The renin-angiotensin system (RAS) plays a key role in hypertension, atherosclerosis, and diabetes, as well as in a number of pathophysiological mechanisms, which leads to major cardiovascular events, such as myocardial infarction, stroke, heart failure, and progression of renal disease toward end-stage renal failure. Since angiotensin II is the biological effector of this system, responsible for the most unfavorable of RAS actions through its binding with the angiotensin II subtype receptor, the pharmacological antagonism of angiotensin II receptors represents an ideal therapeutic target to interfere with the activity of the system and its pathological consequences and, thus, can become a useful tool for the management of cardiovascular and renal diseases.
The use of angiotensin-converting enzyme (ACE) inhibitors has long represented one of the most rational and effective pharmacological approaches to antagonize the unfavorable effects of RAS in different clinical conditions across the cardiovascular continuum. Most recently, the availability of angiotensin II receptor blockers (ARBs) has provided a more selective and well-tolerated pharmacological tool to interfere with the RAS. Results derived from large, international, randomized clinical trials have indicated that ARB-based pharmacological strategies may provide additional benefits in terms of cardiovascular, metabolic, and renal protection, which seem to be, at least partially, independent of their blood-pressure-lowering properties. In particular, the beneficial effects of ARBs in terms of renal protection are well documented, so that these drugs are now indicated in different sets of international guidelines as a preferential strategy to prevent progression of nephropathy in diabetic and nondiabetic patients.
The present work synthetically reviews the pathophysiological rationale of RAS involvement in cardiovascular and renal diseases and focuses on the beneficial effects provided by ARBs on renal protection. In particular, an extensive discussion follows concerning the clinical profile of telmisartan, an ARB characterized by a longlasting
blood-pressure-lowering effect, favorable metabolic properties, and documented action in terms of renal protection.
HYPERTENSION: A GROWING HEALTH CARE PROBLEM
Today hypertension represents a major public concern, affecting more than 20% of the adult population in Western countries and about 1 billion people worldwide [1]. Observational studies have shown a significant and continuous relation between high blood pressure levels and the burden of cardiovascular mortality and morbidity [2]. The presence of elevated blood pressure levels doubles the risk of ischemic heart disease, increases by fourfold the incidence of stroke, and accelerates the progression of renal disease [3]. In contrast, effective treatment of hypertension significantly reduces the incidence of coronary events and ischemic stroke and prevents the development or delays the progression of hypertension-related organ damage to congestive heart failure and end-stage renal disease [4]. In this view, even small reductions in blood pressure levels are associated with large reductions in the incidence of major cardiovascular events, especially in hypertensive patients at high risk, such as those with evidence of organ damage, metabolic syndrome, or diabetes [5]. Despite these evident benefits, only a small proportion of hypertensive patients receive adequate antihypertensive treatment, so that no more than 20% of treated patients with hypertension, on average, have satisfactory blood pressure levels, and even less are controlled within the recommended thresholds of normality [6,7]. In addition, even in the presence of effective antihypertensive treatment, mostly based on the use of diuretics and beta-blockers, patients treated for hypertension have lower long-term survival rates than do their nonhypertensive counterparts matched for age, sex, ethnic features, and geographic origin [8].
Together with many other observations, these data suggest that other factors, beyond blood pressure levels, may influence prognosis and outcome in patients with hypertension, including the frequent concomitant presence of additional risk factors, such as smoking, obesity, dyslipidemia, metabolic syndrome, or diabetes mellitus [9,10]. In addition, a strong negative prognostic role must be attributed to the presence of cardiac and renal organ damage, as well as structural and functional abnormalities. For instance, the presence of left ventricular hypertrophy [11], microalbuminuria (MAU) [12], or a decline in the glomerular filtration rate (GFR) independently and consistently predicts a poor prognosis in hypertensive patients.
The latest sets of European guidelines for management of arterial hypertension have highlighted the need for lowering blood pressure to target levels, especially in those individuals with high or very high-risk profiles, independently of the class of antihypertensive agents used to achieve these goals [9]. The same guidelines, in fact, emphasize the need for properly searching for the presence of organ damage in each patient with hypertension, since they recognize the need for a tighter blood pressure control in those patients with organ damage or diabetes [9]. Not only are the blood pressure thresholds to be achieved lower in these patients, but also, as suggested by the guidelines, specific antihypertensive drugs may be more appropriate than others, thus suggesting the existence of "compelling indications" for specific drug classes that may represent a strategic priority in the management of hypertension [9].
In this latter regard, those agents that counteract the effects of the activation of the RAS, such as ACE inhibitors and ARBs, have been shown to be effective not only in preventing the occurrence or delaying the progression of hypertension, but mostly in promoting regression of organ damage [13]. In particular, ARBs are recommended to limit the progression from MAU to proteinuria, and from overt renal disease to end-stage nephropathy [14,15].
Thus, the new, emergent paradigm in the treatment of hypertension is not only based on the pragmatic need to lower blood pressure, but also on lowering high-risk profile, which is often due to development of organ damage [16,17]. For these reasons, the accumulating evidence supporting the effectiveness of ARBs on renal disease, a key target in the management of hypertension, confers to these agents a central position in the therapeutic strategy of this condition [9].
Pathophysiology of hypertension: focus on the renin-angiotensin system
A large body of evidence has shown that RAS is involved in a number of pathophysiological mechanisms, leading to major cardiovascular events. In this system, angiotensin II, which represents the final biological effector of RAS, plays a key pathophysiological role in the development and progression of cardiovascular diseases [18]. In general, both the endocrine and the autocrine/paracrine properties of angiotensin II may have deleterious effects in patients with hypertension, atherosclerosis, or diabetes, leading to the onset of cardiovascular and renal diseases and events [18]. Pharmacological agents blocking the RAS, particularly ARBs, may represent a fundamental therapeutic strategy in the modern clinical management of patients at different levels of cardiovascular risk. In support of this strategy, recent large, international, randomized trials have shown that ARBs may provide significant benefits across the spectrum of cardiovascular and renal diseases that seem to be, at least partially, additive to their blood-pressure-lowering effect [13].
The RAS is classically viewed as an enzymatic cascade that through the generation of intermediate peptides leads finally to the production of angiotensin II, which is responsible for important and varied functions that have fundamental relevance in both human physiology and pathology [19]. Under physiological conditions, the role of angiotensin II is particularly relevant for the homeostasis of the cardiovascular system, blood pressure control, and sodium and water balance, as well as for cellular growth and replication. A modern view of the enzymatic proteic cascade of the RAS, its components, and possible pharmacological interactions is represented in Figure 1.
 | Figure 1. Pharmacological interventions and the reninangiotensin system (RAS).
(Reproduced with permission from Volpe M, Tocci G, Pagannone E. Activation of the renin-angiotensinaldosterone system in heart failure. Ital Heart J 2005;6(Suppl 1):16S- 23S) |
As shown in Figure 2, the step-limiting factor in the activation and capacity of regulation and response of the system is represented by the biosynthesis and release of renin, an enzyme with a specific action on its substrate of cleavage. Angiotensinogen, leading to the formation of angiotensin I, in turn, is degraded by the action of ACE, thus forming angiotensin II. Among the different peptide fragments generated, angiotensin II has the greatest affinity for the receptor-binding sites, which mediate the principal actions of RAS in the heart, vessels, kidneys, brain, and other tissues, defined as angiotensin II AT1 subtype receptors (AT1). However, the network of cellularbinding sites for angiotensin II also includes other receptor subtypes, mostly the AT2, for which angiotensin II has a lesser affinity.
 | Figure 2. The vicious cycle of hypertension: the renin-angiotensin template for cardiovascular and renal damage. |
The major site of production of renin is localized in the cells of the juxtaglomerular apparatus in the kidney, but renin is also synthesized in a number of other tissues, in which all the components of the RAS have been identified and characterized. Multiple factors may regulate the biosynthesis and secretion of renin in the juxtaglomerular apparatus, mostly the hydrostatic pressure at the level of glomerular and afferent arterioles [19]. The most important regulatory factors are represented by the sympatho-adrenergic drive through the action of beta-adrenoceptors, the distal delivery of sodium at the level of the macula densa. Another important regulating factor is represented by the levels of angiotensin II, which may influence the production and release of renin through negative feedback mechanisms. In addition, the sodium chloride load at the level of the macula densa represents a fundamental mechanism that regulates not only the state of activity of the system, but also the level of natriuresis. Angiotensin II may in turn influence natriuresis by promoting proximal tubular reabsorption of sodium at the proximal level through a direct action, as well as through an indirect influence on the peritubular interstitial pressure, and at the distal level through the indirect stimulation of aldosterone.
