Yamagishi S, Takeuchi M
Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Med Hypotheses. 2005;64(3):476-8. doi: 10.1016/j.mehy.2004.09.015.
The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus. Indeed, hypertension occurs approximately twice as frequently in patients with diabetes compared with in non-diabetic controls. Conversely, hypertensive patients are more likely than normotensive persons to develop diabetes. In addition, up to 75% of CVD in diabetic patients can be attributed to hypertension. Therefore, the primary goals of treating hypertensive patients with insulin resistance are prevention of type 2 diabetes and cardiovascular events. Then, what is the optimal anti-hypertensive approach to target organ protection in these patients? Several clinical trials suggest that the renin-angiotensin system (RAS) plays a pivotal role in the pathogensis of insulin resistance and CVD in diabetes. Interruption of the RAS with angiotensin-coverting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) has been shown to prevent the onset of diabetes in hypertensive patients and to reduce cardiovascular and renal disease progression in diabetic patients with hypertension. However, whether we should recommend ARBs for insulin resistant-hypertensive patients or type 2 diabetic patients without nephropathy due to its insulin-sensitizing property remains to be clarified. Recently, telmisartan, an ARB, was found to act as a patrtial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma influences the gene expression involved in carbohydrate metabolism, and pioglitazone and rosiglitazone, ligands for PPAR-gamma, improve insulin resistance in diabetic patients. Furthermore, there is a growing body of evidence that activators of PPAR-gamma exert anti-inflammatory, anti-oxidative and anti-proliferative effects on vascular wall cells, thus decreasing the risks for atherosclerosis. We hypothesize here that due to its unique PPAR-gamma-modulating activity, telmisartan will become a promising 'cardiometabolic sartan', that targets both diabetes and CVD in hypertensive patients. In this paper, we would like to propose the possible ways of testing our hypothesis. Does telmisartan reduce the development of diabetes and CVD in insulin resistant patients pretreated with maximal doses of other ARBs? Does co-treatment with an activator of PPAR-gamma attenuate the effects of telmisartan in these patients? These clinical studies will provide further information whether the beneficial cardiometabolic actions of telmisartan could be ascribed to its PPAR-gamma-inducing property.
代谢综合征与胰岛素抵抗密切相关，由一系列因素组成，如高血压和高脂血症，这些因素会增加心血管疾病和糖尿病的风险。事实上，糖尿病患者中高血压的发生率约为非糖尿病对照组的两倍。相反，高血压患者比血压正常者更易患糖尿病。此外，糖尿病患者中高达75%的心血管疾病可归因于高血压。因此，治疗伴有胰岛素抵抗的高血压患者的主要目标是预防2型糖尿病和心血管事件。那么，针对这些患者的靶器官保护，最佳的抗高血压方法是什么呢？几项临床试验表明，肾素-血管紧张素系统（RAS）在糖尿病患者胰岛素抵抗和心血管疾病的发病机制中起关键作用。使用血管紧张素转换酶抑制剂（ACEIs）或1型血管紧张素II受体阻滞剂（ARBs）阻断RAS已被证明可预防高血压患者患糖尿病，并减缓糖尿病合并高血压患者的心血管和肾脏疾病进展。然而，由于其胰岛素增敏特性，对于胰岛素抵抗的高血压患者或无肾病的2型糖尿病患者，是否应推荐使用ARBs仍有待阐明。最近，发现ARB类药物替米沙坦可作为过氧化物酶体增殖物激活受体-γ（PPAR-γ）的部分激动剂。PPAR-γ影响参与碳水化合物代谢的基因表达，PPAR-γ的配体吡格列酮和罗格列酮可改善糖尿病患者的胰岛素抵抗。此外，越来越多的证据表明，PPAR-γ激活剂对血管壁细胞具有抗炎、抗氧化和抗增殖作用，从而降低动脉粥样硬化风险。我们在此假设，由于替米沙坦具有独特的PPAR-γ调节活性，它将成为一种有前景的“心脏代谢沙坦”，可针对高血压患者的糖尿病和心血管疾病。在本文中，我们想提出检验我们假设的可能方法。替米沙坦能否降低已接受最大剂量其他ARB类药物预处理的胰岛素抵抗患者患糖尿病和心血管疾病的风险？与PPAR-γ激活剂联合治疗是否会减弱替米沙坦在这些患者中的作用？这些临床研究将提供更多信息，以确定替米沙坦有益的心脏代谢作用是否可归因于其诱导PPAR-γ的特性。
