Statin 合併 Ezetimibe 治療對於慢性腎臟病患者的效益: 系統性回顧與統合分析

Abstract

研究所別：國立台灣大學公共衛生學院公共衛生碩士學位學程 論文名稱：Statin合併Ezetimibe治療對於慢性腎臟病患者的效益： 系統性回顧與統合分析 指導教授：杜裕康 教授、賴台軒 臨床助理教授 研 究 生：林義智 研究背景：慢性腎臟病患者已證實比起一般人與較高的心血管事件和死亡發生風險相關，高膽固醇血症和高血脂症等脂質代謝異常是慢性腎臟病患者常見的合併症之一，其除了會促使進一步的腎功能惡化、腎絲球過濾率的降低以及蛋白尿的增加之外，也會增加重大心血管事件發生的風險，血清低密度脂蛋白膽固醇 ( low-density lipoprotein cholesterol, LDL-C )濃度過高，已被證實是發生動脈粥樣硬化 ( atherosclerosis )的主要危險因子，而動脈粥樣硬化對於冠狀動脈心臟病(coronary heart disease，CHD ) 及其他重大心血管事件的發生扮演重要的角色，因此有效控制血清低密度脂蛋白膽固醇濃度成為預防心血管事件發生的重要治療策略。statin加上ezetimibe的合併治療是否可以成為慢性腎臟病患者另一項加強控制血脂代謝異常的安全治療組合是需要進一步探究的主題，此論點尚未有更具實證客觀的結論，故本研究將以此論點進行文獻整合分析與探討。 研究目的：本研究目的為藉由系統性文獻回顧暨統合分析（systematic review and meta-analysis）的方法來探討慢性腎臟病患者使用statin加上ezetimibe合併治療的對於任何病因死亡或重大心血管事件發生的效益，並分析使用此合併治療安全性的狀況。 研究方法：本研究方法為系統性文獻回顧加上統合分析，文獻資料獲得是透過搜索文獻資料庫，包括PUBMED、EMBASE、MEDLINE及Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library，文獻年份範圍為2018年9月1日以前的相關文獻，收集內容為符合慢性腎臟病患者使用statin加上ezetimibe降血脂藥物合併治療比較單用statin或安慰劑治療效益的隨機控制臨床試驗（randomized controlled trials，RCTs）研究文獻，主要研究終點為任何病因死亡或重大心血管事件，次要研究終點包括血清低密度脂蛋白膽固醇下降之效益以及藥物不良反應或安全性評估。資料統計分析是使用Revman 5.3.5軟體進行資料彙整合成，此研究品質評估將依照PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses)的規範進行。 研究結果：在篩選出的1495篇文獻中，最後符合條件包括7個臨床試驗中的8篇文獻，共計14016位慢性腎臟病參與者，經統計分析後，合併治療組在任何原因死亡或重大心血管事件顯著較少，風險比（risk ratio，RR）為0.87，95%信賴區間為0.81至0.94，p值為0.0002小於0.05。關於治療後血清低密度脂蛋白膽固醇濃度下降效益，statin加上ezetimibe合併治療比起單一statin治療可以多降低平均17.22 mg/dL低密度脂蛋白膽固醇濃度，95%信賴區間為-18.93至-15.51，p值小於0.0001，有達到統計上的顯著差異。在藥物使用安全性評估方面，任何明顯藥物不良反應事件（RR為0.88，95%信賴區間為0.72至1.08，p值為0.24）、肌肉相關症狀（RR為0.96，95%信賴區間為0.77至1.18，p值為0.67）、肝膽腸胃相關症狀或病症（RR為1.01，95%信賴區間為0.66至1.54，p值為0.98）、肝膽方面血清檢驗值異常（RR為0.63，95%信賴區間為0.21至1.91，p值為0.42）以及血清肌肉酵素濃度上升或肌肉病症（RR為0.59，95%信賴區間為0.28至1.27，p值為0.18）上述的發生，除了肝膽腸胃相關症狀或病症外，statin加上ezetimibe合併治療相關副作用的發生率皆低於控制組，但皆未達到統計上的顯著差異。 結論：慢性腎臟病患者使用Statin加上ezetimibe的合併治療比較單獨使用statin或安慰劑治療可以更顯著地降低任何病因死亡或重大心血管事件的發生，此外，合併治療也比單獨使用statin治療可以顯著降低更多血清低密度脂蛋白膽固醇濃度，而藥物不良反應在兩種治療方式下並沒有達到顯著差異。