In addition to these well-known actions, circulating and locally generated angiotensin II exerts other nonhemodynamic effects, which have been implicated in the regulation of cardiac and vascular cell proliferation [19]. In particular, angiotensin II is a potent stimulator of hyperplasia and hypertrophy in vascular smooth muscle cells and contributes to the release of a number of growth factors, including platelet-derived, basic fibroblast, and transforming growth factor, as well as to the activation of protooncogenes such as c-fos, c-myc, and c-jun, which are known to influence cell replication and division. Finally, the novel concept has recently emerged that angiotensin II may participate in the development of atherosclerosis via the generation of reactive oxygen species acting as a proinflammatory mediator.
From the biological point of view, the binding of angiotensin II to the specific sites on the extracellular and membrane-spanning portions of the AT1 subtype receptors results in conformational changes of the receptor molecule that promote its interaction with G proteins, which, in turn, activate signal transduction pathways via several plasma membrane effector systems. Although the AT1 receptor has been reported to interact with several G proteins (Gq or Gi), its major physiological functions are expressed through Gq-mediated activation of phospholipase C (PLC). The binding of angiotensin II to AT1 subtype receptors results in the release of the alpha-subunit of the G protein and the subsequent activation of PLC via Gq. PLC activation results in the generation of inositol-1,4,5,- triphosphate (IP3), responsible of the release of Ca+2 from intracellular stores, and diacylglycerol (DAG) that promotes a subsequent activation of protein kinase C and an increase in intracellular calcium levels via L-type calcium channels. Angiotensin II elicits many intracellular signalling responses that are typically associated with activation of tyrosine-kinase receptors. The growth-factor-like effects of angiotensin II include an increase in tyrosine phosphorylation of numerous intracellular proteins and activation of mitogen-activated protein kinase (MAPK), as well as the activated janus kinases-signal transducer and activators of transcriptors (JAK-STAT) pathway. These pathways, in turn, regulate transcription of several early growth response genes, including c-fos, c-jun, and c-myc.
Although it is clear how the RAS may help to control homeostatic equilibrium of salt-water balance and tissue perfusion in a number of pathophysiological conditions, such as dehydration, thirst, shock, postural changes, and other situations, it has become evident that the activity of the RAS is centrally implied in the pathophysiology and progression of important cardiovascular and renal diseases. In this latter regard, a growing body of evidence recently has demonstrated that angiotensin II is directly involved in switching on or promoting key mechanisms leading to the development of atherosclerotic lesions at both cardiac and peripheral vascular levels [18]. In fact, angiotensin II can promote reactive oxygen species production via NADH/NADPH activation, adhesion molecule expression, aggregation, prothrombotic condition, and endothelial dysfunction (ie, reduced nitric oxide [NO] bioavailability), which in turn induces vascular constriction and inflammation at the vascular wall level. In addition, angiotensin II, through its binding with AT1 subtype receptors, may directly promote cardiac myocyte hypertrophy and extracellular matrix proliferation, leading to left ventricular hypertrophy and fibrosis. At the kidney level, angiotensin II exerts a number of the effects that frequently become deleterious for renal function, thus causing progressive proteinuria and decline of GFR.
The role of RAS in the pathophysiology of several clinical conditions, such as arterial hypertension, myocardial infarction, stroke, heart failure, diabetes, and renal failure, has led in the last two decades to the development of pharmacological agents able to antagonize the effects of RAS activation, and most of all the effects of angiotensin II. As the result of "inverse translational science," a more thorough knowledge of the organization and pathophysiology of the RAS has been derived from the development and use of drugs inhibiting the RAS. For example, this can be seen with the impressive, beneficial effects of ACE inhibitors in cardiac patients with renal disease, where the pathophysiological rationale for using RAS-blocking agents proved effective in reducing cardiovascular morbidity and mortality (Figure 3).
 | Figure 3. Mechanistic rationale for the renin-angiotensinaldosterone system (RAAS) blockade in renal disease. Prevalent dilation of efferent arteriole; reduced vascular trophic remodelling. |
The development of ACE inhibitors has been associated with a revolutionary impact in the treatment of varying clinical conditions, from arterial hypertension, stroke, coronary artery disease, renal failure, and left ventricular dysfunction to heart failure [20-23]. However, it soon became evident that the blockade of this system, achievable with ACE inhibitors, is far from complete, even when these agents are given at doses high enough to inhibit plasma ACEs [24]. At the same time, evidence has accumulated showing that the conversion of angiotensin I to angiotensin II via ACE inhibitors is not an exclusive pathway for angiotensin II generation, especially in cardiovascular tissue [25]. Indeed, angiotensin II can be formed via a number of alternative pathways involving cathepsin G, elastase, tissue plasminogen activator, and, in particular, in cardiovascular tissue involving chymase. These basic considerations have been used to explain the relative failure over time of ACE inhibition in maintaining a complete blockade of the RAS cascade, with obvious implications in the management of clinical conditions [25].
Because of these limitations of the ACE inhibitors in the treatment of hypertension and other cardiovascular and renal diseases, research focused on the AT1 subtype receptor, which mediates most of the biological response to angiotensin II. In fact, the AT1 subtype receptor is expressed in diverse adult tissues and its distribution is strongly indicative of the fundamental role of angiotensin II in the regulation of cardiovascular homeostasis and in the pathophysiology of the heart and vessels [19]. In the kidney, AT1 subtype receptor occurs primarily in glomerular mesangial cells, proximal tubular epithelia, and the inner stripe of the outer medulla, the type 1 renomedullary interstitial cells. This underlies the importance of angiotensin II in the physiological regulation of glomerular filtration, renal cortical and medullary microcirculation, and fluid and electrolyte balance, as well as in promoting renal cell proliferation and extracellular matrix synthesis in progressive renal disease. The distribution of an AT1 subtype receptor in the adrenal gland located in the zona glomerulosa cells of the cortex and chromaffin cells of the medulla is consistent with the angiotensin II-mediated biosynthesis and release of aldosterone and catecholamines from the adrenal glands. Also, the distribution in the heart and vessels is consistent with the known inotropic, chronotropic, and vasomotor effects of angiotensin II. The AT1 subtype receptor mediates angiotensin II-induced coronary vasoconstriction and longterm myocardial trophic effects implicated in the development of cardiac hypertrophy and remodelling processes. The AT1 subtype receptor is also present in the brain and in the presynaptic terminal of the dopamine neurons, highlighting the role of angiotensin II in the release of monoamine neurotransmitters at these sites.
The AT1 subtype receptor virtually mediates all known actions of angiotensin II in cardiovascular, renal, neuronal, endocrine, hepatic, and other target cells. Altogether, these actions largely contribute to the homeostasis of arterial blood pressure, maintenance of electrolyte and water balance, thirst, hormone secretion, renal function, and cellular growth. Indeed, the development of the ARBs accomplished this therapeutic goal.
The clinical experience with ARBs is increasing with approximately more than 100,000 patients involved in completed or ongoing clinical trials [15]. It has indeed been shown that blocking the RAS with ARBs can reduce cardiovascular and renal events in different settings, including patients hypertension at high risk or subjects with left ventricular hypertrophy, ischemic stroke, acute myocardial infarction, coronary artery disease, congestive heart failure with left ventricular dysfunction, type 2 diabetes, and diabetic renal disease. In particular, in a recent meta-analysis performed by Strippoli [26], antihypertensive strategy based on ARBs has been shown to provide beneficial effects across the whole renal and cardiovascular continuum, both preventing the progression from MAU toward proteinuria (Figure 4, panels A and B) and even promoting the regression from MAU to normoalbuminuria (Figure 5, panels A and B). Furthermore, promising results have been accumulated with the use of ARBs in other clinical conditions, such as type 2 diabetes with nephropathy and nondiabetic renal disease.
 | Figure 4 (panel A). Progression from microalbuminuria to nephropathy with angiotensin- converting enzyme inhibitors.
(Reproduced with permission from [26]) |
 | Figure 4 (panel B). Progression from microalbuminuria to nephropathy with angiotensin receptor blockers. Effect of angiotensin II receptor antagonists compared with placebo or no treatment on albuminuria, showing agent reduces risk of progression from microalbuminuria to macroalbuminuria.
