降血脂藥品statins與肝損傷風險:病例對照研究

Statins and the Risk of Liver Injury: A Population-based Case-control Study

陳冠霖(Guan-Lin Chen)

指導教授 ： 沈麗娟

共同指導教授 ： 蕭斐元(Fei-Yuan Sharon Hsiao)

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2013年)

https://doi.org/10.6342/NTU.2013.10503

摘要

研究背景：Statins是目前最廣泛使用在降血脂的藥品，其在上市初期即被關注其可能的肝毒性，但一直以來都缺乏有系統的研究來支持其與肝毒性的相關性。在台灣藥物不良反應通報系統的案例分析中，statins造成的肝損傷有相當高的通報數，此與目前已發表的文獻有所差異。
研究目的：利用台灣健保資料庫來探討statins與肝損傷的相關性，並進一步探討statins之使用狀況與病人的特性是否為肝損傷的風險因子之一。
研究材料與方法　本研究為一病例對照研究，利用健保資料庫2000、2005、2010之百萬承保歸人檔為研究材料（涵蓋人口約300萬人）。研究族群為2001年至2009年間年齡大於等於20歲，並排除進入cohort前被診斷過病毒性肝炎與慢性肝病以外的肝病或資料不全的病人。病例為2002年至2009年間曾因肝損傷而住院的病人，而非因肝損傷住院的病人作為控制組，並藉由性別、年齡與index date作為配對標準，進行1:4的配對。資料分析利用mutivariable conditional logistic regression進行odd ratio的預測並校正干擾因子，也利用分層分析的方式來檢視可能的干擾。
研究結果：在研究期間內收錄研究族群共2,230,087人，排除18449人，最後共2,211,638人進入此研究。得病例共4166人，配對後病例組與對照組共4165人與16660人。結果顯示整體使用statins與肝損傷的相關性並不顯著（adjusted odd ratio(aOR) 1.04; 95% CI [0.90-1.19]），累積暴露≥120天（aOR 1.07; 95% CI [0.91-1.27]）與累積劑量≥120 DDD（aOR 1.14; 95% CI [0.95-1.37]）亦無顯著相關，而statin事件前劑量大於等於1 DDD（aOR 1.55; 95% CI [1.14-2.11]）與事件前使用rosuvastatin（aOR 1.38; 95% CI [1.03-1.85]）有統計上顯著相關。在分層分析中，以病人是否患有肝病來分析，在無肝病的族群中仍存在事件前劑量≥1 DDD與肝損傷的相關性有統計上的顯著（aOR 1.81; 95% CI [1.22-2.67]），但在有患病的病人則沒有看到此一現象。
結論：本研究並未發現整體使用statins與肝損傷的相關性，僅有使用rosuvastatin與statins劑量大於等於1 DDD時可能增加肝損傷的風險，並且有肝病的病人並不會增加statins造成肝損傷的風險。

關鍵字

Statin ； 肝損傷 ； 全民健保資料庫 ； 病例對照研究

並列摘要

Background: Statins are widely used in the treatment of hyperlipidemia in the world. When they were launched into the market, they have been concerned about the side effects of hepatotoxicity. However, there is a lack of systemic studies to support the statin-associated liver injury. Statins were reported with number of cases with liver injury in Taiwan adverse drug reaction (ADR) reporting system. The data conflict with the current concept, rare statin-induced liver injury.
Objective: Using Taiwan's National Health Insurance Research Database (NHIRD), the aim of this study was to evaluate the association between statin use and liver injury in Taiwanese.
Materials and Methods: This is a case-control study using 2000, 2005, 2010 Longitudinal Health Insurance Database(LHID) as study materials (covering about a population of 3 millions). The study population was defined as patients’ age ≥ 20 years old between 2001 and 2009. The exclusion criteria were patients who were diagnosed of liver diseases before the cohort entry date and patients whose data were incomplete. The cases were patients who were admitted with a primary diagnosis of liver injury between 2002 and 2009, and the controls were patients who were admitted without liver injury. The cases were matched with 4 controls by age, sex and the index date. Multivariable conditional regression models were used to estimate odds of liver injury associated with statin use. Furthermore, we conduct stratified analyses to assess the impact of the history of liver diseases on this potential association.
Results: In the study period, 2,230,087 patients met the inclusion criteria. After excluding 18,449 patients, 2,211,638 patients served as the study population and 4,166 patients were the cases. After matching, 4,165 and 16,660 patients were the case and the controls, respectively. Overall, users of statins were not associated with risk of liver injury (adjusted odds ratio (aOR) 1.04; 95% confidence interval (CI) [0.90-1.19]) as compared to non-users. Increased cumulative duration (aOR 1.07; 95% CI [0.91-1.27]) and dose (OR 1.14; 95% CI [0.95-2.11]) of statins were not associated with risk of liver injury. Nevertheless, a higher dose of statin (≥ 1 defined daily dose (DDD) (aOR 1.55; 95% CI [1.14-2.11]) and use of rosuvastatin before event of liver injury (aOR 1.38; 95% CI [1.03-1.85]) were significantly associated with liver injury. In the startifed analyses, patients without liver disease still had significant association with statin’s dose before event ≥ 1 DDD and liver injury (aOR 1.81; 95% CI [1.22-2.67]). However, we do not see this situation in patients with liver diseases.
Conclusions: This population-based study extends previous evidence by exploring the potential association between statins use and risk of liver injury. Liver diseases are not associated with increased risk of statin-induced liver injury in patients. However, our findings suggest that only the dose of statin ≥ 1 DDD and the use of rosuvastion may increase the risk of liver injury.

並列關鍵字

statin ； liver injury ； National Health Insurance Research Database (NHIRD) ； case-control study

參考文獻

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