Hanefeld Markolf, Marx Nikolaus, Pfützner Andreas, Baurecht Werner, Lübben Georg, Karagiannis Efstrathios, Stier Ulf, Forst Thomas
GWT, Center for Clinical Studies, Dresden, Germany.
J Am Coll Cardiol. 2007 Jan 23;49(3):290-7. doi: 10.1016/j.jacc.2006.08.054. Epub 2007 Jan 8.
The purpose of this study was to test the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non-diabetic subjects with cardiovascular disease (CVD) and elevated high-sensitivity C-reactive protein (hs-CRP) levels.
Low-grade inflammation is a pathogenic factor for atherosclerosis. High-sensitivity CRP, matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1 are markers of inflammation. Statins and peroxisome proliferator-activated receptor (PPAR)-gamma agonists lower inflammatory markers and reduce CVD in type 2 diabetes.
In a 12-week, prospective, double-blind trial, 125 subjects were randomized to simvastatin or pioglitazone plus placebo or a simvastatin/pioglitazone combination. We tested changes in hs-CRP by analysis of covariance. A subgroup analysis was performed in patients with and without the metabolic syndrome (MetS). The correlation between changes in hs-CRP and homeostasis model assessment (HOMA; a measure of insulin resistance) was calculated with the Spearman's rank test.
At baseline, there were no significant between-group differences. At 12 weeks, pioglitazone and simvastatin monotherapies significantly reduced hs-CRP (3.64 +/- 2.42 mg/l to 2.48 +/- 1.77 mg/l and 3.26 +/- 2.02 mg/l to 2.81 +/- 2.11 mg/l) and the combination regimen had an additive effect (from 3.49 +/- 1.97 mg/l to 2.06 +/- 1.42 mg/l, p < 0.001). For subgroups, the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without MetS. Homeostasis model assessment decreased in those receiving pioglitazone, and the correlation between changes in HOMA and hs-CRP was significant (r = 0.43; p < 0.05). The PAI-1 decreased significantly in the pioglitazone groups only, and MMP-9 was also significantly lowered in the pioglitazone groups. No treatment-related serious adverse events occurred in any group.
Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.
本研究旨在测试吡格列酮和辛伐他汀联合用药与单独使用每种药物相比，在患有心血管疾病（CVD）且高敏C反应蛋白（hs-CRP）水平升高的非糖尿病受试者中的安全性和有效性。
低度炎症是动脉粥样硬化的致病因素。高敏CRP、基质金属蛋白酶（MMP）-9和纤溶酶原激活物抑制剂（PAI）-1是炎症标志物。他汀类药物和过氧化物酶体增殖物激活受体（PPAR）-γ激动剂可降低炎症标志物并减少2型糖尿病患者的心血管疾病。
在一项为期12周的前瞻性双盲试验中，125名受试者被随机分为辛伐他汀组、吡格列酮加安慰剂组或辛伐他汀/吡格列酮联合组。我们通过协方差分析测试hs-CRP的变化。对有和没有代谢综合征（MetS）的患者进行亚组分析。使用Spearman秩检验计算hs-CRP变化与稳态模型评估（HOMA；胰岛素抵抗的一种测量方法）之间的相关性。
在基线时，组间无显著差异。在12周时，吡格列酮和辛伐他汀单药治疗均显著降低了hs-CRP（从3.64±2.42mg/l降至2.48±1.77mg/l和从3.26±2.02mg/l降至2.81±2.11mg/l），联合治疗方案具有相加作用（从3.49±1.97mg/l降至2.06±1.42mg/l，p<0.001）。对于亚组，单药治疗与联合治疗之间的差异仅在无MetS的患者中，辛伐他汀组与辛伐他汀加吡格列酮组之间显著。接受吡格列酮治疗的患者稳态模型评估降低，HOMA变化与hs-CRP之间的相关性显著（r=0.43；p<0.05）。仅在吡格列酮组中PAI-1显著降低，在吡格列酮组中MMP-9也显著降低。任何组均未发生与治疗相关的严重不良事件。
吡格列酮可能通过降低胰岛素抵抗对患有CVD和高hs-CRP的非糖尿病受试者具有与辛伐他汀相加的抗炎作用。