(Reproduced with permission from [26]) |
 | Figure 5 (panel A). Regression of microalbuminuria achieved by angiotensin-converting enzyme inhibitors.
(Reproduced with permission from [26]) |
 | Figure 5 (panel B). Regression of microalbuminuria achieved by angiotensin receptor blockers. Effect of angiotensin II receptor antagonists compared with placebo or no treatment on rate of regression from microalbuminuria to normoalbuminuria.
(Reproduced with permission from [26]) |
Hypertension-related target organ damage: factors that drive prognosis
Together with the other modifiable cardiovascular risk factors, such as hyperglycemia, hypercholesterolemia, smoking, and obesity, hypertension heavily contributes to the global cardiovascular burden of morbidity and mortality, as well as increases individual absolute cardiovascular risk and estimated life expectancy [1]. Randomized, controlled, clinical trials in hypertension have demonstrated that effective treatment of high blood pressure significantly reduces the incidence of major cardiovascular events, including myocardial infarction and ischemic stroke, and also prevents or delays the development of congestive heart failure and end-stage renal disease [4]. Even small reductions in blood pressure are associated with large reductions in absolute cardiovascular risk, especially in those patients who have hypertension with additional cardiovascular risk factors such as diabetes, organ damage, or associated clinical conditions [4]. However, blood pressure control remains unsatisfactory in most Western countries [6,7], and prognosis remains poor in patients treated for hypertension versus those of similar age who do not have hypertension, even when satisfactory blood pressure control is achieved [8]. Clustering of cardiovascular risk factors in patients with hypertension is indeed an extremely frequent observation in both epidemiological studies and clinical practice, and less than 20% of these patients have no associated risk factors, whereas the remaining 80% have one or more associated risk factors [27].
As stated in the most recent European guidelines on hypertension [9], the concomitant presence of risk factors and organ damage in patients with hypertension translates to progressively higher absolute cardiovascular risk. It follows that for any given blood pressure, the absolute risk of cardiovascular events increases depending on the presence of metabolic abnormalities or organ damage [16,17]. As an example, two patients with the same systolic blood pressure may have very different global cardiovascular risk depending on the presence of cardiac or renal damage, and their absolute risk benefit will be largely influenced by the prevention or treatment of organ damage [16,17]. For these reasons, it is critical to identify and treat organ damage in patients with hypertension.
Also the benefits of reducing blood pressure are proportional to the levels of risk, and in high-risk patients with hypertension presenting with organ damage a tighter control of blood pressure levels and lower blood pressure targets are recommended [9]. Recommendations derived from the guidelines and recent observations from large international trials in hypertension clearly indicate that a prompt and tight control of blood pressure may reduce cardiovascular events in high-risk subjects. Thus, decisions about the management of patients with hypertension (whom to treat, how to treat, and how much to treat) should not be based solely on the level of blood pressure, but also on the proper identification of other risk factors, organ damage, and cardiovascular and renal diseases [16,17]. Depending upon the coexistence of none, one, two, or more risk factors, organ damage, or diabetes, the level of added risk rises from low to moderate or high in an individual patient. It also appears reasonable to postulate that other mechanisms, beyond blood pressure elevation, may operate in patients with hypertension and promote the more frequent development of organ damage. Therefore, it has been suggested that the different classes of antihypertensive drugs may have specific capacities for organ protection and cardiovascular prevention. Accordingly, the "intermediate end points," or disease markers, thoroughly reflect the development of the disease and represent important tools to evaluate the presence of organ damage, as well as to predict cardiovascular events in essential hypertension [13], as schematically shown in Figure 6.
 | Figure 6. Central role of intermediate end points in the cardiovascular and renal continuum and new targets of therapy.
(Reproduced with permission from [13]) |
Comparing the effectiveness of different therapies in cardiovascular and renal protection has classically required the evaluation of hard end points (fatal and nonfatal myocardial infarction, stroke, heart failure, and end-stage renal disease). Because of the long natural history of hypertension, however, it appears very useful to postulate that modifications to measurable intermediate end points may permit prediction of the efficacy of a given treatment in preventing or modifying the course of organ damage, rather than variation in the future risk for development of hard end points associated with hypertension [13]. This is a valuable approach in the clinical practice and can be easily undertaken by physicians to evaluate the status of a patient, the prognosis, and the effectiveness of a treatment. In addition, such an approach will permit a better stratification of absolute cardiovascular risk in individual patients, resulting in a more strict and cost-effective control of blood pressure levels.
Development and progression of renal damage, in particular, is a classical consequence of hypertension and can be easily searched and defined in the clinical practice, so that appropriate follow-up and therapeutic strategies can be undertaken. The next sections analyze the impact of markers of renal disease in hypertension, as well as the influence of antihypertensive treatment on kidney protection.
The continuum from microalbuminuriato renal failure in hypertension
The relation between blood pressure levels and renal function has always represented an important pathophysiological aspect of arterial hypertension, with renal impairment playing a relevant role in the development of high blood pressure levels, and, in turn, elevation of blood pressure being a major contributor of renal impairment [28], as schematically shown in Figure 7.
 | Figure 7. Progression of renal injury in hypertension and cardiovascular (CV) disease. |
A large body of evidence supports a contributing role of chronic nephropathy in the pathophysiology of arterial hypertension, and at the same time a sustained increase in blood pressure levels represents one of the most common causes of new-onset renal diseases and their progression toward end-stage renal failure.
In this view, the first manifestation of renal impairment in hypertension is represented, particularly in diabetes mellitus, by the presence of small amounts of proteinuria, namely MAU, in the urine. This is the consequence of both the hemodynamic abnormalities in the vasculature at the glomerular level and of the progressive deterioration of the glomerular capillary barrier [29]. Further progression of renal impairment will determine an increasing amount of proteinuria, namely macroproteinuria, which may precipitate renal failure and end-stage renal disease, particularly in the presence of concomitant risk factors, including hypertension, and organ damage or diabetes mellitus [29]. The progression from MAU to renal failure is schematically represented in Figure 8, which represents an integrated and updated view of the cardiovascular and renal continuum, originally described by Dzau [30].
 | Figure 8. Cardiovascular and renal continuum.
(Modified with permission from [30]) |
MAU, an abnormal increase in the rate of urinary excretion of albumin between 30 and 300 mg every 24 h, was first described in diabetic patients some 40 years ago. Subsequently, it was recognized as the earliest manifestation of diabetic kidney disease, an early marker of endothelial dysfunction and atherosclerotic disease, and mostly a powerful predictor of progression to diabetic nephropathy, coronary artery disease, and cardiovascular morbidity and mortality, both in the general population as well as in diabetic patients [30]. In the hypertensive population, MAU has been identified as a strong, independent predictor of cardiovascular risk in patients without additional risk factors, as well as in those with concomitant diabetes or coronary artery disease [31,32]. The HOPE study confirmed MAU as an independent contributor to overall cardiovascular risk in a subanalysis of patients, where the primary end point was myocardial infarction, stroke, or cardiovascular death [33]. Therefore, MAU is an important marker for all-cause mortality in hypertension as well. For these reasons, MAU is actually recommended in international treatment guidelines for patients with hypertension, particularly in those with diabetes and hypertension [9].
Clinical and experimental data have also demonstrated that the detection of MAU or overt proteinuria in patients with hypertension may also represent a sensitive and early marker of cardiovascular damage, even independently from the increase in blood pressure [34,35]. This early detection of renal damage becomes even more important in patients with hypertension, in which it may represent a first signal of renal organ damage and contribute to a more comprehensive stratification of those patients at an increased risk of cardiovascular events or end-stage renal disease. Although albuminuria may be the consequence of different types of histological damage, its presence clearly represents a reversible marker of renal damage, leading to an increased level of cardiovascular risk both in patients with diabetes and in patients with essential hypertension [34,35]. In particular, the presence of MAU represents an important predictive index of future development of overt nephropathy and of mortality and cardiovascular morbidity in patients with diabetes mellitus [34,35].
