Department of Diabetes and Endocrinology, University College Hospital, London, UK.
Fundam Clin Pharmacol. 2009 Dec;23(6):675-9. doi: 10.1111/j.1472-8206.2009.00741.x. Epub 2009 Sep 10.
Recent trials of intensive glycaemic control in patients with type 2 diabetes and its impact on cardiovascular disease have led to confusion and speculation amongst physicians. The Action to Control Cardiovascular Risk in Diabetes Study was terminated early because of a significant excess all-cause mortality in the intensively-treated group. Furthermore the ADVANCE and VADT trials did not demonstrate cardiovascular benefit with more intensive glycaemic control. Against this background, it is pertinent to re-visit and critically appraise the results of the PROactive study which examined the effects of the thiazolidinedione, pioglitazone, on cardiovascular end-points in a large, randomized, placebo-controlled clinical trial in type 2 diabetic patients with symptomatic disease. PROactive has been rightly criticized in the choice of its composite primary end-point which included a physician-driven as opposed to a disease-driven outcome, namely peripheral vascular re-vascularization. This was primarily responsible for the primary composite end-point not being achieved; whereas there was a significant beneficial impact on the major secondary end-point of death, non-fatal myocardial infarction and stroke. The results of PROactive have been supported by two subsequent studies examining the impact of pioglitazone on important surrogates of atherosclerosis, namely carotid intima/medial thickness (IMT) and coronary atheroma volume as delineated with intravascular ultrasound. The CHICAGO study demonstrated that IMT in type 2 diabetic patients treated with pioglitazone did not progress whereas those treated with glimepiride showed progression. In PERISCOPE atheroma volume progressed with glimepiride but did not with pioglitazone. This is exciting data pointing to the cardiovascular benefits of pioglitazone. In PROactive, CHICAGO and PERISCOPE there was a sustained effect of pioglitazone on glycaemic control and, in addition, beneficial effects in reducing triglycerides and increasing HDL-cholesterol beyond that seen with concomitant statin therapy. These findings strongly suggest that pioglitazone has an important place in the management of type 2 diabetes.
最近，对 2 型糖尿病患者强化血糖控制的临床试验及其对心血管疾病的影响，导致医生们感到困惑和猜测。由于强化治疗组全因死亡率显著增加，ACTION 研究提前终止。此外，ADVANCE 和 VADT 试验也未能证明更强化的血糖控制可带来心血管益处。在这种背景下，重新审视和批判性评估吡格列酮治疗 2 型糖尿病患者的 PROactive 研究结果是恰当的。PROactive 是一项大型随机安慰剂对照临床试验，研究噻唑烷二酮类药物吡格列酮对心血管终点的影响，该研究中患有症状性疾病的 2 型糖尿病患者。PROactive 因其复合主要终点的选择而受到批评，该终点包括医生驱动而非疾病驱动的结果，即外周血管血运重建。这主要导致主要复合终点未达到；而在死亡、非致死性心肌梗死和中风的主要次要终点上有显著的有益影响。PROactive 的结果得到了两项后续研究的支持，这些研究检查了吡格列酮对动脉粥样硬化重要替代物的影响，即颈动脉内膜中层厚度（IMT）和血管内超声描绘的冠状动脉粥样斑块体积。CHICAGO 研究表明，吡格列酮治疗的 2 型糖尿病患者的 IMT 没有进展，而格列美脲治疗的患者则出现进展。在 PERISCOPE 中，格列美脲治疗的动脉粥样斑块体积进展，但吡格列酮治疗的则没有。这是令人兴奋的数据，表明吡格列酮具有心血管益处。在 PROactive、CHICAGO 和 PERISCOPE 中，吡格列酮对血糖控制有持续的影响，此外，与伴随的他汀类药物治疗相比，还可降低甘油三酯和增加 HDL-胆固醇，带来有益的效果。这些发现强烈表明，吡格列酮在 2 型糖尿病的治疗中具有重要地位。
