他汀藥不只護心！新研究揭示可降低肝癌與肝纖維化風險

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摘要 Abstract

重要性：他汀類藥物可能通過減緩肝纖維化的進展來降低肝細胞癌（HCC）的風險。
Importance: Statins may lower the risk of hepatocellular carcinoma (HCC) by mitigating liver fibrosis progression.

目的：評估他汀類藥物使用與肝細胞癌和肝臟失代償風險之間的關聯，特別強調在慢性肝病（CLD）成人患者中肝纖維化的進展。
Objective: To evaluate the association between statin use and the risk of HCC and hepatic decompensation, with an emphasis on liver fibrosis progression, among adult patients with chronic liver disease (CLD).

設計、環境和參與者：這項隊列研究使用了 2000 年至 2023 年期間的研究患者數據登記處的數據，對象為 40 歲或以上的 CLD 患者，基線纖維化-4（FIB-4）分數為 1.3 或更高。參與者分為他汀類藥物使用者和非使用者。數據分析於 2024 年 8 月 5 日至 2025 年 1 月 3 日進行。
Design, setting, and participants: This cohort study used data from the Research Patient Data Registry from 2000 to 2023 on patients 40 years or older with CLD and a baseline Fibrosis-4 (FIB-4) score of 1.3 or higher. Participants were grouped into statin users and nonusers. Data analysis was conducted from August 5, 2024, to January 3, 2025.

曝露：他汀類藥物使用。 Exposures: Statin use.

主要結果和測量：結果包括肝細胞癌（HCC）和肝臟失代償的 10 年累積發生率，以及根據 FIB-4 分數的肝纖維化風險類別的轉變。使用他汀類藥物的定義為暴露於 30 或以上的累積定義每日劑量（cDDD）。纖維化進展通過隨時間的 FIB-4 組別轉變（低、中、高）進行評估。結果使用調整後的子風險比（aSHR）和序列 FIB-4 分數的趨勢進行分析。
Main outcomes and measures: Outcomes included 10-year cumulative incidence of HCC and hepatic decompensation as well as transitions in liver fibrosis risk categories based on FIB-4 scores. Statin use was defined as exposure to a cumulative defined daily dose (cDDD) of 30 or more. Fibrosis progression was assessed through FIB-4 group transitions (low, intermediate, and high) over time. Outcomes were analyzed using adjusted subhazard ratio (aSHR) and trends in serial FIB-4 scores.