The evaluation of MAU in the clinical management of patients with hypertension may represent an early, easily reproducible, and manageable index to stratify cardiovascular risk in the patient with hypertension, and even to monitor the effectiveness of antihypertensive strategy in terms of renal protection. As addressed by the most recent European guidelines on hypertension [9], MAU is usually defined by an albumin excretion rate in urine between 20 and 200 mg/min (equivalent to 30 to 300 mg every 24 h). However, data from different, large observational surveys have clearly shown that the relation between urinary albumin excretion and excess risk is already apparent at levels of albuminuria currently considered to be normal, and a continuous elevation in cardiovascular risk is observed with values of albuminuria above 10 mg every 24 h. In addition, data from HOPE [32], LIFE [34], and ARAMIS [35] support the concept that threshold levels of normality for MAU should be revised.
Evidence suggested that MAU represents a strong, independent marker of disease and is a valuable predictive index. In addition, increased levels of low-density lipoproteins, triglycerides, obesity, glucose intolerance, insulin resistance, left ventricular hypertrophy, and hyperuricemia frequently cluster with MAU in patients with hypertension. With regard to left ventricular hypertrophy, for instance, recent data from the LIFE study [36], in which urinary albumin excretion rate (UAER) was analyzed through the determination of urine albumin/creatinine ratio, confirmed that in hypertensive patients with left ventricular hypertrophy, abnormal left ventricular geometry and increased left ventricular mass are associated with high urinary albumin excretion independently of age, blood pressure, diabetes, race, serum creatinine, or smoking, suggesting a strict parallelism between cardiac damage and MAU. Finally, MAU also predicts events independently of left ventricular hypertrophy or other associated cardiovascular conditions [36].
The appearance of new-onset MAU in treated essential hypertensive patients is closely related to the slopes of systolic blood pressure and of fasting serum glucose during follow-up. In comparison, the prevalence of MAU is related to the duration and severity of arterial hypertension. In fact, as previously discussed, signs and symptoms of hypertension-related organ damage are commonly observed in hypertensive patients with MAU. In particular, the presence of MAU is often associated with the increase of left ventricular mass, with a higher prevalence of hypertensive retinopathy but also with an increase of the intima-media thickness and with the presence of plaques in carotid arteries.
While a growing body of evidence illustrates the importance of MAU as a strong predictor of cardiovascular risk in the hypertensive population, there is also substantial evidence to show that a reduction in UAER translates into a reduction in cardiovascular events in hypertensive patients when they are treated with RAS-blocking drugs. Together with the predictive value for cardiovascular risk, this may represent a further indication of the recommendation of measuring MAU in all patients with essential hypertension. At the same time, it should be pointed out that measurement of MAU has unquestionable clinical value in specific subsets of hypertensive patients, such as those at high cardiovascular risk, those with left ventricular hypertrophy, congestive heart failure, initial impairment of renal function, or diabetes, both type 1 and type 2; and possibly in patients with multiple risk factors or in the elderly. The additional data on the clinical value of albuminuria that will be derived from several studies will contribute to better defined threshold levels.
MODERN PHARMACOLOGICAL APPROACH TO HYPERTENSION
Beneficial effects of antihypertensive strategies on renal damage
While lowering blood pressure remains a key priority in the treatment of patients with hypertension, evidence derived from international clinical trials on hypertension have demonstrated that antihypertensive strategy based on those pharmacological agents that counteract RAS may confer additional benefit in terms of cardiovascular and renal protection, beyond their blood-pressure-lowering properties [9]. In these populations, for comparable reductions in blood pressure levels, ARB-based antihypertensive therapy demonstrated more effectiveness than did the beta-blockers or calcium channel blockers on major cardiovascular and renal end points in large, interventional studies [9]. Of relevance, in recent clinical trials performed on patients with hypertension or high-risk profiles, ARB-based therapy has been shown to prevent development, to delay progression, or even to promote regression of clinical signs of cardiovascular and renal organ damage (Figure 9) [34,37-41].
 | Figure 9. Natural history and progression of nephropathy.
|
In particular, the reduction of MAU in hypertensive patients is systematically linked to beneficial effects in terms of cardiovascular and renal outcomes [34,37-41]. Some observations have suggested that all antihypertensive therapy is able to reduce MAU with a close relationship to the entity in blood pressure reduction. In spite of this strict relationship between blood pressure levels and MAU, however, ACE inhibitors and, more recently, ARBs seem to exhibit a more marked ability to reduce MAU in hypertensive patients with diabetes mellitus as compared to a number of different therapeutic interventions, for example, with calcium channel blockers, diuretics, and beta-blockers [34,37-41].
Angiotensin-converting enzyme inhibitors and renal protection
Renal protection is another important goal of therapy in diabetes, hypertension, and atherosclerotic diseases and has a significant influence on the overall prognosis of patients. Blocking the RAS represents a successful strategy to slow the progression of renal impairment in these diseases, and this has been confirmed in 3 large clinical trials with either ACE inhibitors or ARBs in diabetic and nondiabetic nephropathy. The first evidence favoring an important clinical benefit provided by RAS-blocking antihypertensive treatments in terms of reduced progression of diabetic renal impairment derived from clinical trials-including that of the CAPPP [42]- performed with ACE inhibitors. This favorable impact is attributed to specific mechanisms associated with RAS blockade and cannot be accounted for solely by the bloodpressure- lowering effects of the comparators (ie, diuretics, beta-blockers, and calcium channel blockers).
More recently, however, reports from the ALLHAT failed to confirm the superiority of ACE-inhibitor-based therapy in terms of renal protection [43]. This large clinical trial was designed to determine whether treatment with a calcium channel blocker or an ACE inhibitor lowered the incidence of coronary heart disease or other cardiovascular disease events, including stroke, compared with a diuretic. A posthoc analysis of ALLHAT was conducted to evaluate whether the renal outcomes were a benefit in terms of incidence of end-stage renal disease and/or a decrement in GFR of 50% or more from baseline. Baseline GFR, estimated by the simplified Modification of Diet in Renal Disease (MDRD) equation, was stratified into normal or increased (≥90 mL/min per 1.73 m2, n = 8126), mild reduction (60 to 89 mL/min per 1.73 m2, n = 18,109), or moderate-severe reduction (<60 mL/min per 1.73 m2, n = 5662). Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of endstage renal disease in patients taking lisinopril or amlodipine in the mild or moderate-severe reduction in GFR groups. In patients with mild and moderate-severe reduction in GFR, the incidence of end-stage renal disease or a 50% or greater decrement in GFR was not significantly different in patients treated with chlorthalidone compared with those treated with lisinopril and amlodipine. No difference in treatment effects occurred for either end point for patients taking amlodipine or lisinopril compared with those taking chlorthalidone across the three GFR subgroups, either for the total group or for participants with diabetes at baseline. At the end of the follow-up, estimated GFR was 3 to 6 mL/min per 1.73 m2 higher in patients assigned to receive amlodipine compared with chlorthalidone, depending on baseline GFR. On the basis of these results, which are represented in Table 1, the investigators concluded that in hypertensive patients with reduced GFR, neither lisinopril nor amlodipine was superior to chlorthalidone in reducing the rate of development of end-stage renal disease or a 50% or greater decrement in GFR.
 | TABLE 1. Coronary artery disease (nonfatal myocardial infarction and fatal coronary artery disease) listed by treatment group using glomerular filtration rate (GFR) at baseline |
More recently, the results of the BENEDICT Trial became available [41]. This multicenter double-blind, randomized trial was designed to assess whether ACE inhibitors and nondihydropyridine calcium channel blockers, alone or in combination, prevent MAU in patients with hypertension, type 2 diabetes mellitus, and normal UAER. A total of 1204 subjects were randomly assigned to receive at least 3 years of treatment with trandolapril (2 mg daily) plus verapamil (sustained-release formulation, 180 mg daily), trandolapril alone (2 mg daily), verapamil alone (sustained-release formulation, 240 mg daily), or placebo. The primary end point of the study was the development of persistent MAU, which was defined as overnight UAER ≥20 μg/min at 2 consecutive visits. At the end of the followup, the primary outcome was reached in 5.7% of the patients receiving trandolapril plus verapamil, 6.0% receiving trandolapril, 11.9% receiving verapamil, and 10.0% receiving placebo. In the presence of quite comparable blood pressure reductions, ACE-inhibitorbased therapy significantly reduced the incidence of the primary end point (ie, trandolapril plus verapamil delayed the onset of MAU by a factor of 2.6 and trandolapril alone delayed it by 2.1) in patients with type 2 diabetes and hypertension but with normoalbuminuria, while the effect of verapamil alone was similar to that of placebo.
