對非糖尿病代謝症候群患者單獨使用胰島素增敏劑或statins或合併使用兩者對代謝症候群各成份、血管內皮細胞功能、及炎性反應指標之影響：兼論患者基因形態對藥物效應之交互作用

背景：許多研究顯示，『胰島素阻抗』可能是造成與其相關的包括高血壓、高血脂、血糖耐 受性不良、內皮細胞功能異常等病狀的根本及共通原因。臨床上將這一類病人定義為『代 謝症候群』患者。邇來，已有提昇人體對胰島素反應的藥物（rosiglitazone ）發展出來。由 於『代謝症候群』患者有相當高的心血管疾病發生率，因此許多研究者均欲探究rosiglitazone 這類胰島素增敏劑是否能夠降低『代謝症候群』患者的心血管疾病危險性。我們最近的研 究首次證明，對於非糖尿病代謝症候群病患使用此類藥物，能夠顯著的提升人體的胰島素 靈敏性、改善血管內皮細胞功能及降低發炎因子的濃度，並且不會造成低血糖。然而，這 類藥物對於血脂肪數值卻有較不利的影響：它會增加低密度脂蛋白膽固醇及脂原蛋白B （apolipoprotein B ）的濃度。由於此往的研究已證明statins 類藥物能夠有效降低『代謝症候 群』患者的血脂肪數值及心血管疾病危險性。因此，在本研究中，我們將分別比較單獨使 用rosiglitazone 或simvastatin 及同時併用兩者對這類病人的療效；我們將以各種心血管疾病 危險因子、血管內皮細胞功能、及各種發炎指標評估作為預測未來心血管疾病發生的指標。 此外，我們也要探討不同的基因形態（如PPAR γ 基因型態多型性C161T 和Pro12Ala 等）對藥 物的反應是否有所不同。 實驗方法：年齡在十八至八十歲，且符合美國NCEP 診斷代謝症候群條件者皆可進入本試 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 ）、rosiglitazone (4 mg/day)合併simvastatin (20 mg/day)、或安慰劑四組。所有的 受試者皆接受八個星期的藥物治療。在這段治療期間，受試者及醫師均不知道受試者接受 何種治療。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 ，FMD ） 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。 結果及臨床意義：儘管最近發表的PROactive 研究顯示，對於第二型糖尿病患，在包含statins 等藥物的標準治療外，使用pioglitazone 能夠有效降低心血管疾病死亡率。但在本研究中， 合併使用rosiglitazone 及simvastatin 與單獨使用相較，無法更加改善FMD ；但對於發炎指 標（包括C-反應蛋白及CD40 ligand ）及血脂肪數值則有較單一治療為佳的降低效果。此外， 這些藥物對內皮細胞功能（FMD ）的改善效果主要乃是經由調控endothelin-1 濃度而來。 基因型態與藥物反應的關聯性並不顯著。 雖然rosiglitazone 目前的適應症僅限於糖尿病患，然而我們及其他研究者的研究顯示 對於非糖尿病患使用rosiglitazone 不僅沒有低血糖的副作用，尚且能明顯的改善各種代謝 症候群的成分及內皮細胞功能。合併使用simvastatin 似乎亦能提供加成的心血管保護作 用。我們亦欲更進一步利用新穎之影像學診斷工具直接探究glitazone 類藥物對冠狀動脈硬 化狀況的效果。Background: The metabolic syndrome consists of insulin resistance, compensatory hyperinsulinemia, hypertension, hypertriglyceridemia, low HDL-C, and obesity. It has been demonstrated that the common denominator of the metabolic syndrome is insulin resistance. Rosiglitazone is a thiazolidinedione (glitazone) developed to reduce insulin resistance in patients with type 2 diabetes. We and other investigators have recently demonstrated that rosiglitazone improved insulin sensitivity and endothelial function, and reduced plasma levels of various inflammatory markers, without causing hypoglycemia, in non-diabetic insulin-resistant subjects. However, we also found that rosiglitazone therapy resulted in untoward changes in lipoprotein metabolism, including increases in LDL-C and apolipoprotein B levels. Given that treatment with rosiglitazone is associated with a worsening of the lipid profile, combination therapy with rosiglitazone plus statins may be an ideal therapeutic option for non-diabetic patients with the metabolic syndrome. In this study, we compared the efficacy of rosiglitazone and statin monotherapy (simvastatin), and in combination, on endothelial function and CRP as well as other novel inflammatory markers, as surrogate indicators of future CHD, and components of the metabolic syndrome in non-diabetic patients with the metabolic syndrome. Furthermore, we analyzed the polymorphism status of various candidate genes (PPAR γ ) and examined whether there is differential response to both study medications. Methods and Materials: Eligible patients, aged 18 to 80 years conformed to the metabolic syndrome criteria in ATP III, 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 = 25), simvastatin (20 mg/d)(n = 25), rosiglitazone (4 mg/d) plus simvastatin (20 mg/d)(n= 25) or matched placebo (n = 25) for the 8-week double-blind phase. 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: Combination therapy with rosiglitazone and simvastatin did not result in a greater improvement in endothelial function than either agent alone in the present study. On the other hand, combination therapy did result in a greater reduction in hs-CRP and CD40 ligand levels than either agent alone, though not statistically significant. Possible explanations for our observation include small sample size, chance finding, or ceiling effect of rosiglitazone on FMD that made further improvement almost impossible. The anti-atherogenic effect of the two most promising pharmacological agents, statins and glitazones, are additive in view of their effects on inflammatory markers. The improvement in FMD independently correlated with changes in endothelin-1 (r=-0.64, p