Effect of Statins and PCSK9 Inhibition on Metabolic Dysfunction–Associated Steatotic Liver Disease

Abstract

Dyslipidemia is common in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and, along with other metabolic comorbidities, accounts for an increased cardiovascular risk. Effective treatment of dyslipidemia not only reduces such risk but may have a beneficial effect on MASLD as well. Here we reviewed published data on the efficacy and safety of available hypolipidemic treatments for MASLD. Statins are the mainstay of hypolipidemic therapy for MASLD. In patients with compensated cirrhosis, statins are safe and can improve the risks of decompensation and hepatocellular carcinoma as well as mortality. However, in those with decompensated cirrhosis, statins should not be used unless there are strong indications that outweigh the risk of adverse events. Studies on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors acting as the second-line therapy in MASLD remain scarce. Preliminary clinical data support their protective roles in MASLD; however, preclinical data raise concerns regarding safety, in particular with complete PCSK9 inhibition due to hepatocyte lipid accumulation. While more evidence is required to elucidate the role of PCSK9 inhibitors, statins should be used for the treatment of hyperlipidemia in patients with MASLD according to their cardiovascular risk stratification.

Keywords

dyslipidemias / hydroxymethylglutaryl-CoA reductase inhibitors / metabolic dysfunction–associated steatotic liver disease / PCSK9 inhibitors

References

[1] Z. Younossi, F. Tacke, M. Arrese, et al., “Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis,” Hepatology 69, no. 6 (2019): 2672–2682.

[2] Q. Ye, B. Zou, Y. H. Yeo, et al., “Global Prevalence, Incidence, and Outcomes of Non-Obese or Lean Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis,” Lancet Gastroenterology & Hepatology 5, no. 8 (2020): 739–752.

[3] P. Angulo, D. E. Kleiner, S. Dam-Larsen, et al., “Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-Term Outcomes of Patients With Nonalcoholic Fatty Liver Disease,” Gastroenterology 149, no. 2 (2015): 389–397.e10.

[4] L. A. Adams, J. F. Lymp, J. St Sauver, et al., “The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study,” Gastroenterology 129, no. 1 (2005): 113–121.

[5] M. E. Rinella, B. A. Neuschwander-Tetri, M. S. Siddiqui, et al., “AASLD Practice Guidance on the Clinical Assessment and Management of Nonalcoholic Fatty Liver Disease,” Hepatology 77, no. 5 (2023): 1797–1835.

[6] F. Kanwal, B. A. Neuschwander-Tetri, R. Loomba, and M. E. Rinella, “Metabolic Dysfunction-Associated Steatotic Liver Disease: Update and Impact of New Nomenclature on the American Association for the Study of Liver Diseases Practice Guidance on Nonalcoholic Fatty Liver Disease,” Hepatology 79, no. 5 (2024): 1212–1219.

[7] X. Fan, B. Zhang, Y. Shi, L. Liu, and J. Zhao, “Systemic Metabolic Abnormalities: Key Drivers of Complications and Mortality in MASLD,” Journal of Hepatology 80, no. 6 (2024): e246–e248.

[8] M. S. Siddiqui, M. Fuchs, M. O. Idowu, et al., “Severity of Nonalcoholic Fatty Liver Disease and Progression to Cirrhosis Are Associated With Atherogenic Lipoprotein Profile,” Clinical Gastroenterology and Hepatology 13, no. 5 (2015): 1000–1008.e3.

[9] M. Abdallah, L. Brown, J. Provenza, R. Tariq, S. Gowda, and A. K. Singal, “Safety and Efficacy of Dyslipidemia Treatment in NAFLD Patients: A Meta-Analysis of Randomized Controlled Trials,” Annals of Hepatology 27, no. 6 (2022): 100738, https://doi.org/10.1016/j.aohep.2022.100738.

[10] V. G. Athyros, K. Tziomalos, T. D. Gossios, et al., “Safety and Efficacy of Long-Term Statin Treatment for Cardiovascular Events in Patients With Coronary Heart Disease and Abnormal Liver Tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: A Post-Hoc Analysis,” Lancet 376, no. 9756 (2010): 1916–1922.

[11] M. Ekstedt, L. E. Franzén, U. L. Mathiesen, M. Holmqvist, G. Bodemar, and S. Kechagias, “Statins in Non-Alcoholic Fatty Liver Disease and Chronically Elevated Liver Enzymes: A Histopathological Follow-Up Study,” Journal of Hepatology 47, no. 1 (2007): 135–141.

[12] P. Dongiovanni, S. Petta, V. Mannisto, et al., “Statin Use and Non-Alcoholic Steatohepatitis in at Risk Individuals,” Journal of Hepatology 63, no. 3 (2015): 705–712.

[13] D. E. Kaplan, M. A. Serper, R. Mehta, et al., “Effects of Hypercholesterolemia and Statin Exposure on Survival in a Large National Cohort of Patients With Cirrhosis,” Gastroenterology 156, no. 6 (2019): 1693–1706.e12.