Angiotensin II receptor blockers on renal protection
In September 2001, the New England Journal of Medicine published the results of PRIME- the first clinical program to show beneficial effects in patients with hypertension and type 2 diabetes mellitus across the spectrum of early- and late-stage kidney disease. It consisted of two studies: the IRMA-2 [37] and the IDNT [38].
The IRMA-2 study [37] showed that ARBs delay the progression from MAU to macroalbuminuria. A total of 590 patients who had hypertension, type 2 diabetes, and MAU were enrolled in this multinational, randomized, double-blind, placebo-controlled study of irbesartan, at a dose of either 150 or 300 mg daily, and were followed for 2 years. The primary outcome was the time of the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a UAER that was greater than 200 μg/min and at least 30% higher than baseline. At the end of the follow-up period, in the presence of quite comparable blood pressure reductions, 19 (9.8%) of the 194 patients in the 300-mg group and 19 (9.7%) of the 195 patients in the 150-mg group reached the primary end point, as compared with 30 (14.9%) of the 201 patients in the placebo group (Figure 10).
 | Figure 10. Benefits of angiotensin receptor blocker-based therapy on the primary composite end point (progression of diabetic nephropathy) in the presence of comparable blood pressure reductions.
(Reproduced with permission from [37]. Copyright © 2001 Massachusetts Medical Society.
All rights reserved) |
The IDNT study [38] evaluated the renoprotective effect of the ARB-based therapy in hypertensive patients with type 2 diabetes and MAU. A total of 1715 hypertensive patients with nephropathy due to type 2 diabetes were randomly assigned to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mmHg or less in all groups. The main outcome of the study was the time to the primary composite end point of a doubling of the baseline serum creatinine concentration, the development of end-stage renal disease, or death from any cause. During a mean follow-up of 2.6 years, treatment with irbesartan was associated with a risk of the primary composite end point that was 20% lower than that in the placebo group and 23% lower than that in the amlodipine group. The risk of a doubling of the serum creatinine concentration was 33% lower in the irbesartan group than it was in the placebo group and 37% lower in the irbesartan group than in the amlodipine group. Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23% lower than that in both other groups. The serum creatinine concentration increased 24% more slowly in the irbesartan group than it did in the placebo group (p = .008) and 21% more slowly than it did in the amlodipine group (p = .02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point.
On the basis of the results of the PRIME studies, namely the observed differences not explained by achieved differences in the blood pressure levels, the investigators suggested that irbesartan should be considered effective in protecting against the progression of nephropathy due to type 2 diabetes, independently of the reduction in blood pressure levels.
In the same issue of the New England Journal of Medicine, the results of the RENAAL study were reported [39]. In this study, the effects of losartan in 1513 patients with type 2 diabetes mellitus and overt nephropathy were examined. As shown in Figure 11, there was a 28% reduction in the risk of developing end-stage renal disease when losartan was included in the antihypertensive treatment regimen, and hospitalization for congestive heart failure decreased by 32%.
 | Figure 11. Benefits of angiotensin receptor blockers-based therapy on the primary composite end point (time to doubling of serum creatinine, end-stage renal disease, or death) and secondary end point (first hospitalization for heart failure) in the presence of comparable blood pressure reductions.
(Reproduced with permission from [39]. Copyright © 2001 Massachusetts Medical Society.
All rights reserved) |
Subsequently, data from the MARVAL study [40] further extended the observation of a beneficial effect provided by ARBs in renal protection, demonstrating that in the presence of similar blood pressure reduction, ARBs significantly reduced MAU excretion when compared to the comparator amlodipine. This study, in fact, was designed to evaluate the blood-pressure-independent effect of valsartan on UAER in patients with type 2 diabetes and MAU. A total of 332 patients with type 2 diabetes and MAU, with or without hypertension, were randomly assigned to 80 mg daily valsartan or 5 mg daily amlodipine for 24 weeks. The researchers aimed for a target blood pressure level of 135/85 mmHg by dose-doubling followed by adding bendrofluazide and doxazosin, if needed. The primary end point of the study was the percent change in UAER from baseline to 24 weeks. The UAER at 24 weeks was 56% of the baseline with valsartan and 92% of the baseline with amlodipine. Valsartan lowered UAER similarly in both the hypertensive and normotensive subgroups. More patients reversed to normoalbuminuria with valsartan (29.9 vs 14.5%; p = .001). During the follow-up period, blood pressure reductions were similar between the two treatments and at no time was there a between-group significant difference in blood pressure values in either the hypertensive or the normotensive subgroup.
More recently, in the LIFE study [44], the ARB-based antihypertensive regimen significantly reduced the risk of the combined end points of cardiovascular death, stroke, and myocardial infarction, compared with atenolol-based regimens. These beneficial effects were observed in the presence of quite comparable blood pressure reduction between the treatment groups. In addition, ARB-based therapy significantly reduced the development of MAU, and its progression to overt proteinuria has been associated with a lower cardiovascular morbidity and mortality when compared to atenolol therapy as described in a LIFE substudy [36] (Figure 12). The renal protective effect of the ARB telmisartan [45] will be discussed in detail later.
 | Figure 12. Benefits of angiotensin receptor blocker-based therapy on the secondary end points in the presence of comparable blood pressure reductions in hypertension trials.
Reproduced with permission from Ibsen H, Wachtell K, Olsen MH, et al. Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy. J Hypertension 2004;2:1805-1811) |
The overall findings of the previously mentioned clinical trials again suggest that properties of ARBs, which go beyond blood pressure control, are relevant to cardiovascular and renal protection, as schematically shown in Figure 13. In fact, the reduction of MAU and its progression to overt proteinuria has been associated with a lower cardiovascular morbidity and mortality in all the trials presented.
 | Figure 13. Integrating cardiorenal care: blockade of angiotensin II subtype 1 receptor.
(Based on [15]) |
FOCUS ON TELMISARTAN
In 1995, the discovery, clinical development, and availability of a new pharmacological class of antihypertensive agents, which selectively block the deleterious effects of the binding between angiotensin II and AT1 receptors, began with the marketing approval of losartan by the U.S. Food and Drug Administration (USDA) [46]. Telmisartan belongs to the second generation of ARBs and was approved for use with hypertension by the USDA in November 1998 and by the European Medicine Agency in December 1998 [46]. Since then, a vast clinical program focused on disease markers in hypertension coupled with the largest morbidity and mortality trials ever performed has been undertaken.
Telmisartan is an orally active nonpeptide AT1 receptor antagonist that lowers blood pressure with once-daily dosing over a 24-h dosing interval. The antihypertensive effect of once-daily dosing of telmisartan in patients with mild-to-moderate hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, with usually little or no orthostatic change. The starting dose of telmisartan is 40 mg once daily, with the option to increase to the most frequently used dosage of 80 mg daily. Both these dosages have been shown to significantly reduce systolic and diastolic blood pressure. The antihypertensive activity occurs within 2 h after a single-dose administration, and it is maintained for the full 24-h dosing interval. With ambulatory blood pressure monitoring, the 24-h trough-to-peak ratio for telmisartan was determined to be at least 80% for both systolic and diastolic blood pressure.
Biochemical and pharmacological properties of telmisartan
Telmisartan is a highly selective, competitive nonpeptide AT1 receptor antagonist of angiotensin II, the primary effector of the RAS with a so-called insurmountable binding to the AT1 subtype receptors [46]. In other words, when these drugs are acting, even increasing the concentrations, angiotensin II cannot bind the AT1 receptors. The drug has no affinity for AT2 or other receptors. In normotensive volunteers, once-daily telmisartan 20 to 80 mg dosedependently attenuated angiotensin II-induced increases in diastolic and systolic blood pressure. Maximal dosedependent increases in plasma levels of angiotensin II and active renin were detected 4 h after treatment. At 20- to 80- mg doses, telmisartan inhibited the response to repeated angiotensin II challenges by >25% for 26.9 to 40.5 h, respectively. In preclinical studies, telmisartan (but not other AT1 receptor antagonists) has been shown to act as a partial agonist of the peroxisomal proliferator-activated receptor (PPAR)-gamma at clinically relevant levels. The drug also decreased serum glucose and serum triglyceride levels and increased glucose uptake and glucose transporter-4 (GLUT4) protein expression. In patients with mild-to-moderate hypertension and impaired insulin sensitivity, telmisartan, but not losartan, significantly increased the glucose infusion rate. With regard to organ damage, telmisartan is associated with a significant reduction in left ventricular mass index, posterior and septal wall thickness, and left atrial maximal and minimal volumes in patients with essential hypertension and mildto- moderate left ventricular hypertrophy.
