS

The liver serves as the central regulator of lipid homeostasis through coordinated apolipoprotein synthesis, VLDL assembly and secretion, and receptor-mediated LDL clearance[45-47]. In cirrhosis, progressive loss of functional hepatocyte mass disrupts these processes, resulting in impaired apolipoprotein production, reduced VLDL export, and downregulation of LDL receptors, with consequent declines in total cholesterol, LDL, and HDL that closely track disease severity[35,48]. Accordingly, lipid concentrations show consistent inverse associations with Child-Pugh and Model for End-Stage Liver Disease scores, positioning hypocholesterolemia not merely as a biochemical abnormality but as a surrogate of hepatic reserve and prognosis (Figure 1)[48]. Yet this pattern is not linear: Cholestasis fundamentally alters cholesterol excretion and lipid absorption, producing paradoxical hypertriglyceridemia via impaired lipoprotein lipase activity and reduced clearance of triglyceride-rich lipoproteins[49,50]. In this setting, accumulation of abnormal lipoproteins, particularly lipoprotein X and the hepatotoxic LDL-like lipoprotein Z, distorts conventional lipid metrics, mimics an atherogenic profile, and independently predicts worse survival[51-53].

Figure 1 Molecular mechanisms of dyslipidemia in liver cirrhosis. Progressive hepatocellular dysfunction, cholestasis, and inflammation alter apolipoprotein synthesis, lipoprotein remodeling, and receptor-mediated clearance, promoting lipid imbalance and oxidative injury. ApoA1: Apolipoprotein A1; ApoB₁₀₀: Apolipoprotein B100; VLDL: Very low-density lipoprotein; HDL: High-density lipoprotein; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; ACAT: Acyl-coenzyme A cholesterol acyltransferase; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; IL: Interleukin; TNF: Tumor necrosis factor; SREBP-2: Sterol regulatory element-binding protein 2; PPAR: Peroxisome proliferator-activated receptor.

By contrast, viral and metabolic liver diseases impose distinct molecular perturbations that further reshape the cirrhotic lipid landscape. Hepatitis C virus hijacks the VLDL assembly pathway to form lipoviral particles, suppresses microsomal triglyceride transfer protein, and selectively lowers LDL while enriching triglyceride fractions within HDL[54,55]. Concurrently, MASLD-related genetic variants, including patatin-like phospholipase domain-containing protein 3 I148M and transmembrane 6 superfamily member 2 E167K, exacerbate intrahepatic triglyceride retention and limit VLDL secretion, thereby reinforcing steatosis and an atherogenic lipoprotein phenotype despite declining synthetic capacity[48,56]. These lipid abnormalities are biologically active rather than epiphenomenal: Oxidized LDL amplifies Kupffer cell activation and hepatic stellate cell fibrogenesis[57], hypocholesterolemia correlates with inferior transplant-free survival[18,55], and persistent dysregulated hyperlipidemia in MASLD accelerates fibrosis progression and hepatocarcinogenesis, as supported by emerging lipidomic signatures in hepatocellular carcinoma[58-60]. Collectively, cirrhosis establishes a self-reinforcing loop in which hepatic dysfunction distorts lipoprotein metabolism, while altered lipid species actively propagate inflammation, fibrosis, and malignant transformation (Table 1).

Table 1 Risk factors, mechanisms, and clinical manifestations of dyslipidemia in cirrhosis.

Risk factor	Pathophysiological mechanisms	Clinical manifestations	Ref.
Cardiometabolic comorbidities (diabetes, hypertension, obesity, MASLD)	(1) Insulin resistance promotes hepatic de novo lipogenesis and VLDL secretion; (2) Adipokine imbalance (↑leptin, ↓adiponectin); and (3) PNPLA3 and TM6SF2 variants impair triglyceride mobilization and VLDL secretion, fostering steatosis and atherogenic dyslipidemia	(1) Overlap of MetS and cirrhosis (up to 60% of patients); and (2) Central obesity, hypertriglyceridemia and low HDL-C accelerate fibrosis and CV events (“liver-heart-metabolism” axis)	[4,20,24-26,37-41]
Hepatic dysfunction and impaired lipid handling	(1) Loss of hepatocyte mass reduces apolipoprotein synthesis (ApoA-I and ApoB), VLDL secretion and LDL receptor activity to ↓total cholesterol, LDL-C, HDL-C; and (2) Cholestasis to paradoxical hypertriglyceridemia (impaired LPL activity)	(1) In compensated cirrhosis: Modest lipid reductions and near-normal TG; (2) In decompensated cirrhosis: Lowest TC and HDL-C in Child-Pugh C; and (3) Hypocholesterolemia predicts poor survival and transplant-free mortality	[8,9,11,20-23,28,31-33]
Chronic systemic inflammation and viral/metabolic injury	(1) Oxidative LDL uptake by Kupffer cells to cytokine release (TNF-α, IL-6); (2) Stellate cell activation to fibrosis; (3) HCV alters VLDL assembly and lowers LDL-C; (4) MASLD dyslipidemia promotes lipotoxicity and carcinogenesis; and (5) Lipidomic signatures in HCC	(1) Increased sd-LDL and oxidized LDL despite low absolute LDL-C; (2) Paradoxical ↑CAD incidence in cirrhosis; and (3) Dyslipidemia linked to fibrogenesis, HCC risk and extra-hepatic morbidity	[24,25,27,29,30,34-36,41]

