Abstract

The renin–angiotensin system (RAS) has been a drug target of particular interest because of its involvement in the cardiovascular and renal disease progression. The angiotensin-converting enzyme (ACE) inhibitors and the selective angiotensin II receptor blockers (ARBs) inhibit the RAS by different mechanisms of action that may have therapeutic implications. The ACE inhibitors have been proven effective for reducing cardiovascular events and mortality in patients with cardiovascular disease. Evidence from clinical trials has shown that ARBs and ACE inhibitors can reduce the risk of cardiovascular and renal events in specific patient populations. Ramipril is an ACE inhibitor proven, in the HOPE trial, to reduce cardiovascular risk. Telmisartan is an ARB with a high degree of lipophilicity, tissue penetration, and high affinity for the angiotensin II type 1 receptor. The ONTARGET study demonstrated that telmisartan provided equivalent efficacy to ramipril in preventing morbidity and mortality from cardiovascular causes in a broad cross section of high-risk patients, but with better tolerability and fewer discontinuations. The combination of telmisartan and ramipril was no more effective but was associated with worse tolerability.

Introduction

The renin–angiotensin system (RAS) evolved to preserve fluid volume during periods of restricted dietary salt and to prevent ischaemia during acute volume loss. The main effector peptide of the RAS, angiotensin II, induces vasoconstriction and sympathetic activation, raises aldosterone levels, and promotes renal salt and water retention via the angiotensin II type 1 (AT1) receptor.1 Over the last few decades, the RAS has been a drug target of particular interest because of its involvement in cardiovascular and renovascular disease.

Cardiovascular and renovascular disease can be understood as a continuum of risk factors, target organ damage, events, and mortality. Risk factors (such as hypertension, dyslipidaemia, diabetes, and smoking) lead to the development of target organ damage including atherosclerosis, left ventricular hypertrophy, and renal impairment. Target organ damage progressively worsens, leading ultimately to myocardial infarction, heart failure, end-stage renal disease, stroke, or death.2 Angiotensin II, the main effector peptide of the RAS, plays an active role during all stages of this continuum.3 The two major classes of drugs that target the RAS are the angiotensin-converting enzyme (ACE) inhibitors and the selective AT1 receptor blockers (ARBs). Although both of these drug classes target angiotensin II, the differences in their mechanisms of action have implications for their effects on other pathways and receptors that may have therapeutic implications.3,4 Both ACE inhibitors and ARBs are effective antihypertensive agents that have been shown to reduce the risk of cardiovascular and renal events.3 However, pertinent questions remained prior to the publication of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study results. For example, when should therapy to block the RAS be initiated? Is telmisartan as effective as ramipril across a broad range of high-risk patients? And does the combination of the two, which should provide a more complete blockage of RAS, provide greater therapeutic benefit?

Angiotensin-converting enzyme inhibition

The ACE inhibitors reduce RAS activation by blocking the conversion of angiotensin I to angiotensin II, leading to decreased activation of both AT1 and AT2 receptors. Angiotensin II type 1 receptors predominantly mediate the pathological effects of angiotensin II, including vasoconstriction and other mechanisms that raise blood pressure as well as vascular hypertrophy, endothelial dysfunction, atherosclerosis, inflammation, and apoptosis.5 Angiotensin II type 2 receptors, in contrast, mediate mostly opposing and beneficial effects, promoting anti-proliferation, differentiation, regeneration, anti-inflammation, and apoptosis.

In addition to blocking the conversion of angiotensin I to angiotensin II, ACE inhibitors block the enzymatic degradation of bradykinin. Increased levels of bradykinin contributes to the positive effects of ACE inhibitors since activation of B2 receptor leads to release of nitric oxide, with vasodilatory and tissue protective results. In addition, evidence is accumulating that ACE itself can act as a cell-surface receptor and that binding of an ACE inhibitor to the enzyme triggers a signalling cascade that leads ultimately to PGI2 generation and additional vasodilatory effects.6–8

Although acute treatment with an ACE inhibitor reduces circulating angiotensin II to negligible levels, chronic treatment has been associated with re-emergence of angiotensin II, a phenomenon referred to as ‘reactivation’. In a study of patients with congestive heart failure (CHF) on long-term ACE inhibitor therapy, reactivation of angiotensin II occurred in approximately one in every six patients and reactivation of aldosterone in about one in every three patients.9 Reactivation of the RAS in patients receiving ACE inhibitors has been linked to poorer outcomes.10