[14] J. G. Abraldes, C. Villanueva, C. Aracil, et al., “Addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Does Not Reduce Rebleeding but Increases Survival in Patients With Cirrhosis,” Gastroenterology 150, no. 5 (2016): 1160–1170.e3.

[15] R. Vijayaraghavan, A. Jindal, V. Arora, A. Choudhary, G. Kumar, and S. K. Sarin, “Hemodynamic Effects of Adding Simvastatin to Carvedilol for Primary Prophylaxis of Variceal Bleeding: A Randomized Controlled Trial,” American Journal of Gastroenterology 115, no. 5 (2020): 729–737.

[16] E. Alvarado-Tapias, A. Brujats, A. Puente, et al., “Hemodynamic Effects of Carvedilol Plus Simvastatin in Cirrhosis With Severe Portal Hypertension and Suboptimal Response to β-Blockers: A Double-Blind, Placebo-Controlled, Randomized Trial,” Hepatology 82, no. 1 (2025): 140–154.

[17] N. G. Seidah and D. Garçon, “Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond,” Current Atherosclerosis Reports 24, no. 10 (2022): 821–830.

[18] A. Eshraghian, E. Moasser, N. Azarpira, et al., “Variations in TM6SF2, PCSK9 and PCSK7 Genes and Risk of Hepatic Steatosis After Liver Transplantation: A Cross-Sectional Study,” BMC Gastroenterology 21, no. 1 (2021): 458, https://doi.org/10.1186/s12876-021-02041-8.

[19] S. Grimaudo, S. Bartesaghi, R. Rametta, et al., “PCSK9 rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals With NAFLD,” Liver International 41, no. 2 (2021): 321–332.

[20] M. Ruscica, N. Ferri, C. Macchi, et al., “Liver Fat Accumulation Is Associated With Circulating PCSK9,” Annals of Medicine 48, no. 5 (2016): 384–391.

[21] M. Paquette, D. Gauthier, A. Chamberland, et al., “Circulating PCSK9 Is Associated With Liver Biomarkers and Hepatic Steatosis,” Clinical Biochemistry 77 (2020): 20–25.

[22] Y. He, R. M. Rodrigues, X. Wang, et al., “Neutrophil-to-Hepatocyte Communication via LDLR-Dependent miR-223-Enriched Extracellular Vesicle Transfer Ameliorates Nonalcoholic Steatohepatitis,” Journal of Clinical Investigation 131, no. 3 (2021): e141513, https://doi.org/10.1172/JCI141513.

[23] A. Dimakopoulou, V. Athyros, and G. Sfikas, “PCSK9 Administration Ameliorates Non Alcoholic Fatty Disease in Patients With Heterozygous Familial Hyperlipidemia,” Hellenic Journal of Atherosclerosis 9 (2018): 1–2, https://www.researchgate.net/publication/326518938_PCSK9_administration_ameliorates_non_alcoholic_fatty_disease_in_patients_with_heterozygous_familial_hyperlipidemia.

[24] R. Scicali, A. Di Pino, F. Urbano, et al., “Analysis of Steatosis Biomarkers and Inflammatory Profile After Adding on PCSK9 Inhibitor Treatment in Familial Hypercholesterolemia Subjects With Nonalcoholic Fatty Liver Disease: A Single Lipid Center Real-World Experience,” Nutrition, Metabolism, and Cardiovascular Diseases 31, no. 3 (2021): 869–879.

[25] M. Shafiq, T. Walmann, V. Nutalapati, C. Gibson, and Y. Zafar, “Effects of Proprotein Convertase Subtilisin/Kexin Type-9 Inhibitors on Fatty Liver,” World Journal of Hepatology 12, no. 12 (2020): 1258–1266.

[26] X. L. Zhang, Q. Q. Zhu, L. Zhu, et al., “Safety and Efficacy of Anti-PCSK9 Antibodies: A Meta-Analysis of 25 Randomized, Controlled Trials,” BMC Medicine 13 (2015): 123, https://doi.org/10.1186/s12916-015-0358-8.

[27] P. F. Lebeau, J. H. Byun, K. Platko, et al., “Pcsk9 Knockout Exacerbates Diet-Induced Non-Alcoholic Steatohepatitis, Fibrosis and Liver Injury in Mice,” JHEP Reports 1, no. 6 (2019): 418–429.

[28] G. N. Ioannou, S. P. Lee, P. S. Linsley, et al., “Pcsk9 Deletion Promotes Murine Nonalcoholic Steatohepatitis and Hepatic Carcinogenesis: Role of Cholesterol,” Hepatology Communications 6, no. 4 (2022): 780–794.

[29] F. S. Fan, “Small-Interfering RNA Targeting Proprotein Convertase Subtilisin/Kexin Type 9 Might Promote Fatty Liver Disease and Hepatocellular Carcinoma Through Upregulation of CD36,” Tumour Biology 45, no. 1 (2023): 73–80.

[30] C. Oleaga, M. D. Shapiro, J. Hay, et al., “Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies,” Journal of the American College of Cardiology 78, no. 14 (2021): 1437–1449.

RIGHTS & PERMISSIONS

2025 The Author(s). Journal of Digestive Diseases published by Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.