Telmisartan is rapidly absorbed with a mean absolute bioavailability of approximately 50%. Peak plasma concentrations (Cmax) of telmisartan are reached in 0.5 to 1.0 h after single-dose administration, and telmisartan has a half-life of about 24 h. Steady-state plasma concentrations are reached after 5 to 7 days of administration, and drug accumulation after prolonged administration appears unlikely. Following oral or intravenous administration, telmisartan is excreted largely unchanged in the feces, via biliary excretion, while less than 1% is excreted in the urine. Studies in healthy volunteers demonstrate the low potential for drug interactions between telmisartan and simvastatin, amlodipine, glibenclamide (glyburide), ibuprofen, paracetamol (acetaminophen), and hydrochlorothiazide. Since median Cmax and trough concentrations of digoxin are increased when the drug is coadministered with telmisartan, digoxin levels should be monitored when initiating, adjusting, and discontinuing telmisartan therapy.
Metabolic properties of telmisartan
Among ARBs, telmisartan has been demonstrated to have a potent and long-lasting antihypertensive effect that may be associated with the partial agonism of PPAR-gamma [47]. Although this action has also been observed with other ARBs, such as irbesartan and losartan, telmisartan seems to exert a more effective and specific action on this target to influence beneficially adipocyte metabolism, metabolic syndrome, diabetes mellitus, and insulin
resistance. In humans, mutations in PPAR-gamma have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPAR-gamma have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes.
Recent evidence demonstrated that telmisartan can function as a partial agonist of PPAR-gamma, influence the expression of PPAR-gamma target genes involved in carbohydrate and lipid metabolism, and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, highcarbohydrate diet [47]. In 2002, Sharma and colleagues [48] suggested that blockade of the RAS may prevent diabetes by promoting adipogenesis, thereby allowing redistribution of fat from dangerous visceral and ectopic fat deposits to less dangerous subcutaneous deposits. This hypothesis is based on the observation that angiotensin II inhibits human preadipocyte differentiation. Subsequently, it has been demonstrated to increase RAS activity in obese subjects, thus suggesting that RAS should be the treatment of choice in obesity-related hypertension. In 2004, Benson et al [49] reported the novel observation that the highly lipophilic ARB, telmisartan, may directly stimulate PPARgamma, a key inducer of adipocyte differentiation. Although this property has since been reported for irbesartan and a losartan metabolite as well, there is no doubt that telmisartan is the most powerful stimulator of PPARgamma activity among the ARBs. Because thiazolidinediones, a class of even more potent PPAR-gamma agonists ("glitazones"), are widely used as insulin sensitizers in the treatment of type 2 diabetes mellitus and promote both adipocyte proliferation and fat redistribution, the report that telmisartan may have similar glitazone-like properties led to widespread and enthusiastic speculations regarding the possible metabolic benefits of this compound.
Telmisartan and renal protection: the PROTECTION Program
Besides its powerful, long-term, and well-tolerated antihypertensive effect, telmisartan provides a wide range of protective actions on organ damage. To further investigate the effects of telmisartan on organ damage, a comprehensive, international program of 11 clinical trials has been developed and conducted over the last few years, involving more than 5500 patients enrolled in 19 countries worldwide at different degrees of cardiovascular risk (Figure 14) [45].
 | Figure 14. The PROTECTION program.
(Adapted with permission from [30]) |
The PROTECTION program [45] is currently evaluating the effects of telmisartan on patients at increased risk of organ damage, including special patient populations such as those with type 2 diabetes mellitus and hypertension, renal impairment with albuminuria, and obese subjects with hypertension, aimed at interrupting the progressive and adverse natural history of hypertensive and renal diseases. It includes the following trials:
• The PRISMA I and II studies, aimed at comparing the effects of telmisartan 80 mg and ramipril 10 mg on the early morning blood pressure of patients with mild-tomoderate hypertension [50,51]
• The SMOOTH study, designed to compare the effect of telmisartan plus hydrochlorothiazide versus valsartan plus hydrochlorothiazide on early morning blood pressure in obese patients with diabetes [52]
• The ATHOS study, aimed at comparing the effect of telmisartan plus hydrochlorothiazide versus amlodipine plus hydrochlorothiazide on the early morning blood pressure of elderly patients with predominantly systolic hypertension [53]
• The ARBs FDC study, aimed at comparing the effect of high- and low-dose telmisartan plus hydrochlorothiazide versus losartan plus hydrochlorothiazide on early morning blood pressure [54]
• The TELMAR study, designed to assess the effect of telmisartan beyond blood pressure reduction on left ventricular mass versus metoprolol succinate [55]
In particular, the benefits of telmisartan, independent of blood pressure, on delaying the progression of renal disease have been investigated as a part of PROTECTION [45] in 3 different clinical studies: AMADEO, VIVALDI, and TRENDY [57].
The AMADEO study was a long-term trial comparing the effects of telmisartan versus losartan, an ARB with an indication to slow diabetic nephropathy progression on proteinuria [58]. This randomized, multicenter, doubleblind, forced-titration study included patients with the following characteristics: type 2 diabetes mellitus, systolic blood pressure >130 mmHg, diastolic blood pressure >80 mmHg, morning spot urinary protein/creatinine [UPC] ≥700 mg/gCr and serum creatinine ≥265 μmol/L (≥3.0 mg/dL) in women and 283 μmol/L (≥3.2 mg/dL) in men, and those receiving antihypertensive medications.
A shown in Figure 15, run-in patients were randomized to either telmisartan 40 mg or losartan 50 mg for 2 weeks and then titrated to telmisartan 80 mg or losartan 100 mg for the remaining 50-week follow-up. Concomitant antihypertensive drugs were allowed except for ARBs, ACE inhibitors, and direct vasodilators. The primary end point at year 1 was change from baseline in morning spot UPC (mg/gCr). A total of 1566 patients from 124 centers in 10 countries were enrolled, of which 860 were randomized and 687 (80%) of those completed the follow-up. Baseline demographic and clinical characteristics were comparable for both groups. At the end of the follow-up telmisartan was found to be superior to losartan on reducing the incidence of the primary end point (mean [95% CI] baseline: end point ratio 0.71 [0.66, 0.77] vs. 0.80 [0.74, 0.87], respectively, p = .028). This translates to reductions from baseline of 29% for telmisartan (mean baseline UPC = 2773 mg/gCr) and 20% for losartan (mean baseline UPC = 2824 mg/gCr). No significant differences in mean blood pressure reduction from baseline systolic and diastolic blood pressure levels between the two treatment groups was noted (telmisartan, -4.8 ± 0.9/-3.2 ± 0.5 mmHg versus losartan -2.7 ± 0.9/-2.9 ± 0.5 mmHg, p = .06 for the systolic and p = .62 for the diastolic blood pressure levels). On the basis of these results, telmisartan was superior to losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy despite similar blood pressure control.
 | Figure 15. Study design: prospective, randomized, doubleblind, double-dummy, forcedtitration, multicenter, parallel-group, 1-year treatment.
(Based on [58]) |
The VIVALDI trial [56] was designed as a prospective, multicenter, randomized, double-blind, parallel group trial (Figure 16). The primary goal was to show the noninferiority of telmisartan 80 mg versus valsartan 160 mg in reducing proteinuria after 1 year of treatment. Furthermore, the treatment effects for telmisartan 80 mg versus valsartan 160 mg with regard to several renal function parameters, clinical end points, and parameters of endothelial function and oxidative stress after 1 year of treatment have recently been evaluated.
 | Figure 16. Study design: prospective, randomized, doubleblind, double-dummy, forced-titration, multicenter, parallel-group, 1-year treatment.