MASLD: Metabolic dysfunction-associated steatotic liver disease; VLDL: Very low-density lipoprotein; PNPLA3: Patatin-like phospholipase domain-containing protein 3; TM6SF2: Transmembrane 6 superfamily member 2; ApoA-I: Apolipoprotein A-I; ApoB: Apolipoprotein B; LDL: Low-density lipoprotein; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; LPL: Lipoprotein lipase; TNF: Tumor necrosis factor; IL: Interleukin; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; MetS: Metabolic syndrome; CV: Cardiovascular; TG: Triglycerides; TC: Total cholesterol; sd-LDL: Small dense low-density lipoprotein; CAD: Coronary artery disease.

CLINICAL MANIFESTATIONS

The clinical expression of dyslipidemia in cirrhosis is stage dependent and closely mirrors hepatic reserve rather than conventional cardiovascular risk. In compensated cirrhosis, lipid profiles typically show low-normal total cholesterol, LDL-C, and HDL-C, with preserved or mildly elevated triglycerides; however, progression to decompensation is marked by progressive hypocholesterolemia, most pronounced in Child-Pugh C, while triglycerides may paradoxically increase, in part due to portal hypertension-associated insulin resistance[22,58,61]. Importantly, contemporary studies identify low cholesterol levels as a robust prognostic marker, independently associated with reduced transplant-free survival, higher short-term mortality after acute gastrointestinal bleeding, and adverse outcomes in critical illness, whereas preserved or elevated cholesterol reflects retained synthetic capacity and improved survival[62,63]. Nevertheless, despite declining absolute lipid concentrations, qualitative molecular alterations persist: Enrichment of small dense and oxidized LDL particles confers heightened atherogenic potential, helping to explain the comparable or increased burden of coronary artery disease observed in cirrhosis, particularly among patients with cardiometabolic comorbidities[41,64,65]. Metabolic syndrome, affecting up to 60% of cirrhotic patients, further amplifies risk through central obesity, hypertriglyceridemia, low HDL-C, and insulin resistance[31,66,67], while insulin resistance mechanistically promotes hepatic steatosis, accelerates fibrogenesis, and reinforces systemic inflammation, consolidating the bidirectional “liver-heart-metabolism” axis[68-70]. Emerging lipidomic studies corroborate these observations by demonstrating disease-specific alterations in fatty acid composition and apolipoprotein expression that translate into distinct circulating lipid signatures with prognostic relevance for both hepatic and cardiovascular outcomes[70].

MOLECULAR CHALLENGES

In advanced cirrhosis, progressive reductions in total cholesterol and LDL-C undermine their reliability as cardiovascular risk markers, complicating both risk stratification and therapeutic decision-making[71]. Consequently, attention has shifted toward molecularly informative biomarkers that better reflect atherogenic burden, including apolipoprotein B (ApoB), which captures the total number of atherogenic particles, and lipoprotein(a), which confers cardiovascular risk even at low LDL-C concentrations[72]. More recently, multi-omics approaches, integrating lipidomic, proteomics, and HDL functional assays, have revealed qualitative alterations in lipoprotein composition and function that are not apparent on standard lipid panels, offering a more precise framework for risk assessment in cirrhosis.

THERAPEUTIC LIMITS

Despite growing therapeutic options, dyslipidemia management in cirrhosis remains constrained by altered pharmacokinetics and a paucity of cirrhosis-specific evidence. Most non-statin agents were validated in non-cirrhotic populations, rendering their application in liver disease largely extrapolative[73-75]. While selected therapies may be cautiously used in compensated cirrhosis under close monitoring, decompensated disease markedly increases the risk of drug accumulation and hepatotoxicity, particularly for agents with biliary or hepatic metabolism such as ezetimibe and fibrates (Table 2)[76,77]. Thus, treatment decisions must balance molecular efficacy against stage-dependent hepatic vulnerability.

Table 2 Efficacy and safety of emerging non-statin lipid-lowering agents in compensated and advanced cirrhosis.

Therapy	Main mechanism of action	Use in compensated cirrhosis	Main risk in cirrhosis (advanced/decompensated)
Ezetimibe	Inhibits intestinal cholesterol absorption (NPC1 L1 transporter)	Possible, with caution	Increased drug exposure in Child-Pugh B/C, higher risk of hepatotoxicity
Fibrates	Activate PPAR-α to ↓triglycerides, ↑HDL	Possible, under monitoring	Elevation of liver enzymes, cholestasis, rhabdomyolysis (especially if combined with statins)
PCSK9 inhibitors (alirocumab, evolocumab)	Monoclonal antibodies inhibiting PCSK9 to ↑LDL receptor recycling, ↓LDL-C	Data limited; theoretically safer since not hepatically metabolized	Limited clinical data in cirrhosis, safety in advanced liver disease not established
Bempedoic acid	Inhibits ATP-citrate lyase (upstream of HMG-CoA reductase)	Potential option, but limited data in cirrhosis	No robust studies in advanced liver disease; potential risk of hepatotoxicity
Inclisiran	Small interfering RNA targeting hepatic PCSK9 synthesis, leading to sustained LDL receptor upregulation and LDL-C reduction	Potential option; limited but favorable pharmacologic profile given minimal hepatic metabolism	Very limited clinical data in cirrhosis; safety in Child-Pugh B/C not established