Graduate school: Master of Public Health Degree Program, College of Public Health, National Taiwan University Title of practicum report (thesis): The Effects of Statins plus Ezetimibe therapy in Patients with Chronic Kidney Disease：A Systematic Review and Meta-analysis Adviser: Professor Tu, Yu-Kang; Lai, Tai-Shaun, Ph.D. Graduate student: Lin, Yi-Chih Background: Chronic kidney disease (CKD) is associated with increased risks of cardiovascular disease, end stage renal disease (ESRD), and death. Dyslipidemia is one of the most common complication in patients with CKD, and it promote further renal damage and deterioration of renal function. Statin (3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) has been the most common medicine for treatment of dyslipidemia and generally used for prevention of cardiovascular events in patients with cardiovascular disease. Ezetimibe is an inhibitor of cholesterol intestinal absorption. Co-administered statin with ezetimibe therapy provided an additional lipid-lowering effect and allow more patients to reach goal of the serum low-density lipoprotein cholesterol (LDL-C). Hence, we conducted a systematic review and meta-analysis to clarify the effect and safety about statin plus ezetimibe combined therapy in patients with CKD. Objectives: To evaluate the efficacy of all-causes mortality or MACEs and the safety of statin plus ezetimibe combined therapy in patients with CKD. Methods: This study design was a systemic review and meta-analysis. The data sources were derived from four databases, including PUBMED, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library. We enrolled studies consisting of randomized controlled trials (RCTs) with comparing statin plus ezetimibe combined therapy with statin monotherapy or placebo in patients with CKD. The primary outcome was all-causes mortality or MACEs. The second outcomes were the decreased degree of serum LDL-C and associated adverse events, including muscle related symptoms, gastrointestinal or hepatobiliary symptoms or illness, abnormal laboratory values of the hepatobiliary system and muscle destruction. Results: We included 14,016 patients with chronic kidney disease in total seven screened RCTs. All-causes mortality or MACEs in statin plus ezetimibe combined therapy group were significantly decreased than those in statin monotherapy or placebo group (RR 0.87, 95% CI 0.81 to 0.94, p=0.0002). Statin plus ezetimibe combined therapy had significant effect on reduction of serum LDL-C level (mean difference 17.22 mg/dL, 95% CI -18.93 to -15.51, p<0.0001). Concerned about evaluation of safety, any events of adverse effects (RR 0.88, 95% CI 0.72 to 1.08，p=0.24）, muscle related symptoms (RR 0.96, 95% CI 0.77 to 1.18，p=0.67）, gastrointestinal or hepatobiliary symptoms or illness (RR 1.01，95% CI 0.66 to 1.54，p=0.98), abnormal laboratory values of the hepatobiliary system(RR 0.63, 95% CI 0.21 to 1.91, p=0.42) and myopathy or rhabdomyolysis (RR 0.59, 95% CI 0.28 to 1.27, p=0.18), there were no significant difference between statin and ezetimibe combination therapy and statin monotherapy. Conclusion: Statin and ezetimibe combination therapy not only significantly reduced all-causes mortality or MACEs comparing with statin monotherapy or placebo but also serum LDL-C level comparing with statin monotherapy in patients with CKD. There was no obvious difference in evaluation of safety and adverse events between statin and ezetimibe combination therapy and statin monotherapy.