Adv Ther (2010) 27(5):257-284. DOI 10.1007/s12325-010-0028-3 REVIEW Comparing Angiotensin II Receptor Blockers on Benefits Beyond Blood Pressure Helmy M. Siragy Received: March 11, 2010 / Published online: June 1, 2010 © Springer Healthcare 2010 0028‑3 ABSTRACT some with additional indications beyond blood pressure reduction. Considering that 5 The renin-angiotensin-aldosterone system ARBs share a similar mechanism of action 257 (RAAS) is one of the main regulators of and exhibit similar tolerability profiles, it is blood pressure, renal hemodynamics, and assumed that a class effect exists and that volume homeostasis in normal physiology, they can be used interchangeably. However, and contributes to the development of renal pharmacologic and dosing differences and cardiovascular (CV) diseases. Therefore, exist among the various ARBs, and these pharmacologic blockade of RAAS constitutes differences can potentially influence their an attractive strategy in preventing the individual effectiveness. Understanding these progression of renal and CV diseases. This differences has important implications when concept has been supported by clinical choosing an ARB for any particular condition trials involving patients with hypertension, in an individual patient, such as heart failure, diabetic nephropathy, and heart failure, and stroke, and CV risk reduction (prevention those after myocardial infarction. The use of myocardial infarction). A review of the of angiotensin II receptor blockers (ARBs) in literature for existing randomized controlled clinical practice has increased over the last trials across various ARBs clearly indicates decade. Since their introduction in 1995, differences within this class of agents. seven ARBs have been made available, with Ongoing clinical trials are evaluating the role approved indications for hypertension and of ARBs in the prevention and reduction of CV rates of morbidity and mortality in high- risk patients. Helmy M. Siragy () Department of Medicine, Director, Hypertension Center, Keywords: atherosclerosis; atrial fibrillation; University of Virginia, angiotensin receptor blockers; heart failure; left PO Box 801409 Charlottesville, VA 22908, ventricular remodeling; myocardial infarction; USA. renin-angiotensin-aldosterone system; Email: [email protected] renoprotection; stroke 258 Adv Ther (2010) 27(5):257-284. INTRODUCTION treatment in these patients in whom broader risk factor reduction is necessary for influencing Decisions surrounding antihypertensive long-term morbidity/mortality. treatment are influenced by the myriad of Angiotensin-converting enzyme inhibitors hypertension-induced (eg, heart failure [HF], (ACEIs) and angiotensin II receptor blockers ischemic heart or cerebrovascular disease, renal (ARBs) lower BP through blockade of the renin- disease) and hypertension-associated (eg, type 2 angiotensin-aldosterone system (RAAS), targeting diabetes [T2D] or prediabetes, atherosclerosis) the vasoconstrictive/antinatriuretic hormone conditions, with each additional cardiovascular angiotensin II.4 The RAAS has significance (CV) risk factor potentiating the risk in a given beyond hypertension given the putative role of patient.1 Approximately 75% of the hypertensive angiotensin II in the pathogenesis of various CV population is estimated to have at least one (atherosclerosis, hypertensive left ventricular additional CV risk factor (Figure 1).2 With respect hypertrophy [LVH], HF- and atrial fibrillation to HF, regarded as the most rapidly escalating [AF]-associated remodeling) and renal diseases.5,6 CV condition in North America,3 up to 90% The adverse effect of angiotensin II on the CV of cases are preceded by hypertension1 and system is multifaceted (Figure 2), with the approximately one-third occur in conjunction promotion of oxidative stress representing with renal insufficiency.3 Overall, given that only one of several mechanisms by which it most patients with hypertension present with may influence the pathogenesis of target organ or develop comorbid CV and/or renovascular damage.6,7 The ARB class was introduced into disease over their lifetime, blood pressure clinical practice in 1995, when losartan was (BP) lowering is unlikely to be the sole goal of granted approval as an antihypertensive, and Figure 1. Coexistence of hypertension and cardiovascular/renal comorbidities (based on the National Health and Nutrition Examination Survey [NHANES] 2003-2004).2 CAD=coronary artery disease; CHF=congestive heart failure; CKD=chronic kidney disease; Dys=dyslipidemia; MetS=cardiometabolic syndrome; PAD=peripheral arterial disease. 