Clin Mol Hepatol > Volume 30(3); 2024 > Article
Clinical and Molecular Hepatology 2024;30(3): 468-486.
doi: https://doi.org/10.3350/cmh.2024.0038
Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy
Pei-Chien Tsai1,2, Chung-Feng Huang1,2, Ming-Lun Yeh1,2, Meng-Hsuan Hsieh1,2,3, Hsing-Tao Kuo4, Chao-Hung Hung5, Kuo-Chih Tseng6, Hsueh-Chou Lai7, Cheng-Yuan Peng7, Jing-Houng Wang8, Jyh-Jou Chen9, Pei-Lun Lee9, Rong-Nan Chien10, Chi-Chieh Yang11, Gin-Ho Lo12, Jia-Horng Kao13,14, Chun-Jen Liu13,14, Chen-Hua Liu13,14, Sheng-Lei Yan15, Chun-Yen Lin10, Wei-Wen Su16, Cheng-Hsin Chu17, Chih-Jen Chen17, Shui-Yi Tung7, Chi‐Ming Tai12, Chih-Wen Lin12, Ching-Chu Lo18, Pin-Nan Cheng19, Yen-Cheng Chiu19, Chia-Chi Wang20, Jin-Shiung Cheng21, Wei-Lun Tsai21, Han-Chieh Lin22, Yi-Hsiang Huang22,23, Chi-Yi Chen24, Jee-Fu Huang1,2, Chia-Yen Dai1,2, Wan-Long Chung1,2, Ming-Jong Bair25 , Ming-Lung Yu1,2,8,26 , T-COACH Study Group
1Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Centre, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
2Hepatitis Research Centre, School of Medicine and Centre for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
3Health Management Centre, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
4Division of Hepatogastroenterology, Department of Internal Medicine, Chi Mei Medical Centre, Tainan, Taiwan
5Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
6Department of Gastroenterology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
7Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
8Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
9Division of Gastroenterology and Hepatology, Chi-Mei Medical Centre, Liouying, Tainan, Taiwan
10Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Centre, Chang Gung Memorial Hospital, Keelung, Taiwan
11Division of Gastroenterology, Department of Internal Medicine, Show Chwan Memorial Hospital, Changhua, Taiwan
12Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital and School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
13Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
14Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan
15Division of Gastroenterology, Department of Internal Medicine, Chang Bing Show-Chwan Memorial Hospital, Changhua, Taiwan
16Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
17Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
18Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital-Daya, Chiayi, Taiwan
19Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
20Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, New Taipei, Taiwan
21Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
22Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
23Institute of Clinical Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
24Department of Internal Medicine, Chiayi Christian Hospital, Chiayi, Taiwan
25Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung; Mackay Medical College, Taipei, Taiwan
26School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Centre of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
Correspondence :  Ming-Jong Bair ,
Tel: +886-89-310150, Fax: +886-89-361491, Email: a5963@mmh.org.tw
Ming-Lung Yu ,
Tel: +886-73121101 #7475, Fax: +886-73123955, Email: fish6069@gmail.com
Received: January 16, 2024  Revised: April 18, 2024   Accepted: April 18, 2025
ABSTRACT
Background/Aims
Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients.
Methods
We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development.
Results
Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients.
Conclusions
Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.
KeyWords: Hepatitis C; Hepacivirus; Hepatocellular carcinoma; Metformin; Statins

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