Pleiotropic effects of telmisartan: still more to come?

Since losartan, the first angiotensin receptor blocker (ARB), was approved in 1994, the number of available ARBs has increased considerably. ARBs are mainly prescribed for hypertensive patients and are widely recognized because of their good tolerability, the possibility of convenient once-daily dosing, and their efficient blood pressure-lowering properties [1]. The growing attention being paid to this class of antihypertensive drugs is reflected in the steadily increasing total prescription volume [2]. For example, the prescription of ARBs by German physicians rose from 680 million defined daily doses (DDD) in the year 2002 to 1.028 billion DDD in the year 2005, and a further increase is expected when patent protection of several ARBs will expire and treatment-associated costs will decrease in the near future [2]. The role of hypertension as a cardiovascular and renal risk factor with high prevalence has been well established [3,4]. A plethora of experimental and clinical evidence point to a key role of the renin–angiotensin system and its main effector peptide, angiotensin II, in the pathophysiology of hypertension. Moreover, angiotensin II is associated with the development and progression of macrovascular disease and end-organ damage, for example, coronary heart disease, stroke, heart failure, and chronic renal failure [4–7]. Apart from its effects on vascular tone and systemic blood pressure, angiotensin II is believed to promote the formation of atherosclerotic plaques via induction of processes such as endothelial dysfunction, vascular smooth muscle cell growth and migration, vascular inflammation and fibrosis through the activation of its subtype 1 (AT1) receptor [8–11]. Furthermore, angiotensin II is known to amplify neointima formation after vascular injury [12]. In accordance with these observations, pharmacological inhibition of angiotensin II production by ACE inhibitors and high-affinity antagonism of AT1 receptors by ARBs have proven successful strategies in reducing blood pressure and in preventing hypertension-induced cardiovascular events and end-organ damage [13]. Apart from high-affinity antagonism of the AT1 receptor, additional ‘pleiotropic’ pharmacodynamic effects of distinct ARBs have been reported, which may contribute to vascular and end-organ protection conferred by these compounds. In this regard, two recent studies showing that the ARB telmisartan activates peroxisome proliferator-activated receptors (PPAR-gamma) have received great attention and emphasize the notion of pharmacodynamic heterogeneity within the class of ARBs [14,15]. In recent years, however, only modest scientific efforts have been undertaken in experimental and clinical head-to-head comparison to elucidate further potential differences in the pharmacodynamic profile of the various ARBs. Hence the article by Benson et al.[16], which appears in this issue of Journal of Hypertension and compares the effects of five ARBs on cardiovascular cell proliferation, is a desirable and valuable contribution to this matter. After the release of their seminal paper on the PPAR-gamma-activating properties of telmisartan, Benson et al.[16] again brought up an apparently unique pharmacodynamic feature of this ARB, namely the inhibition of cardiovascular cell proliferation. Intriguingly, telmisartan – but not candesartan, eprosartan, valsartan, or irbesartan – efficiently and potently inhibited the proliferation of vascular smooth muscle cells (VSMC) and cardiac fibroblasts in vitro. These cell types are known to play key roles in atherosclerosis, neointima formation after vascular injury, as well as cardiac fibrosis [8,17]. Importantly, proliferation inhibition of both cell types was evident at concentrations close to those observed in clinical studies investigating the pharmacokinetical properties of the compound [18]. This is important from a therapeutic point of view, as the PPAR-gamma-activating properties of telmisartan, which were found to occur at a similar concentration range in vitro, could be reproduced recently in clinical studies by us and others [19,20]. Moreover, telmisartan inhibited platelet-derived growth factor (PDGF) and serum-induced proliferation, DNA synthesis, and cyclin D1 expression in VSMC and cardiac fibroblasts, thereby indicating that it may interfere with signaling cascades activated by mitogenic molecules in the cardiovascular system. In this regard, antagonism of the AT1 receptor in the absence of exogenous angiotensin II did not appear to play a role in telmisartan-mediated inhibition of cell proliferation as telmisartan also decreased the proliferation of Chinese hamster ovary (CHO) cells, which lack functional AT1 receptors [21]. In addition, lack of toxicity and reversibility of the effect upon withdrawal of the compound render nonspecific effects of telmisartan on cell proliferation as an unlikely explanation of this phenomenon. As PPAR-gamma has been shown to control cell proliferation in vascular cells [22], the authors investigated whether inhibition of cell proliferation was attributable to the PPAR-gamma-activating properties of telmisartan. Rather surprisingly, the PPAR-gamma antagonist GW9662 did not reverse telmisartan-induced effects. The authors conclude from these data that PPAR-gamma is not involved in telmisartan-mediated inhibition of VSMC and cardiac fibroblasts proliferation. A persuasive explanation for the key observation of this manuscript, however, is not yet available. Hence mechanisms underlying the antiproliferative effects of telmisartan remain speculative. In this matter, two very recently published papers may help elucidate the underlying pharmacodynamic actions of telmisartan. First, telmisartan has been shown to possess potent antioxidant properties, which may enable this molecule to interfere with redox-signaling cascades induced by PDGF in vascular cells [23,24]. Second, telmisartan may not only activate PPAR-gamma but also PPAR-alpha, a receptor subtype which was shown to inhibit VSMC proliferation via downregulation of cyclin D1 [15,25]. Thus, further investigations should be carried out to determine whether PPAR-alpha-activating properties of telmisartan may contribute to the inhibitory effect of this ARB on cell proliferation. Moreover, future studies are also needed to understand relevant cardiovascular signaling pathways initiated by telmisartan. Although further evidence is required to assess whether these actions of telmisartan contribute to the therapeutic effects of this drug in vivo, the observations of Benson et al.[16] may have important pharmacological and clinical implications. First, the results of the study point to a unique antiatherosclerotic and antiproliferative pharmacodynamic profile of telmisartan within the class of ARBs, which may exceed its known blood pressure-reducing, AT1 receptor-antagonizing, and PPAR-gamma-activating properties. Most interestingly, a recently published clinical trial which compared the effect of telmisartan and valsartan on late lumen loss 8 months after sirolimus-eluting stent implantation in patients with coronary heart disease and hypertension, demonstrated that telmisartan attenuated late lumen loss more significantly than valsartan, despite identical blood pressure-lowering effects [26]. Second, telmisartan-induced inhibition of cardiac fibroblast proliferation may affect hypertension-induced changes of cardiac structure and function, a topic that will soon be addressed by a substudy of the ONgoing Telmisartan Alone and in combination with Rampiril Global Endpoint Trial (ONTARGET) [27]. Third, antiproliferative properties of telmisartan could positively affect microvascular complications in diabetic patients, for example, proliferative retinopathy. In summary, the study by Benson et al.[16] adds to the available data on potential pleiotropic effects of telmisartan. Nevertheless, the results will have to be confirmed in appropriate animal models of vascular injury and atherosclerosis in which the possibly unique antiproliferative effects of telmisartan have to be tested against those of ARBs and ACE inhibitors with equal blood pressure lowering potential. Moreover, large well designed clinical trials are needed to answer the question whether the unique pharmacodynamic profile of telmisartan indeed translates into a superior protection of cardiovascular high-risk patients. In this regard, the results of the ONTARGET and Telmisartan Randomized AssessmeNt Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND) trial programme are eagerly awaited. Nonetheless, the clinical importance of the issue warrants future research for resolving these open questions.