結果：分析包括 16,501 名參與者（平均[標準差]年齡，59.7 [11.0]歲；6750 名女性[40.9%]和 9751 名男性[59.1%]）患有慢性肝病，其中 3610 名為他汀類藥物使用者，12,891 名為非使用者。他汀類藥物使用者的肝細胞癌（HCC）10 年累積發生率顯著較低（3.8%對 8.0%；風險差異，-4.2%；95% CI，-5.3 至-3.1%）及肝臟失代償（10.6%對 19.5%；風險差異，-9.0%；95% CI，-10.6 至-7.3）相比於非使用者。HCC 的調整風險比（aSHR）為 0.67（95% CI，0.59 至 0.76），肝臟失代償的調整風險比為 0.78（95% CI，0.67 至 0.91）。接觸脂溶性他汀類藥物及他汀類藥物使用時間（≥600 cDDDs）與 HCC 及肝臟失代償風險的進一步降低相關。在 7038 名具有序列 FIB-4 數據的患者中，基線 FIB-4 分數中等的患者中，14.7%（95% CI，13.0%至 16.6%）的他汀類藥物使用者轉變為高風險組，而非使用者中為 20.0%（95% CI，18.6%至 21.5%）。對於基線 FIB-4 分數較高的患者，31.8%（95% CI，28.0% 至 35.9%）的他們在使用他汀類藥物後轉入中等風險組，7.0%（95% CI，5.2% 至 9.6%）轉入低風險組，而非使用者則分別為 18.8%（95% CI，17.2% 至 20.6%）和 4.3%（95% CI，3.5% 至 5.2%）（P < .001）。
Results: The analysis included 16 501 participants (mean [SD] age, 59.7 [11.0] years; 6750 females [40.9%] and 9751 males [59.1%]) with CLD, including 3610 statin users and 12 891 nonusers. Statin users exhibited a significantly lower 10-year cumulative incidence of HCC (3.8% vs 8.0.%; risk difference, -4.2%; 95% CI, -5.3 to -3.1%) and hepatic decompensation (10.6% vs 19.5%; risk difference, -9.0%; 95% CI, -10.6 to -7.3) compared with nonusers. The aSHR was 0.67 (95% CI, 0.59 to 0.76) for HCC and 0.78 (95% CI, 0.67 to 0.91) for hepatic decompensation. Exposure to lipophilic statins and duration of statin use (≥600 cDDDs) were associated with further reductions in HCC and hepatic decompensation risks. Among 7038 patients with serial FIB-4 data, patients with intermediate baseline FIB-4 scores, 14.7% (95% CI, 13.0% to 16.6%) of statin users transitioned to the high group compared with 20.0% (95% CI, 18.6% to 21.5%) of nonusers. For patients with high baseline FIB-4 scores, 31.8% (95% CI, 28.0% to 35.9%) of statin users transitioned to the intermediate group and 7.0% (95% CI, 5.2% to 9.6%) transitioned to the low-risk group, compared to 18.8% (95% CI, 17.2% to 20.6%) and 4.3% (95% CI, 3.5% to 5.2%) of nonusers, respectively (P < .001).

結論與相關性：這項隊列研究發現，他汀類藥物的使用與慢性肝病患者的肝細胞癌（HCC）和肝臟失代償風險降低相關，並且隨著時間的推移，FIB-4 組別的轉變有所改善。這些發現支持他汀類藥物在預防 HCC 和肝病進展中的潛在作用。
Conclusions and relevance: This cohort study found that statin use was associated with a reduced risk of HCC and hepatic decompensation in patients with CLD, as well as improved FIB-4 group transitions over time. These findings provide support for the potential role of statins in prevention of HCC and liver disease progression.

