B型肝炎病人使用statin和metformin對癌症風險之世代研究

Abstract

中文摘要 研究目的: HBV感染者可能會增加肝臟和非肝臟癌症的發病率。可能的原因包括HBV感染的直接效應，在宿主的免疫系統因為慢性感染而造成免疫系統的變化。因此，服用statins類藥物或metformin可以降低炎症浸潤且降低發炎反應，導致減少癌症的形式有可能的。使用statins類藥物和metformin與癌症風險之間的連接，目前還不清楚，我們的研究在調查是否statins類藥物和metformin的使用是否有可能降低HBV感染患者的癌症發病率。本研究的目的是假設statins類藥物和metformin可以減少癌症在HBV感染相關慢性肝病患者的發病率。 方法: 使用台灣健保資料庫從2000年到2008年，這個世代研究包括HBV患者（N=71,847），從2000年1月1日和2008年12月31日之間的診斷記錄。直到2008年年底。 HBV患者的statins類藥物和/或metformin的用法和癌症的風險之間的相關性進行了分析。使用Cox風險回歸分析來評估已知的干擾因素調整後的發病率。利用Kaplan-Meier檢驗statins類藥物或metformin服用後的癌症的累積風險。 結果: 一共有71,824 HBV感染患者被納入世代研究。我們的研究結果發現metformin或statins類藥物的使用，可以減少癌症的發病率。尤其在兩藥同時服用時癌症減少更明顯。HBV患者只服用statins類藥物的話，所有的癌症，肝癌，肝癌，肺癌，胃癌，大腸癌，食道癌，前列腺癌和不常見的癌症的發生率均有達統計意義的下降。我們似乎可以觀察到statins類藥物和metformin聯合使用時具有協同效應，可以發現在單獨使用statins類藥物或metformin時無統計意義的癌症，在女性HBV感染患者的乳腺癌，胰腺癌，乳腺癌和子宮頸癌發生率有達統計意義的下降。而男性患者中的大腸癌也有達統計意義的下降。在劑量使用上也發現了具有劑量依賴效應。 結論: 我們的世代研究發現statins類藥物和metformin對B肝帶原者中具有其癌症保護作用。我們的研究顯示，statins類藥物或metformin在降低癌症的發病率與劑量反應效應上均具備其正向且獨立的化學預防效果。且合併使用statins和metformin時，在多種癌症上面顯現出加成或是具有藥物協同的抗癌效果。

Abstract Background: Chronic infection with hepatitis B virus (HBV) often causes chronic inflammation of the liver with an increased incidence of hepatocellular carcinoma. HBV-infected individuals also may be at increased incidence of non-liver cancers. Taking a statin or metformin may decrease inflammation and infiltration, which may, as a result, reduce the risk of liver cancer or other major cancers in patients with HBV infection. The purpose of this study was to evaluate the hypothesis that a statin and metformin could reduce the incidence of liver cancer (HBV) or non-liver cancers in patients with hepatitis B virus. Method: Using the Taiwan Longitudinal Health Insurance Database 2000 to 2008, this cohort study comprised patients with a recorded diagnosis of HBV (N=71,847) between January 1, 2000 and December 31, 2008. Each patient was followed until the end of 2008. The occurrence of HCC or a non-liver cancer was evaluated in patients who either were or were not taking a statin or metformin. Cox proportional hazard regressions were used to evaluate the cancer incidence after adjusting for known confounding factors. Results: A total of 71,824 HBV-infected patients comprised the study cohort. Our study showed that either metformin or statin use was associated with a reduction in the incidence of cancer. This was most prominent in patients taking both a statin and metformin. The adjusted HRs for patients using only a statin were 0.52 (95% CI, 0.48 to 0.57) for all cancers, 0.28 (95% CI, 0.23 to 0.35) for liver cancers, and 0.63 (95% CI, 0.57 to 0.70) for non-liver cancers. Patients taking only metformin had risk-adjusted HRs of 0.82 (95% CI, 0.75 to 0.90) for all cancers, 0.97 (95% CI, 0.84 to 1.14) for liver cancers, and 0.75 (95% CI, 0.67 to 0.84) for non-liver cancers. A dose-dependent effect of statin use for chemoprevention was observed for all cancers, including both liver cancer and non-liver cancers. A dose-dependent effect of metformin was also seen in liver cancers and non-liver cancers without stratification into different cDDDs of statin use. Conclusion: This population-based cohort study investigated the protective effect of a statin and metformin against cancer events in the patients with HBV infection. Our study demonstrated that either a statin or metformin were independent chemo-preventive agents with a dose-response effect in reducing the incidence of cancer with a dose-response effect of the agents and an additive or synergistic effect of combining a statin and metformin use in reducing the incidence of many cancers.