Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy

Tsai, Pei-Chien; Huang, Chung-Feng; Yeh, Ming-Lun; Hsieh, Meng-Hsuan; Kuo, Hsing-Tao; Hung, Chao-Hung; Tseng, Kuo-Chih; Lai, Hsueh-Chou; Peng, Cheng-Yuan; Wang, Jing-Houng; Chen, Jyh-Jou; Lee, Pei-Lun; Chien, Rong-Nan; Yang, Chi-Chieh; Lo, Gin-Ho; Kao, Jia-Horng; Liu, Chun-Jen; Liu, Chen-Hua; Yan, Sheng-Lei; Lin, Chun-Yen; Su, Wei-Wen; Chu, Cheng-Hsin; Chen, Chih-Jen; Tung, Shui-Yi; Tai, Chi‐Ming; Lin, Chih-Wen; Lo, Ching-Chu; Cheng, Pin-Nan; Chiu, Yen-Cheng; Wang, Chia-Chi; Cheng, Jin-Shiung; Tsai, Wei-Lun; Lin, Han-Chieh; Huang, Yi-Hsiang; Chen, Chi-Yi; Huang, Jee-Fu; Dai, Chia-Yen; Wan-Long, Wan-Long; Bair, Ming-Jong; Yu, Ming-Lung; ,

doi:.0..

Original Article

Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy

Pei-Chien Tsai¹, Chung-Feng Huang¹, Ming-Lun Yeh¹, Meng-Hsuan Hsieh^1,2, Hsing-Tao Kuo³, Chao-Hung Hung⁴, Kuo-Chih Tseng⁵, Hsueh-Chou Lai⁶, Cheng-Yuan Peng⁶, Jing-Houng Wang⁷, Jyh-Jou Chen⁸, Pei-Lun Lee⁸, Rong-Nan Chien⁹, Chi-Chieh Yang¹⁰, Gin-Ho Lo¹¹, Jia-Horng Kao^12,13, Chun-Jen Liu^12,13, Chen-Hua Liu^12,13, Sheng-Lei Yan¹⁴, Chun-Yen Lin⁹, Wei-Wen Su¹⁵, Cheng-Hsin Chu¹⁶, Chih-Jen Chen¹⁶, Shui-Yi Tung⁶, Chi‐Ming Tai¹¹, Chih-Wen Lin¹¹, Ching-Chu Lo¹⁷, Pin-Nan Cheng¹⁸, Yen-Cheng Chiu¹⁸, Chia-Chi Wang¹⁹, Jin-Shiung Cheng²⁰, Wei-Lun Tsai²⁰, Han-Chieh Lin²¹, Yi-Hsiang Huang^21,22, Chi-Yi Chen²³, Jee-Fu Huang¹, Chia-Yen Dai¹, Wan-Long Wan-Long¹, Ming-Jong Bair²⁴, Ming-Lung Yu^1,7,25, T-COACH Study Group

¹Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Centre, Kaohsiung Medical University Hospital; Hepatitis Research Centre, School of Medicine and Centre for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
²Health Management Centre, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
³Division of Hepatogastroenterology, Department of Internal Medicine, Chi Mei Medical Centre, Tainan, Taiwan
⁴Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
⁵Department of Gastroenterology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
⁶Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
⁷Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
⁸Division of Gastroenterology and Hepatology, Chi-Mei Medical Centre, Liouying, Tainan, Taiwan
⁹Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Centre, Chang Gung Memorial Hospital, Keelung, Taiwan
¹⁰Division of Gastroenterology, Department of Internal Medicine, Show Chwan Memorial Hospital, Changhua, Taiwan
¹¹Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital and School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
¹²Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
¹³Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan
¹⁴Division of Gastroenterology, Department of Internal Medicine, Chang Bing Show-Chwan Memorial Hospital, Changhua, Taiwan
¹⁵Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
¹⁶Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
¹⁷Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital-Daya, Chiayi, Taiwan
¹⁸Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
¹⁹Division 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
²⁰Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
²¹Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
²²Institute of Clinical Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
²³Department of Internal Medicine, Chiayi Christian Hospital, Chiayi, Taiwan
²⁴Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung; Mackay Medical College, Taipei, Taiwan
²⁵School 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 ,
Email: a5963@mmh.org.tw
Ming-Lung Yu ,
Email: fish6069@gmail.com

Received: January 16, 2024 Revised: April 18, 2024 Accepted: April 18, 2025

ABSTRACT

Backgrounds
and Aim: Chronic hepatitis C (CHC) patients who fail antiviral therapy have a high risk of developing hepatocellular carcinoma (HCC). We investigated the effects of metformin and statins, commonly used to treat diabetes mellitus (DM) and hyperlipidemia (HLP), on HCC risk in CHC patients who failed antiviral therapy.
Methods
CHC patients with failed interferon-based therapy were enrolled in a large-scale multicenter cohort study in Taiwan (T-COACH). HCC occurrence 1.5 years after the end of antiviral therapy was identified by linking to the cancer registry databases from 2003 to 2019. After considering death and liver transplantation as competing risks, Gray's cumulative incidence and Cox sub-distribution hazards for HCC development were used.
Results
Among the 2,779 CHC patients, 480 (17.3%) developed new-onset HCC and 238 (8.6%) died after antiviral therapy. Metformin non-users with DM had a 51% higher risk of liver cancer than patients without DM, while statin users with HLP had a 50% lower risk of liver cancer than patients without HLP. The 5-year cumulative incidence of HCC was 16.5% in metformin non-users, significantly higher in metformin non-users than in patients without DM (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Conversely, HLP statin users had a significantly lower HCC risk than patients without HLP (3.8% vs. 12.5%; aSHR=0.50; P<0.001). Notably, the unfavorable effect of non-metformin use on increased HCC risk was mainly observed among patients without cirrhosis but not in patients with cirrhosis. In contrast, a favorable effect of statins reduced the risk of HCC in both cirrhotic and non-cirrhotic patients.
Conclusion
Metformin for DM and statins for HLP have chemopreventive effects on HCC risk in CHC patients who failed antiviral therapy. These findings emphasize the importance of personalized preventive strategies for managing patients with these clinical profiles.

KeyWords: Hepatitis C; Hepacivirus; hepatocellular carcinoma; metformin; statins