參考文獻 Reference

1. 金亨洙，艾爾-塞拉格。美國肝細胞癌的流行病學。當前胃腸病學報告。2019;21(4):17。doi:10.1007/s11894-019-0681-x – DOI – PubMed
  Kim HS, El-Serag HB. The epidemiology of hepatocellular carcinoma in the USA. Curr Gastroenterol Rep. 2019;21(4):17. doi:10.1007/s11894-019-0681-x – DOI – PubMed
1. Younossi Z, Stepanova M, Ong JP 等；全球非酒精性脂肪肝炎委員會。非酒精性脂肪肝炎是肝臟移植候選者中增長最快的肝細胞癌原因。臨床胃腸病學與肝臟病學。2019;17(4):748-755.e3. doi:10.1016/j.cgh.2018.05.057 – DOI – PubMed
  Younossi Z, Stepanova M, Ong JP, et al. ; Global Nonalcoholic Steatohepatitis Council . Nonalcoholic Steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol. 2019;17(4):748-755.e3. doi:10.1016/j.cgh.2018.05.057 – DOI – PubMed
1. Kim MH, Kim MY, Salloum S 等。阿托伐他汀有利於調節臨床肝細胞癌風險基因簽名。肝臟通訊。2022;6(9):2581-2593. doi:10.1002/hep4.1991 – DOI – PMC – PubMed
  Kim MH, Kim MY, Salloum S, et al. . Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature. Hepatol Commun. 2022;6(9):2581-2593. doi:10.1002/hep4.1991 – DOI – PMC – PubMed
1. Kim G, Kang ES。通過他汀類藥物預防肝細胞癌：臨床證據和合理機制。肝臟疾病研討會。2019;39(2):141-152. doi:10.1055/s-0039-1679956 – DOI – PubMed
  Kim G, Kang ES. Prevention of hepatocellular carcinoma by statins: clinical evidence and plausible mechanisms. Semin Liver Dis. 2019;39(2):141-152. doi:10.1055/s-0039-1679956 – DOI – PubMed
1. Arnaud C, Burger F, Steffens S 等。他汀類藥物減少人類肝細胞中白介素-6 誘導的 C 反應蛋白：他汀類藥物直接抗炎作用的新證據。動脈硬化、血栓形成與血管生物學。2005;25(6):1231-1236. doi:10.1161/01.ATV.0000163840.63685.0c – DOI – PubMed
  Arnaud C, Burger F, Steffens S, et al. . Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins. Arterioscler Thromb Vasc Biol. 2005;25(6):1231-1236. doi:10.1161/01.ATV.0000163840.63685.0c – DOI – PubMed
1. Pinyopornpanish K, Al-Yaman W, Butler RS, Carey W, McCullough A, Romero-Marrero C。他汀類藥物對非酒精性脂肪肝炎肝硬化患者肝細胞癌的化學預防效果。美國胃腸病學雜誌。2021;116(11):2258-2269. doi:10.14309/ajg.0000000000001347 – DOI – PubMed
  Pinyopornpanish K, Al-Yaman W, Butler RS, Carey W, McCullough A, Romero-Marrero C. Chemopreventive effect of statin on hepatocellular carcinoma in patients with nonalcoholic steatohepatitis cirrhosis. Am J Gastroenterol. 2021;116(11):2258-2269. doi:10.14309/ajg.0000000000001347 – DOI – PubMed
1. Sharma R, Simon TG, Hagström H 等人。使用他汀類藥物與非肝硬化慢性肝病患者嚴重肝病風險降低相關。臨床胃腸病學與肝臟病學。2024;22(4):749-759.e19. doi:10.1016/j.cgh.2023.04.017 – DOI – PubMed
  Sharma R, Simon TG, Hagström H, et al. . Statins are associated with a decreased risk of severe liver disease in individuals with noncirrhotic chronic liver disease. Clin Gastroenterol Hepatol. 2024;22(4):749-759.e19. doi:10.1016/j.cgh.2023.04.017 – DOI – PubMed
1. Simon TG, Duberg AS, Aleman S 等人。脂溶性他汀類藥物與慢性病毒性肝炎患者肝細胞癌及死亡風險的關聯：來自瑞典全國人口的結果。內科年鑑。2019;171(5):318-327. doi:10.7326/M18-2753 – DOI – PMC – PubMed
  Simon TG, Duberg AS, Aleman S, et al. . Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population. Ann Intern Med. 2019;171(5):318-327. doi:10.7326/M18-2753 – DOI – PMC – PubMed
1. Zou B, Odden MC, Nguyen MH. Statin use and reduced hepatocellular carcinoma risk in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2023;21(2):435-444.e6. doi:10.1016/j.cgh.2022.01.057 – DOI – PubMed
1. Hsiang JC, Wong GL, Tse YK, Wong VW, Yip TC, Chan HL. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: A propensity score landmark analysis. J Hepatol. 2015;63(5):1190-1197. doi:10.1016/j.jhep.2015.07.009 – DOI – PubMed
1. Simon TG, King LY, Zheng H, Chung RT. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C. J Hepatol. 2015;62(1):18-23. doi:10.1016/j.jhep.2014.08.013 – DOI – PMC – PubMed