(Based on [56]) |
Between April 2003 and November 2004, 884 patients aged 30 to 80 years old with type 2 diabetes, hypertension, and overt nephropathy (defined by proteinuria in 24-h urine 900 mg and serum creatinine 265 mmol/L or 3.0 mg/dL) were randomized in the study. Study medication was given while other antihypertensive therapy was maintained, with the exception of ACE inhibitors and other ARBs. If the goal blood pressure of 130/80 mmHg was not reached with the high dose of study medication, other antihypertensive medication was given at any time during the study, starting 4 weeks after randomization. The sample size of the per protocol analysis population was set to include a total of 680 patients, 340 administered telmisartan 40 mg daily with mandatory titration after 2 weeks to 80 mg daily, and 340 patients taking valsartan 80 mg daily, with mandatory titration after 2 weeks to 160 mg daily. The primary efficacy variable was the change from baseline in 24-h proteinuria, after 1 year of treatment with telmisartan 80 mg versus valsartan 160 mg. Secondary end points were the following: renal parameters (24-h UAER, creatinine clearance, GFR, serum creatinine, 24-h sodium excretion in urine); clinical end points (composite of doubling of the serum creatinine concentration, end-stage renal disease or all-cause death; composite of morbidity and mortality from cardiovascular causes); parameters characterizing endothelial dysfunction and oxidative stress (change from baseline in C-reactive protein, asymmetric dimethy-Larginine, and 8-iso-PGF2α levels); and parameters characterizing insulin sensitivity (change from baseline in homeostasis model assessment index in patients not receiving insulin therapy; change from baseline in adiponectin). Taken together, the VIVALDI trial evaluated different aspects of the effects of the ARBs telmisartan and valsartan on renal function and the processes underlying the pathogenesis and facilitating the prevention of diabetic nephropathy [56].
The goal of the TRENDY study [57] was to demonstrate the efficacy of telmisartan in improving endothelial dysfunction in the kidneys of patients who have hypertension and diabetes with normal to low-grade albuminuria.
This was the first study planned to analyze NO activity in the renal circulation of patients with type 2 diabetes and to compare directly the effects of two different classes of agents that target the RAS. As shown in Figure 17, it compared the effects of telmisartan 40 to 80 mg and ramipril 5 to 10 mg on endothelial function in the renal circulation of patients with type 2 diabetes and mild-tomoderate hypertension (90-140 to 110-180 mmHg). A total of 96 patients in the prospective, parallel-group, doubleblind, forced-titration study were randomized to active treatment for 9 weeks. To be eligible, patients had to have a creatinine clearance of >80 mL/min and either normoalbuminuria or MAU, but not overt proteinuria. The primary end point was the improvement of renal endothelial function as assessed by the change from baseline in renal plasma flow (RPF) in response to the infusion of NG-monomethyl-L-arginine acetate (L-NMMA), reflecting the magnitude of NO activity.
 | Figure 17. Study design: prospective, randomized, doubleblind, double-dummy, forcedtitration, multicenter, parallel-group, 9-week treatment.
(Based on [57]) |
The TRENDY study [57] also compared RPF and renal vascular resistance at rest (ie, without stimulation by infusion of L-NMMA). The mean fall in RPF in response to intravenous L-NMMA increased with telmisartan from 71.9 ± 9.0 mL/min before therapy to 105.2 ± 9.7 mL/min at the end of treatment (p <.001). With ramipril, RPF response to L-NMMA increased from 60.1 ± 12.2 to 87.8 ± 9.2 mL/min (p <.018). Accordingly, telmisartan increased RPF at rest, without adding L-NMMA, from 652.0 ± 27.0 to 696.1 ± 31.0 mL/min (p <.05), whereas ramipril produced no significant changes in RPF. The findings of the TRENDY study provided evidence showing the benefit of telmisartan when given at a very early stage of renal impairment, even before albuminuria has developed. It shows that telmisartan can improve renal function and may therefore prevent the progression to overt renal disease in patients with type 2 diabetes.
More recently, the results of a relatively small clinical trial, conducted to evaluate the efficacy of an ARB in preventing transition from MAU to overt nephropathy in Japanese patients have become available. In fact, almost all evidence for long-term renoprotection with ARBs has come exclusively from Caucasian patients. The INNOVATION study [59] was a randomized, multicenter, double-blind, placebo-controlled trial, which recruited Japanese patients aged 30 to 74 years old with type 2 diabetes and urinary albumin-to-creatinine ratio (UACR) 100 to 300 mg/g and serum creatinine 1.5 mg/dL (men) and 1.3 mg/dL (women). As shown in Figure 18 (panel A) transition rates to overt nephropathy were 80 mg telmisartan (n = 168) 16.7%, 40 mg telmisartan (n = 172) 22.6%, and placebo (n = 174) 49.9% (both telmisartan doses versus placebo, p <.0001). In addition, transition rates in normotensive patients (n = 163) were 80 mg telmisartan (n = 51) 11.0%, 40 mg telmisartan (n = 58) 21.0%, and placebo (n = 54) 44.2% (both telmisartandoses versus placebo, p <.01) as shown in Figure 18 (panel B).
 | Figure 18 (panels A and B). Kaplan-Meier curves for transition from incipient to overt nephropathy in patients treated once daily with 80 mg telmisartan (T80), 40 mg telmisartan (T40), and placebo.
(Reproduced with permission from [59]) |
At the end of the follow-up, telmisartan at 80 mg and 40 mg reduced mean UACR at final observation by 58.8 and 37.9 mg/g, respectively, and placebo increased UACR by 40.9 mg/g (both telmisartan doses versus placebo, p <.0001). MAU remission at final observation occurred in 21.2% with 80 mg telmisartan, 12.8% with 40 mg telmisartan, and 1.2% with placebo (both telmisartan doses vs placebo, p <.001). Thus, the INNOVATION trial [59] demonstrated that patients with type 2 diabetes and MAU receiving 80 or 40 mg telmisartan achieved superior renal protection, demonstrated by lower transition rates to overt nephropathy, compared with placebo, even in high-risk subjects. In addition, telmisartan also reduced transition to overt nephropathy in normotensive patients, suggesting telmisartan had a blood-pressure-independent effect.
HEAD-TO-HEAD COMPARISON BETWEEN ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS
There are two already completed clinical trials directly comparing ACE inhibitor-based strategy (one with enalapril and the other one with ramipril) and telmisartan in terms of renal protection: the DETAIL [60] and ARAMIS [35] studies. In addition, there is one ongoing trial that will evaluate the effectiveness of telmisartan in very high cardiovascular risk hypertensive patients: the ONTARGET/TRANSCEND [61] study.
The DETAIL study [60] compared the renoprotective effects in patients with type 2 diabetes and early nephropathy, randomized to receive either the ARB telmisartan or the ACE Inihibitor enalapril. In this prospective, multicenter, double-blind, 5-year study, 250 patients with type 2 diabetes and early nephropathy were randomly assigned to receive either the ARB telmisartan (n = 120, 80 mg daily) or the ACE inhibitor enalapril (n = 130, 20 mg daily). The primary end point of the study was the change in the GFR (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the 5-year treatment period. Secondary end points included the annual changes in the GFR, serum creatinine level, UAER, and blood pressure; the rates of end-stage renal disease and cardiovascular events; and the rate of death from all causes.
At the end of the follow-up (Figure 19), telmisartan-treated patients showed a -17.5 mL/min/1.73 m2 reduction of the GFR as compared to that observed in the enalapriltreated patients (15.0 mL/min/1.73 m2). The treatment difference was thus -2.6 mL/min/1.73 m2. The effects of the two agents on the secondary end points were not significantly different after 5 years. On the basis of these results, telmisartan is not inferior to enalapril in providing long-term renal protection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of ARBs and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events.
 | Figure 19. Changes from baseline in the glomerular filtration rate, based on analyses of the complete 5-year data, according to treatment group.
(Reproduced with permission from [60]. Copyright © 2004 Massachusetts Medical Society. All rights reserved) |
The ARAMIS study [35] was a preplanned substudy of a large, multicenter, double-blind, placebo-controlled, randomized trial aimed at examining the effect of telmisartan or hydrochlorothiazide on the control of UAER in patients with isolated systolic hypertension unselected for albuminuria. A total of 1039 patients with isolated systolic hypertension were randomly assigned to receive for 6 weeks a once-daily fixed dose of telmisartan 20 to 80 mg versus hydrochlorothiazide 12.5 mg or placebo. The prospective substudy analyzed UAER using spot morning samples.
As shown in Figure 20, the urinary albumin (>2.2 to 901.6 mg/L) was detected at baseline in 614 out of 918 patients who were included in the substudy analysis. As presented in Figure 21, the telmisartan group (n = 354, all doses combined) showed a median reduction in UAER from a baseline of 14.1 versus 1.1% in the hydrochlorothiazide group (n = 140) and 2.7% in the placebo (n = 120) group. In the presence of comparable blood pressure reduction, the difference between telmisartan and hydrochlorothiazide was significant (p = .017). Reductions in UAER with telmisartan were observed in patients with baseline normoalbuminuria, MAU, or macroalbuminuria.
 | Figure 20. Distribution of baseline urinary albumin excretion (UAE) in patients with spot urine evaluation (n = 918).
