高雄醫學大學研究發展處 - Metformin降低臺灣糖尿病和慢性C型肝炎患者抗病毒治療成功後的肝細胞癌發病率

Metformin降低臺灣糖尿病和慢性C型肝炎患者抗病毒治療成功後的肝細胞癌發病率
Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan

Metformin降低臺灣糖尿病和慢性C型肝炎患者抗病毒治療成功後的肝細胞癌發病率
Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan

Metformin降低臺灣糖尿病和慢性C型肝炎患者抗病毒治療成功後的肝細胞癌發病率

目前已知糖尿病會增加慢性C型肝炎患者罹患肝細胞癌的風險。Metformin目前作為糖尿病治療的一線藥物，根據糖尿病患者的兩項系統性研究結果得知，Metformin的使用與HCC發生的風險較低相關，此外與使用其他抗糖尿病療法的患者相比，HCC患者在Metformin治療糖尿病後的總體生存期和無復發生存期更長。然而，尚不清楚Metformin是否有助於抗病毒治療後降低 HCC 風險。本研究是以在臺灣的一個大規模多研究中心計畫中（T-COACH）根據干擾素治療后達到持續病毒學反應（SVR）的慢性C型肝炎患者族群，目的是評估Metformin是否可以降低糖尿病和慢性C型肝炎患者在成功抗病毒治療後的肝細胞癌發病率。慢性C型肝炎患者具SVR至少 1年發生HCC的病例通過與疾病和癌症登記資料庫的鏈接確認。在7249個慢性C型肝炎患者中，781(佔10.8%)個案為糖尿病患者，其中接受Metformin治療的有647個案(佔82.8%)。在追蹤期間(中位數為4.4年)中，有227個患者發生HCC。非Metformin治療的患者5年累積肝細胞癌發病率為10.9%，使用Metformin治療的患者則為 2.6%，而無糖尿病患者的5年累積肝細胞癌發病率為3.0% (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively)。在利用Cox回歸分析中，肝硬化是與發生HCC高風險顯著相關的最重要因素，其他重要因素依次如糖尿病非Metformin治療，年齡較大者，男性和肥胖都有相關，而使用statin類藥物治療高脂血症的患者與HCC發生的風險相關較低。在使用兩個最關鍵的危險因素，肝硬化和非Metformin治療因子，構建了一個簡單的風險模型，可以預測SVR後慢性C型肝炎患者HCC發生的風險。Metformin的使用被證明可以降低所有肝臟相關併發症的風險。總而言之，對患有糖尿病和慢性C型肝炎的個體進行成功的抗病毒治療後，Metformin的使用大大降低了HCC風險。建構肝硬化和糖尿病非Metformin使用的簡單風險分層模型可以預測慢性C型肝炎患者SVR後的長期結果。本研究證明在一項大規模的全國性多研究中心計畫中，Metformin治療在糖尿病和慢性C型肝炎患者中成功抗病毒治療后可以降低肝細胞癌（HCC）的發病率。雖然成功的抗病毒治療大大降低了慢性C型肝炎患者的肝細胞癌風險，但肝硬化、糖尿病、肥胖症和老年人罹患肝細胞癌的風險仍然很高。本研究建構由兩個關鍵的不利因素組成的簡單風險模型，即非Metformin治療糖尿病和肝硬化的患者，可以預測慢性C型肝炎患者成功抗病毒治療後，肝細胞癌和主要肝臟相關併發症的風險.強烈建議糖尿病和慢性C型肝炎患者在病毒根除後使用Metformin治療，以降低肝細胞癌的風險。

圖形摘要

余明隆 Metformin

【應用與亮點】：

1.糖尿病與慢性C型肝炎患者產生肝細胞癌風險增加有關。

2.在成功治療C型肝炎病毒後，糖尿病仍會增加肝細胞癌產生的風險。

3.使用metformin治療糖尿病可大大降低成功抗C型肝炎病毒後產生肝細胞癌的風險。

4.利用一個簡單的風險分層模型可以預測肝細胞癌和其他主要肝臟相關併發症的風險。

【研究團隊】

團隊成員：蔡佩倩助理研究員、余明隆教授、莊萬龍教授、戴嘉言教授、黃志富教授、黃釧峰教授、葉明倫教授

代表單位：液態生物檢體暨世代研究中心及醫學院肝炎研究中心

團隊簡介：余明隆教授研究團隊，皆任職於是高雄醫學大學附設中和紀念醫院肝膽胰內科的主治醫師，同時也是醫學院肝炎研究中心及液態生物檢體暨世代研究中心的成員，致力於肝臟疾病之病因、致病機轉、治療及預防的研究及服務。

研究聯繫：fish6069@gmail.com

【論文資訊】

論文出處： J Hepatol.2023 Feb;78(2):281-292.

全文下載: https://doi: 10.1016/j.jhep.2022.09.019.

Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan

Background & aims: Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). Metformin is recommended as a first-line medication for DM treatment. Two systematic reviews on individuals with diabetes documented that metformin use was associated with a lower risk of HCC, and longer overall and recurrence-free survival after curative therapies for those with HCC, compared to those using other antidiabetic therapies. However, it is not known whether metformin has a role in HCC risk reduction after antiviral therapy. In this study, We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy. Methods: Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases. Results: Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications. Conclusions: Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR.

Impact and implications: The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.

Graphical Abstract

余明隆 Metformin

Application and Highlights:

1.Diabetes mellitus is associated with an increased risk of HCC in individuals with CHC.

2.Diabetes mellitus still increases the risk of HCC after successful antiviral therapy.

3.Use of metformin for DM greatly reduces HCC risk after successful antiviral therapy.

4. A simple risk stratification model could predict the risk of HCC and other major liver-related complications.

Research Team Members:

Pei-Chien Tsai, Ming-Lung Yu, Wan-Long Chuang, Chia-Yen Dai, Jee-Fu Huang, Chung-Feng Huang, Ming-Lun Yeh

Representative Department:

Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University.

Introduction of Research Team:

Professor Ming-Lung Yu are members of the Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University. They dedicate to the research and service of Liver diseases, including etiologies, epidemiology, pathogenesis, therapeutic modalities, and prevention of hepatitis B, hepatitis C, steatohepatitis, and liver cancers.

Contact Email: fish6069@gmail.com

Publication: J Hepatol.2023 Feb;78(2):281-292.

Full-Text Article: https://doi: 10.1016/j.jhep.2022.09.019.

Metformin降低臺灣糖尿病和慢性C型肝炎患者抗病毒治療成功後的肝細胞癌發病率

Metformin降低臺灣糖尿病和慢性C型肝炎患者抗病毒治療成功後的肝細胞癌發病率

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