1. Simon TG, Bonilla H, Yan P, Chung RT, Butt AA. Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: results from ERCHIVES. Hepatology. 2016;64(1):47-57. doi:10.1002/hep.28506 – DOI – PMC – PubMed
1. Vallet-Pichard A, Mallet V, Nalpas B, et al. . FIB-4: 一種在 HCV 感染中便宜且準確的纖維化標記。與肝活檢和纖維測試的比較。肝臟學。2007;46(1):32-36. doi:10.1002/hep.21669 – DOI – PubMed
  Vallet-Pichard A, Mallet V, Nalpas B, et al. . FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and fibrotest. Hepatology. 2007;46(1):32-36. doi:10.1002/hep.21669 – DOI – PubMed
1. Tsan YT, Lee CH, Wang JD, Chen PC. 他汀類藥物與乙型肝炎病毒感染患者肝細胞癌風險的關係。J Clin Oncol. 2012;30(6):623-630. doi:10.1200/JCO.2011.36.0917 – DOI – PubMed
  Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol. 2012;30(6):623-630. doi:10.1200/JCO.2011.36.0917 – DOI – PubMed
1. Zhou XD, Kim SU, Yip TC, et al. ; VCTE-Prognosis Study Group . Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease. Gut. 2024;73(11):1883-1892. doi:10.1136/gutjnl-2024-333074 – DOI – PubMed
1. Lee JI, Lee HW, Lee KS, Lee HS, Park JY. Effects of statin use on the development and progression of nonalcoholic fatty liver disease: a nationwide nested case-control study. Am J Gastroenterol. 2021;116(1):116-124. doi:10.14309/ajg.0000000000000845 – DOI – PubMed
1. Kim G, Jang SY, Nam CM, Kang ES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study. J Hepatol. 2018;68(3):476-484. doi:10.1016/j.jhep.2017.10.018 – DOI – PubMed
1. McGlynn KA, Hagberg K, Chen J, et al. . Statin use and risk of primary liver cancer in the Clinical Practice Research Datalink. J Natl Cancer Inst. 2015;107(4):djv009. doi:10.1093/jnci/djv009 – DOI – PMC – PubMed
1. Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med. 2020;382(11):1018-1028. doi:10.1056/NEJMoa1912035 – DOI – PMC – PubMed
1. Simon TG, Ma Y, Ludvigsson JF, et al. . Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol. 2018;4(12):1683-1690. doi:10.1001/jamaoncol.2018.4154 – DOI – PMC – PubMed
1. Trebicka J, Hennenberg M, Odenthal M, et al. . Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol. 2010;53(4):702-712. doi:10.1016/j.jhep.2010.04.025 – DOI – PubMed
1. SenBanerjee S, Lin Z, Atkins GB, et al. . KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med. 2004;199(10):1305-1315. doi:10.1084/jem.20031132 – DOI – PMC – PubMed
1. Alvarado-Tapias E, Brujats A, Puente A, 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. 2024. doi:10.1097/HEP.0000000000001148 – DOI – PubMed
1. Kato S, Smalley S, Sadarangani A, et al. . Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase. J Cell Mol Med. 2010;14(5):1180-1193. doi:10.1111/j.1582-4934.2009.00771.x – DOI – PMC – PubMed
1. Thakkar N, Slizgi JR, Brouwer KLR. Effect of liver disease on hepatic transporter expression and function. J Pharm Sci. 2017;106(9):2282-2294. doi:10.1016/j.xphs.2017.04.053 – DOI – PMC – PubMed
1. Chang FM, Wang YP, Lang HC, et al. . Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: a population-based study. Hepatology. 2017;66(3):896-907. doi:10.1002/hep.29172 – DOI – PubMed
1. Mohanty A, Tate JP, Garcia-Tsao G. 他汀類藥物與患有乙型肝炎相關的代償性肝硬化的退伍軍人中，脫補償和死亡風險降低相關。胃腸病學。2016;150(2):430-40.e1. doi:10.1053/j.gastro.2015.10.007 – DOI – PMC – PubMed
  Mohanty A, Tate JP, Garcia-Tsao G. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis c-related compensated cirrhosis. Gastroenterology. 2016;150(2):430-40.e1. doi:10.1053/j.gastro.2015.10.007 – DOI – PMC – PubMed