100 90 81.8 80 76.8 71.4 73.0 73.7 70 69.5 61.5 60 51.8 50 40 Prevalence (%) Prevalence 30 23.1 20 10 0 No comorbidity No (without diabetes) (without Hypertension+Dys Hypertension+PAD (hypertension alone)(hypertension Hypertension+MetS Hypertension+CHF Hypertension+CAD Hypertension+CKD Hypertension+stroke Hypertension+diabetes Adv Ther (2010) 27(5):257-284. 259 includes a total of seven agents approved for the and conclusions should not be interpreted as treatment of hypertension (and, in some cases, implying an overall class effect. In the case of for additional indications) (Table 1).8-14 A number the ARBs, important differences exist across the of meta-analyses have calculated risk reductions pharmacologic and pharmacokinetic profiles of for the ARB class of agents in areas outside of the individual agents, including their binding hypertension and, when taken together, suggest affinity and selectivity for the angiotensin II 4 favorable effects in terms of preventing stroke type 1 receptor (AT1). When given at their and improving renal function and left ventricular highest recommended doses for the treatment (LV) mass, an uncertain risk/benefit profile in LV of hypertension, differences in BP lowering dysfunction and HF, and a potential increased have been described.23 Clinically, the extent to risk for myocardial infarction (MI) in non-HF which the AT1 binding affinity/selectivity-related patients.15-22 Although conducting meta-analyses differences within the ARB class influence BP that capture multiple agents within a drug class control or long-term cardiorenal morbidity/ is a common practice (with a tendency to also mortality is unknown.4 group data across ARBs and ACEIs to assess the The vast randomized controlled trial (RCT) broader RAAS inhibitor category) and may yield experiences during which ARB-associated effects clinically interesting information, the results on outcomes beyond BP control have been compared with those for non-ARB agents are Figure 2. Schematic representation of the central role captured in Table 2.24-105 Herein, key RCTs of played by angiotensin (Ang) type 1 receptor-mediated signaling in hypertension and cardiovascular disease ARBs are reviewed with the intent to identify 5 progression. AT1R=angiotensin type 1 receptor; any notable distinctions among losartan, the BP=blood pressure; MI=myocardial infarction; first ARB introduced to treatment, and the NE=norepinephrine. other ARBs (valsartan, candesartan, irbesartan, Ang II telmisartan, eprosartan, or olmesartan) in terms of effectiveness outside of BP control. Relevant AT R 1 RCT data across the various agents will be discussed as well as additional RCTs, irrespective Reactive O2 species vascular inammation of size, that directly compared losartan against cell growth, brosis another ARB. aldosterone, NE release CLINICAL OUTCOMES BEYOND BP Glucose Elevated Atherosclerosis LOWERING IN RCT intolerance BP Atherosclerosis Remodeling of Plaque heart and vessels progression Key RCT Data for Losartan Data for the antiatherosclerotic effects MI of losartan compared with another Stroke antihypertensive agent are only available from very small series, including a 57-patient Japanese study in which losartan led to no Death change in carotid intima-media thickness (IMT) 260 Table 1. Approved indications and dosing for angiotensin II receptor blockers. Usual starting and maintenance dosing (as specified in the US product labeling) Adult Post-myocardial Heart failure CV risk reduction in Stroke reduction in Nephropathy in hypertension infarction (NYHA class II-IV) ACEI-intolerance* hypertensive LVH type 2 diabetes Losartan8 50 mg/day starting† Not indicated Not indicated Not indicated 50 mg/day starting‡ 50 mg/day starting 25-100 mg/day ↑ to 100 mg/day ↑ to 100 mg/day maintenance and/or add HCTZ§ per BP response per BP response Valsartan9 80 or 160 mg/day 20 mg BID starting¶ 40 mg BID starting Not indicated Not indicated Not indicated starting† ↑ to 40 mg BID within ↑ to 80 mg BID and to 80-320 mg/day 7 days and titrate to target target maintenance of maintenance maintenance of 160 mg 160 mg BID as tolerated BID as tolerated** Candesartan10 8 mg/day starting† Not indicated 4 mg/day starting Not indicated Not indicated Not indicated 8 mg maintenance (usual) ↑ to target maintenance but may ↑ to 16 or of 32 mg/day as tolerated 32 mg/day Irbesartan11 150 mg/day starting† Not indicated Not indicated Not indicated Not indicated Target maintenance of ↑ to 300 mg/day if 300 mg/day needed Telmisartan12 40 mg/day starting† Not indicated Not indicated 80 mg/day starting Not indicated Not indicated 40-80 mg/day 80 mg/day maintenance maintenance Eprosartan13 600 mg/day starting† Not indicated Not indicated Not indicated Not indicated Not indicated 400-800 mg/day maintenance Olmesartan14 20 mg/day starting† Not indicated Not indicated Not indicated Not indicated Not indicated ↑ to 40 mg/day if needed after 2 weeks