(Reproduced with permission from [35]) |
 | Figure 21. Adjusted mean (95% CI) urinary albumin excretion (UAE), systolic blood pressure (SBP), and diastolic blood pressure (DBP) after 6 weeks treatment with placebo (n = 120), hydrochlorothiazide (HCTZ) 12.5 mg (n = 140) and telmisartan 20-80 mg (n = 354).
Reproduced with permission from [35]) |
The ONTARGET/TRANSCEND trial
As previously discussed, the RAS plays a key role in the pathophysiology of hypertension and cardiovascular disease, and its pharmacological antagonism represents the most effective strategy in a number of clinical conditions. Among the different approaches to inhibit RAS, the selective blockade of the receptor of angiotensin II with ARBs appears to be the most rational. Clinical studies suggest that ARBs can contribute to improvement in the prognosis of cardiovascular disease and provide clinical benefits beyond the blood-pressure-lowering effect and across the spectrum of cardiovascular risk (Figure 22). The benefits obtained with an ARB-based antihypertensive regimen cannot be strictly attributed to the blood-pressurelowering effect, suggesting that ARBs may improve prognosis through effects independent of blood pressure reduction. In fact, recent studies suggest that ARBs confer vascular protection independent from blood pressure control. For these reasons, ARBs are an appropriate therapy for patients with arterial hypertension at any stage of the disease.
 | Figure 22. Implementing cardiovascular and renal care: action of telmisartan beyond blood pressure (BP) control. |
The ONTARGET/TRANSCEND Program [61] is a large international, randomized, double-blind, controlled trial comparing the ARB telmisartan with the ACE inhibitor ramipril and the combination of the two in more than 30,000 high-risk individuals with coronary, peripheral, or cerebrovascular disease or diabetes with organ damage in terms of reduced incidence of the primary composite outcome of cardiovascular death, myocardial infarction, stroke, or hospitalization for congestive heart failure. In addition, in this trial the incidence of the secondary end points, such as development of congestive heart failure, cardiovascular revascularization, nephropathy, new-onset type 2 diabetes mellitus, cognitive decline and dementia, and new-onset atrial fibrillation, will also be evaluated.
The TRANSCEND part of the study will determine if the telmisartan-based regimen is superior to placebo in about 5000 patients who are intolerant of ACE inhibitors. As shown in Figure 23, this trial also includes seven substudies that evaluate the benefits of an antihypertensive regimen based either on treatment with ARB or ACE inhibitors or a combination of them in different clinical settings (ie, ambulatory blood pressure monitoring, cardiac magnetic resonance imaging, erectile dysfunction, health economics, blood markers, arterial stiffness, or oral glucose tolerance test).
 | Figure 23. Substudies of the ONTARGET trial.
(Reproduced with permission from [62]) |
The primary end points for both trials are the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. At this time, recruitment has been completed, with 25,620 patients randomized in ONTARGET and 5926 in TRANSCEND [62].
As shown in Figure 24, baseline patient characteristics are similar to those in the HOPE study, except that the current trials have greater ethnic diversity (including an important Asian cohort). The ONTARGET/TRANSCEND population are slightly older and mean blood pressure at randomization is again normal, but slightly lower than that in the HOPE study [31]. Finally, according to recent guidelines and recommendations, the use of beta-blockers and lipid-lowering therapy is also higher in the ONTARGET/TRANSCEND trial than it is in HOPE trial.
 | Figure 24. Diagnosis at study entry for patients in ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease), and HOPE (Heart Outcomes Prevention Evaluation) trials.
(Reproduced with permission from [62]) |
In order to compare the results of ONTARGET/ TRANSCEND with those of HOPE [31], the study design, patient population, and primary outcomes have been carefully chosen to mirror those of HOPE [31]. The primary outcomes for ONTARGET and TRANSCEND are extended from those of HOPE [31] and include hospitalization for heart failure, in addition to incidence of cardiovascular death, myocardial infarction, or stroke. ONTARGET finished recruiting patients in July 2003 and had randomized 25,620 patients from 730 centers in 40 countries. TRANSCEND finished recruitment in April 2004 and had enrolled 5926 patients. The baseline demographics are very similar for all 3 studies.
The reasons for nonrandomization in ONTARGET and TRANSCEND following the run-in phase are very similar to those of HOPE [31]: lack of compliance or patients unwilling to participate in the full-length follow-up of the trials. The incidence of nonrandomization due to increased creatinine or potassium levels is also very low (<1% of patients for either trial) and similar to that seen in the previous study. The distribution and type of diagnosed comorbidity in the study populations at baseline are comparable for all 3 trials, with the majority of enrolled patients having a history of coronary artery disease or diabetes mellitus. The proportion of patients with cerebrovascular disease (stroke or transient ischemic attack) in the current trials is slightly higher than it is in HOPE [31].
A difference in the patient demographics is that there is far greater ethnic diversity in ONTARGET and TRANSCEND, largely as a result of recruitment from Asian countries, which represent approximately 19% of the total. This important ethnic group has often been underrepresented in other clinical trials and its inclusion in the current studies is seen as an important advance.
The physical characteristics of patients recruited into ONTARGET and TRANSCEND, such as age, gender, body mass index, and waist-to-hip ratio, are generally similar to those of patients in HOPE [31], except that individuals are slightly older and in TRANSCEND the ratio of women to men is higher than it is in the other two trials. The percentage of patients with a history of a prior cardiovascular event is comparable between the trials, although in HOPE [31] slightly more patients had angina. The surgical histories of patients in the 3 trials reflect the changing trends in cardiovascular surgery in recent years; a higher proportion of patients in HOPE [31] had undergone coronary artery bypass graft than in the current trials, and more patients in ONTARGET and TRANSCEND have a history of percutaneous transluminal coronary angioplasty or percutaneous coronary intervention than in HOPE [31]. Finally, one remarkable difference is that a history of stroke or transient ischemic event is twice as prevalent in the ONTARGET/TRANSCEND population as it is in that of HOPE [31].
The proportion of patients with diabetes is the same in all 3 trials, but a history of hypertension is greater in the current trials than it is in HOPE [31]: two-thirds of patients in ONTARGET and TRANSCEND, as opposed to about one-half of the patients in HOPE [31]. Correspondingly, the baseline blood pressures in ONTARGET and TRANSCEND are slightly higher than they are in HOPE [31].
As shown in Table 2, baseline medication use in the 3 trials again reflects changing trends in prescribing due to an increased awareness of the benefits of certain drugs on mortality or morbidity. More patients in ONTARGET and TRANSCEND than in HOPE [31] had been treated prior to enrollment with ACE inhibitors or ARBs; all patients were required to stop ACE and ARB treatment during the run-in phase. Slightly more than one half the patients in the current trials received beta-blockers, whereas in HOPE [31] over one third used beta-blockers.
The other notable difference in baseline medications is the use of statins, which is considerably higher in ONTARGET (60.7%) and TRANSCEND (54.4%) than it is in HOPE (28.9%), reflecting the improved outcomes now known to be associated with these agents. Actually, ONTARGET represents the largest comparison to date of ARB and ACE inhibitor therapy in high-risk patients with controlled blood pressure, and the results will contribute significantly to the future treatment of cardiovascular disease.
 | TABLE 2. Baseline medications for patients in ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease), and HOPE (Heart Outcomes Prevention Evaluation) trials |
CONCLUSIONS
The progression of abnormalities of renal structure and function plays an important role in the natural history of cardiovascular diseases, especially in hypertension and diabetes, as well as in patients at high cardiovascular risk. For these reasons, renal protection represents a key target in the modern therapeutic strategy of these conditions. ARBs have been extensively studied in all stages of kidney involvement, especially in diabetes and hypertension. Within the class of ARBs, telmisartan, a compound characterized by a potent and long-standing bloodpressure-lowering effect, as well as by a favorable metabolic profile, has been thoroughly studied with regard to its renoprotective properties, and the trials discussed here convincingly document that these protective
properties are at least as good as the existing gold standards (ACE inhibitors and ARBs), and even better in some instances. A next important step in this clinical development program is the ONTARGET/TRANSCEND study [62], which will represent a cornerstone in the clinical management of hypertensive patients.
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