降血脂藥物對於慢性腎臟病合併血脂異常之患者在心血管事件與腎功能之效益

Abstract

研究背景: 慢性腎臟病是發生心血管疾病的主要危險因素之一，也是導致死亡的主要原因之一，慢性腎臟病患者已被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。 由於在 尿毒環境中使得血清脂蛋白代謝失調，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，而脂質代謝異常若未加以控制，除了可能導致腎功能更 加惡化外，也會增加重大心血管事件發生的風險，繼而造成死亡風險的上升。對於慢性 腎臟病又合併脂質代謝異常患者，此類患者將可能暴露更高的心血管疾病和事件發生和 腎臟功能更加惡化的風險。因此，妥善控制慢性腎臟病患者的脂質代謝異常的問題是相 當重要的臨床議題。降血脂藥物，如 statin、ezetimibe 以及 fibrates 等，已被用於減少血 脂異常患者的主要不良心血管事件和治療動脈粥狀硬化性心血管疾病。然而，這類藥物 對於慢性腎臟病合併血脂異常患者在心血管疾病或事件和腎臟疾病預後的影響仍欠缺客 觀實證的結論; 此外，這些臨床上已在使用的降血脂藥物其各自對於慢性腎臟病族群在 心血管和腎功能預後的效益程度仍有待進一步比較，以提供臨床工作者更適當的藥物選擇。 研究目的: 本研究目的為藉由競爭性風險存活分析進行單一醫學中心資料回溯性世代研究(retrospective cohort study)，以了解降血脂藥物使用於慢性腎臟病合併血脂異常患者在心血管疾病事件發生以及不良腎臟預後的保護效益。此外，為了研究不同類別的 statin 和近期發展出的降血脂藥物在慢性腎臟病患者的保護作用之差異並獲得最佳降血脂藥物 選擇的資訊，透過系統性回顧和網絡統合分析(systematic review and network meta-analysis)，比較各種降血脂藥物在降低重大心血管事件發生和不良腎臟預後風險的功效差異，以提供臨床工作者更適當的藥物選擇。 研究方法: 本論文包括兩個主要研究計畫所組成。第一個研究計畫是單一醫學中心資料回溯性世代 研究，評估降血脂藥物對於慢性腎臟病第3b、4 或5期合併血脂異常之成年患者在末期腎疾病、重大心血管事件發生以及全因死亡率的影響。參與者於2008年1月1日至2018年12月 31日期間所招募，並將其分為使用降血脂藥物組以及未使用降血脂藥物組，最終追蹤日期為2020年12月31日。主要研究終點為複合不良腎臟結果發生，包括末期腎疾病發生或因腎衰竭死亡，次要研究終點為重大心血管事件發生，以多變項調整(包括隨時間變化自變項-血脂濃度)之亞分佈風險回歸模型(Sub-distribution hazard regression models)進行存活分析。第二個研究計畫是使用頻率學派隨機效應網絡統合分析(frequentist random-effects network meta-analysis)，客觀比較使用於臨床之各種降血脂 藥物對於慢性腎臟病患者的保護效果。分析資料來源為PubMed、Embase、Web of Science 和 Cochrane Library 資料庫，收集內容為2022年10月31日之前包括慢性腎臟 病患者且為降血脂藥物彼此比較或降血脂藥物比較控制組效益的隨機對照試驗(randomized controlled trials，RCTs)，主要研究終點是重大心血管事件的發生，次要研究終點包括全因死亡發生、末期腎疾病發生、腎絲球過濾率變化、蛋白尿的變化以及降血脂藥物副作用發生。 研究結果: 在6,740位慢性腎臟病患者的回溯性世代研究中，最終是4,280位慢性腎臟病合併血脂異常的參與者完成了主要分析，其中872位歸於使用降血脂藥物組，3,408位歸於未使用降血脂藥物組。多變量分析結果顯示，使用降血脂藥物組的複合不良腎臟結果發生風 險(調整後風險比為0.76;95%信賴區間為 0.65-0.89)和重大心血管事件發生率(調整後風險比為0.75;95%信賴區間為 0.62–0.93)顯著低於未使用降血脂藥物組。加上調整 隨時間血脂濃度變化的自變項後，使用降血脂藥物組的複合不良腎臟結果發生風險(調 整後風險比為0.78;95%信賴區間為0.65-0.93)和重大心血管事件發生風險(調整後風 險比為 0.77;95%信賴區間為 0.60-0.98)仍顯著低於未使用降血脂藥物組。在系統性回 顧和網絡統合分析研究，共納入了49個符合條件的隨機對照試驗資料，包括77,826名慢性腎臟病參與者以及13 種藥物和對照組。參與者的平均年齡在38.7歲至80.6歲之間，其中 62.6%為男性(比例範圍為24.3%至89.7%)。經證據品質和可信度評估後，rosuvastatin 和 atorvastatin 比起對照組顯著地降低重大心血管發生風險，其中 rosuvastatin 的風險比為0.55(95%信賴區間為 0.33-0.91)，atorvastatin為0.67(95%信賴區間為 0.49-0.90)。在腎絲球過濾率變化方面，相較於控制組，atorvastatin(平均值差為 1.40;95%信賴區間為 0.61 至 2.18)、rosuvastatin(平均值差為1.73;95%信賴區間為0.63至2.83)和statin 合併 ezetimibe 治療(平均值差為2.35; 95%信賴區間為0.44至4.26)顯著地增加平均腎絲球過濾率。 結論: 對於中晚期慢性腎臟病合併血脂異常的成年患者，降血脂藥物使用者之複合不良腎臟結果和重大心血管事件的發生風險顯著低於未使用降血脂藥物者，而且除了降低血脂外，降血脂藥物本身可能就具有腎臟和心血管保護作用。就現有的研究證據資料分析各種降血脂藥物的效益結果顯示，與對照組相比，rosuvastatin 和 atorvastatin 顯著地降低重大心血管事件發生風險以及增加平均腎絲球過濾率。

