Kawamori Ryuzo
Sportology Center, Juntendo University Graduate School of Medicine.
Nihon Rinsho. 2010 Feb;68(2):235-41.
Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of PPARgamma could reduce macrovascular complications. PROactive Study was conducted to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. Subjects were 5,238 patients with type 2 diabetes who had evidence of macrovascular disease. Subjects were assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2,605) or matching placebo (n=2,633), to be taken in addition to their glucose-lowering drugs and other medications. The primary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. The average time of observation was 34.5 months. 514 of 2,605 patients in the pioglitazone group and 572 of 2,633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, nonfatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Thus, pioglitazone reduced the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events. PERISCOPE Study, double-blind, randomized, multicenter trial in 543 patients with coronary disease and type 2 diabetes, was conducted to find out the reasons why pioglitazone demonstrated the anti-atherosclerotic action. A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination. As far as the change in percent atheroma volume (PAV) from baseline to study completion is concerned, mean PAV increased 0.73% (95% CI, 0.33-1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57-0.25%) with pioglitazone (p=0.002). Thus, in patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride.
2型糖尿病患者发生致命性和非致命性心肌梗死及中风的风险很高。有间接证据表明，PPARγ激动剂可降低大血管并发症的发生风险。开展PROactive研究旨在确定吡格列酮是否能降低2型糖尿病高危患者的大血管发病率和死亡率。研究对象为5238例有大血管疾病证据的2型糖尿病患者。将患者随机分为口服吡格列酮组（从15毫克滴定至45毫克，n = 2605）或匹配的安慰剂组（n = 2633），在服用降糖药物和其他药物的基础上加用上述药物。主要终点为全因死亡率、非致命性心肌梗死、中风、急性冠状动脉综合征、冠状动脉或腿部动脉的血管内或外科干预以及踝关节以上截肢的复合终点。分析采用意向性治疗。平均观察时间为34.5个月。吡格列酮组2605例患者中有514例、安慰剂组2633例患者中有572例在主要复合终点至少发生了1次事件（风险比0.90，95%可信区间0.80 - 1.02，p = 0.095）。主要次要终点为全因死亡率、非致命性心肌梗死和中风的复合终点。吡格列酮组301例患者、安慰剂组358例患者达到该终点（0.84，0.72 - 0.98，p = 0.027）。因此，吡格列酮降低了有大血管事件高风险的2型糖尿病患者全因死亡率、非致命性心肌梗死和中风的复合终点事件发生率。开展PERISCOPE研究，这是一项针对543例冠心病合并2型糖尿病患者的双盲、随机、多中心试验，旨在找出吡格列酮具有抗动脉粥样硬化作用的原因。共有543例患者接受了冠状动脉血管内超声检查，并随机接受1至4毫克格列美脲或15至45毫克吡格列酮治疗18个月，如能耐受则滴定至最大剂量。通过重复血管内超声检查测量动脉粥样硬化进展情况。就从基线至研究结束时动脉粥样硬化体积百分比（PAV）的变化而言，格列美脲组PAV平均增加0.73%（95%可信区间，0.33 - 1.12%），吡格列酮组PAV平均降低0.16%（95%可信区间， - 0.57 - 0.25%）（p = 0.002）。因此，在2型糖尿病合并冠状动脉疾病患者中，与格列美脲相比，吡格列酮治疗使冠状动脉粥样硬化进展率显著降低。
