對非糖尿病合併型血脂肪過高患者使用PPARg agonist、PPARa agonist、或HMGCoA還原酶對各種嶄新心血管疾病危險因子之影響

背景：在臨床上，血液中總膽固醇及中性脂肪濃度同時不正常升高（又稱合併型血脂肪 異常「combined hyperlipidemia 」），往往合併有所謂的『胰島素阻抗』症狀。目前的觀 念，認為『胰島素阻抗』可能是造成與其相關的包括高血壓、高血脂、內皮細胞功能異 常等病狀的根本及共通原因。邇來，已有提昇人體對胰島素反應的藥物（PPARg agonist ， 如rosiglitazone ）發展出來；雖然這類藥物目前主要使用於糖尿病病人，然而已有相關 研究指出，這類藥物使用於非糖尿病的胰島素阻抗病人亦有提升人體胰島素反應性的療 效，且並無低血糖的副作用。由於合併型血脂肪異常也是胰島素阻抗症候群的典型表現 之一，因此我們想要探究PPARg agonist 這類胰島素增敏劑是否對這類病人也有降低心 血管疾病的療效。此外，對於合併型血脂肪異常病人的降血脂肪藥物使用，一直有「究 竟該先使用statin 類藥物或fibrate 類藥物」的爭論。到目前為止，還沒有一個大型研究 針對合併型血脂肪異常患者使用statin 類或fibrate 類藥物究竟在降低心血管疾病方面何 者效果較好的研究發表。在本研究中，我們計畫針對合併型血脂肪異常患者，以其血管 內皮細胞功能及發炎指標（包括hs-CRP ，IL-1 ，IL-6 ，sCD40 ，及sCD40L 等）作為預 測未來心血管疾病發生的指標，評估使用PPARg agonist 、statin 單一治療、或fibrate 單 一治療的效果孰優孰劣。此外，我們也將受試者依照其基礎狀態的血脂肪及發炎指標數 值加以分組，試圖找出是否不同的血脂肪或發炎指標數值會使受試者對藥物的反應產生 具有差別性的影響。除了血脂肪及發炎指標之外，我們也試圖分析eNOS 基因型態多型 性（4a/b 和Glu298Asp ）對藥物反應的影響。 實驗方法：年齡在十八至八十歲，且血清中性脂肪數值介於200 至500mg/dL ，總膽固 醇=200mg/dL 且總膽固醇/HDL 膽固醇比值.>5 者皆可進入本試驗。受試者先接受八個星 期的飲食治療，在此期間內，停止使用所用降血脂肪藥物。在完成了八個星期的藥物清 除期後，受試者隨機分配為接受rosiglitazone （4 mg/day ），simvastatin （20 mg/day ）或 接受micronized fenofibrate （200 mg/day ）三組。所有的受試者皆接受八個星期的藥物 治療。在接受藥物治療前，每位受試者均接受兩次血液抽驗（藥物清除期前及隨機分配 前一週）；藥物治療後受試者亦接受兩次血液抽驗（七週半及八週）。此外，在隨機分配 前一週及接受八週的藥物治療後，進行右肱動脈的血管內皮細胞功能檢驗。我們利用超 音波機器評估與內皮細胞功能相關的血流引致血管擴張（flow- mediated vasodilation ）現 象及硝化甘油引致的血管擴張（nitroglycerin- induced vasodilation ）現象作為內皮細胞功 能的指標。本試驗預計約需一百二十名受試者。 結果及臨床意義：本研究首次顯示使用simvastatin ，fenofibrate ，或rosiglitazone 均能有 效降低合併型血脂肪異常患者的體內發炎程度、及改善內皮細胞功能異常狀況。若就內 皮細胞功能改善程度細加分析，可以發現Fenofibrate 對於基礎HDL 膽固醇數值小於40 mg/dL 者特別有效，而simvastatin 則對於基礎HDL 膽固醇數值大或等於40 mg/dL 者特 別有效。本研究的另一貢獻為，首次證明對於非糖尿病合併型血脂肪異常病患使用 rosiglitazone 不僅沒有低血糖的副作用，且能明顯的改善其內皮細胞功能及體內胰島素 阻抗性。惟所測試之eNOS 基因多型性無法作為預測病患對於藥物反應之指標。Background: Combined hyperlipidemia is characterized by elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides and decreased levels of high-density lipoprotein cholesterol (HDL-C). It is the pathognomonic dyslipidemia observed in individuals with insulin resistance syndrome. However, it is still uncertain whether PPARg agonist (e.g. rosiglitazone) had beneficial effects on the prevention of coronary heart disease (CHD) in individuals with combined hyperlipidemia. Moreover, given that combination therapy with fibrate plus statin confers a risk of rhabdomyolysis, it is also worthwhile to determine whether optimal therapy for patients with combined hyperlipidemia should consist of fibrate monotherapy or statin monotherapy. Until now, however, no head-to-head comparison of the therapeutic effects (on CHD events) of fibrate monotherapy with statin monotherapy in individuals with combined hyperlipidemia has been published. In this study, we will compare the effects of PPARg agonist, statin monotherapy and fibrate monotherapy on both endothelial function and markers of inflammation (hs-CRP, IL-1, IL-6, sCD40, and sCD40L), as surrogate indicators of future CHD, in patients with combined hyperlipidemia. We will further examine the therapeutic effects of these agents in subgroups stratified by various baseline characteristics and genotypes of eNOS (4a/b and Glu298Asp) to see if there were any differential effects among these agents. Methods: Eligible patients, aged 18 to 80 years with plasma triglyceride levels between 200 and 500 mg/dL, total cholesterol level =200 mg/dL, and total cholesterol/HDL cholesterol ratio>5, will be instructed to adhere to the AHA Step 1 diet throughout the study and undergo an 8-week run-in period during which previous lipid-lowering therapy will be discontinued. After the run- in phase, patients will be randomized to receive rosiglitazone (4 mg/d)(n = 40), simvastatin (20 mg/d)(n = 40) or micronized fenofibrate (200 mg/d)(n = 40) for 8 weeks. The patients will be seen at the screening visit (i.e. before the 8-week run- in), 1 week before randomization, at entry (randomization), and 4 and 8 weeks of treatment. Two fasting blood samples will be obtained at baseline 7 days apart and at the end of the 8-week drug-therapy phase (weeks 7.5 and 8). Endothelium-dependent flow- mediated vasodilation in response to reactive hyperemia and nitroglycerin- induced vasodilation will be evaluated in the right brachial artery 1 week before randomization and after 8 weeks of active treatment. Results and Clinical Significance: Our study for the first time demonstrated that simvastatin, fenofibrate, and rosiglitazone markedly reduced plasma levels of high-sensitivity CRP, IL-1, and sCD40L, and improved endothelium-dependent FMD without mutual differences. The improvement in FMD with fenofibrate treatment correlated inversely with baseline HDL-C levels, whereas the improvement in FMD with simvastatin treatment was positively related to HDL-C levels. Accordingly, in the subgroup with a baseline HDL-C of £ 40 mg/dl, only fenofibrate significantly improved the endothelium-dependent FMD. On the other hand, in the subgroup with HDL-C > 40 mg/dl, only treatment with simvastatin achieved significant improvement in FMD. Furthermore, we demonstrated the safety and benefits of rosiglitazone use in ameliorating endothelial dysfunction and inflammation, reversing insulin resistance, and lowering blood pressures in non-diabetic patients with the metabolic syndrome. The predictive value of eNOS polymorphisms studied on pharmacological responses has not been proved