PCSK9: Proprotein convertase subtilisin/kexin type 9; NPC1 L1: Niemann-Pick C1-like 1 transporter; PPAR: Peroxisome Proliferator-activated receptor; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; LDL-C: Low-density lipoprotein cholesterol; ATP: Adenosine triphosphate; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A.

MOLECULAR TARGETS

Mechanistically distinct non-statin therapies enable pathway-specific modulation of hepatic and systemic lipid metabolism. However, ezetimibe, by inhibiting Niemann-Pick C1-Like 1-mediated intestinal cholesterol absorption, lowers LDL-C, whereas MASLD studies report inconsistent effects on steatosis and inflammation despite modest improvements in liver enzymes and fibrosis[73,78]. Similarly, fibrates activate peroxisome proliferator activated receptor-α (PPAR-α) to reduce triglycerides and raise HDL-C and appear safe in primary biliary cirrhosis; nevertheless, data in other cholestatic disorders remain limited[74,79]. By contrast, bempedoic acid, an adenosine triphosphate-citrate lyase inhibitor acting upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, achieves moderate LDL-C reductions but still lacks direct evidence in cirrhotic populations[75,80]. In sharp contrast, PCSK9 inhibitors enhance hepatic LDL receptor recycling and produce profound LDL-C lowering with proven cardiovascular benefit in high-risk patients[81]. Notably, omega-3 fatty acids exert pleiotropic effects by activating PPAR-α and hepatocyte nuclear factor-4α (HNF4α), enhancing β-oxidation via CPT1A and acyl-CoA oxidase 1, suppressing sterol regulatory element-binding protein 1c (SREBP-1c)-driven lipogenesis, and attenuating nuclear factor kappa B–mediated inflammation; clinically, they are safe in compensated cirrhosis and effective for isolated hypertriglyceridemia[82]. Finally, emerging RNA-based therapies, including siRNA, antisense oligonucleotides, and gene-editing platforms, offer liver-specific lipid modulation; however, evidence in cirrhosis remains minimal outside early-phase studies[83-85].

THYROID SIGNALING

Disrupted intrahepatic thyroid hormone signaling has emerged as a key molecular driver of lipid dysregulation in liver disease. Although first-generation thyroid hormone receptor β-agonists such as sobetirome and eprotirome effectively reduced LDL-C but were limited by off-target skeletal toxicity[86,87]. In contrast, second-generation, liver-directed agents demonstrate improved selectivity: VK2809 enhances hepatic fatty acid oxidation, reduces steatosis, and lowers LDL and triglycerides with favorable safety profiles in compensated cirrhosis[88,89]. More importantly, resmetirom, now approved for metabolic dysfunction-associated steatohepatitis, restores hepatic thyroid hormone receptor β signaling, reduces liver fat, and improves systemic lipid profiles with good tolerability, positioning thyroid hormone analogues as a mechanistically precise strategy for dyslipidemia in liver disease[90,91].

FUTURE DIRECTIONS

Current evidence supports a paradigm shift from LDL-C-centric assessment toward molecular risk markers such as ApoB, non-HDL-C, and lipoprotein(a), complemented by omics-based profiling[72]. Accordingly, among non-statin therapies, PCSK9 inhibitors and inclisiran appear most promising in Child-Pugh A-B patients, particularly in statin intolerance or when substantial LDL reduction is required, with genetic data suggesting favorable hepatic safety[80,81,92]. Nevertheless, robust evidence in advanced cirrhosis remains scarce: Bempedoic acid is under investigation in MASLD[93], ezetimibe trials largely exclude cirrhotic patients, and PCSK9-targeted therapies lack data in Child-Pugh C. Therefore, the next critical step is the development of dedicated, stage-specific trials to define safety, efficacy, and molecular predictors of response, enabling evidence-based integration of non-statin therapies into cirrhosis care.

CONCLUSION

Dyslipidemia in cirrhosis reflects a stage-dependent disruption of hepatic lipid regulation rather than a conventional cardiovascular risk state. As liver function deteriorates, molecular lipid markers, such as ApoB, no-HDL-C, lipoprotein(a), and emerging omics signatures, provide more accurate risk stratification than LDL-C. Among non-statin therapies, PCSK9 inhibitors, inclisiran, and liver-directed thyroid hormone receptor β agonists emerge as the most mechanistically grounded options in compensated cirrhosis, while evidence in advanced disease remains limited. Progress in this field will depend on dedicated, stage-specific clinical trials to establish safety, efficacy, and precision-guided treatment strategies.