Background: Chronic kidney disease (CKD) is a significant risk factor for cardiovascular disease (CVD) and is one of the leading causes of mortality in the world. Patients with CKD are prone to dyslipidemia, leading to CKD progression and cardiovascular complications due to dysregulation of lipoprotein metabolism in uremic serum. Lipid-lowering drugs (LLDs), such as statins, ezetimibe, and fibrates, have been used to reduce major adverse cardiovascular events (MACEs) and treat atherosclerotic CVD in patients with dyslipidemia. However, the effects of LLDs on cardiovascular and renal outcomes in patients with advanced CKD and dyslipidemia are not fully understood. Furthermore, the impact of specific classes of LLDs on these outcomes in this population is not well characterized. Objectives: We conducted a retrospective, single-center cohort study using competing risk survival analysis to elucidate whether LLDs could protect against poor cardiovascular and renal outcomes in patients with CKD and dyslipidemia. Furthermore, to investigate the protective effects of different classes of statins and newer LLDs and to determine the best choice of LLD for patients with non-dialysis CKD, we conducted a systematic review and network meta-analysis to compare their efficacy in reducing the risk of MACEs and poor renal outcomes. Methods: The thesis consisted of two major projects. First, a retrospective cohort study was conducted to evaluate the effect of LLDs on end-stage kidney disease (ESKD), MACEs, and all-cause mortality in adult patients with CKD stage 3b, 4, or 5 and dyslipidemia. Participants were recruited between January 1, 2008, and December 31, 2018, and were classified as LLD or non-LLD users; the final follow-up date was December 31, 2020. The primary outcome was time to ESKD or death due to renal failure. Sub-distribution hazard regression models adjusted for multivariable, including time-varying lipid profile covariates, were used for the analysis. Second, a frequentist random-effects network meta-analysis of randomized controlled trials (RCTs) will be used to assess the protective effect of the LLDs in non-dialysis CKD patients. The databases of PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for relevant trials, comparing the efficacy between at least two included LLDs or between one of the included LLDs and non-pharmacological treatment, such as placebo, diet control, and usual care, defined as the control group in patients with CKD, published before October 31, 2022. The primary outcome was the incidence of MACEs. The secondary outcomes included all-cause mortality, ESKD, changes in estimated glomerular filtration rate (eGFR), proteinuria, and lipid profiles, and safety. Results: In the retrospective cohort study with 6,740 participants, 4,280 patients with CKD and dyslipidemia, including 872 using LLDs and 3,408 not using LLDs, completed the primary analysis. The multivariable analyses showed that LLD users had a significantly lower risk of time to the composite renal outcome (adjusted hazard ratio [aHR], 0.76; 95% confidence interval [CI], 0.65-0.89) and MACE incidence (aHR, 0.75; 95% CI, 0.62–0.93) than did non- LLD users. After adjusting for time-varying covariates of the lipid profile, there was a significant difference in the composite renal outcome (aHR, 0.78; 95% CI, 0.65-0.93) and MACEs (aHR, 0.77; 95% CI, 0.60-0.98). The systematic review and network meta-analysis included forty-nine eligible RCTs with 77,826 participants with non-dialysis CKD, 13 medications, and the control group. The mean age of the participants was between 38.7 and 80.6 years, and 62.6% were men (range, 24.3%–89.7%). With moderate confidence in the evidence, rosuvastatin and atorvastatin showed significant efficacy in reducing the risk of MACE, with a pooled risk ratio of 0.55 (95% CI 0.33-0.91) for rosuvastatin and 0.67 (0.49- 0.90) for atorvastatin, respectively, compared with the control group. For the change in the eGFR, atorvastatin (mean difference [MD], 1.40; 95% CI, 0.61 to 2.18), rosuvastatin (MD, 1.73; 95% CI, 0.63 to 2.83), and statin plus ezetimibe (MD, 2.35; 95% CI, 0.44 to 4.26) showed significant increases in the mean eGFR. Conclusion: In adult patients with advanced CKD and dyslipidemia, LLD users have a significantly lower risk of composite renal outcomes and MACEs than non-LLD users. In addition to reducing lipid profile, using LLDs is associated with renal and cardiovascular protective effects. There is also sufficient evidence to show that rosuvastatin and atorvastatin significantly reduced the risk of MACEs and increased mean eGFR compared with control groups.