As MacFadyen et al.9 have speculated, ACE reactivation may have occurred in some of the patients because of poor compliance. Many factors affect patients' compliance with therapy, one of which is tolerability of the treatment. The tolerability profile of ACE inhibitors is marked by a considerable incidence of cough, affecting up to 35% of patients.11 The cough occurring with ACE inhibitor therapy is related to increased levels of kinins, and it is the most frequent reason for discontinuation of treatment with an ACE inhibitor.12

Angiotensin-converting enzyme inhibition has also been associated with angio-oedema, which occurs much less frequently than cough (<1%). However, angio-oedema affecting the respiratory passages can be life-threatening.13

An additional disadvantage of ACE inhibition is that it reduces activity of the AT2 receptor along with the AT1 receptor. The functions of the AT2 receptor are generally opposed to those of the AT1 receptor; the AT2 receptor has anti-proliferative, pro-differentiation properties and mediates anti-inflammatory responses.5

Despite their drawbacks, ACE inhibitors are an important drug class because of their proven effectiveness for reducing cardiovascular events and mortality in patients with advanced cardiovascular disease evidenced by CHF or a history of myocardial infarction (MI). However, ACE inhibitors may also reduce cardiovascular risk in patients with less advanced coronary heart disease. This was demonstrated in the landmark Heart Outcomes Prevention Evaluation (HOPE) study, which compared ramipril with placebo. The HOPE study was the first large (n = 9297), long-term trial in patients without low ejection fraction, heart failure, recent MI, or stroke, but who had a high risk for cardiovascular events.14 Over a mean follow-up period of 5 years, ramipril 10 mg once daily was associated with a 26% reduction in risk for death from cardiovascular causes (26%; P < 0.001), MI (20%; P < 0.001), stroke (32%; P < 0.001), and all-cause mortality (16%; P < 0.001). Although the incidence of new-onset diabetes was not a primary or secondary endpoint in the HOPE study, these data were collected prospectively. Patients in the ramipril arm had a relative risk for developing diabetes of 0.66 compared with the placebo arm (95% CI: 0.51–0.85; P < 0.001).

It is not known to what extent blood pressure reduction contributed to the positive outcomes seen in the HOPE study.15–17 However, fewer than half of the patients were hypertensive at baseline, and the mean difference in blood pressure between the ramipril and standard of care arms at the end of follow-up (3/2 mmHg) cannot fully account for all of the risk reduction observed in this trial.18

Selective angiotensin II type 1 receptor blockade

The ARBs block the RAS by antagonizing the binding of angiotensin II to the AT1 receptor. Because the ARBs are selective for the AT1 receptor, these agents have a greater potential for providing a complete inhibition of the RAS than ACE inhibitors.3 In addition, ARBs have minimal affinity for the AT2 and thus permit activation of the AT2 receptor by angiotensin II to proceed unopposed, possibly providing beneficial anti-proliferative and anti-inflammatory effects. It should be noted that the potential clinical significance of AT2 receptor-mediated actions is not universally accepted.5

Unlike ACE inhibitors, ARBs have no effects on bradykinin accumulation and do not induce NO and PGI2 via the B2 receptor. The clinical implications of this difference between the ARBs and the ACE inhibitors, aside from the absence of kinin-related cough with ARBs, are not known.3 The ARBs have been associated with a highly favourable tolerability profile, better than that of any of the other classes of antihypertensives.19

The clinical evidence for the efficacy of ARBs in reducing cardiovascular events has become quite strong as a result of recent major outcome trials included in the meta-analysis developed by the Blood Pressure Lowering Treatment Trialists' Collaboration (Figure 1). For example, from the results of four trials assessing efficacy for preventing stroke that enrolled 16 791 patients demonstrated that treatment with an ARB reduced the risk for this event by 21% compared with other antihypertensive drug classes. The difference in blood pressure between the ARB and non-ARB cohorts was only −2/−1 mmHg, suggesting that the protection from stroke conferred by ARB therapy was independent of blood pressure effects.20

Figure 1

Meta-analysis by the Blood Pressure Lowering Treatment Trialists' Collaboration of data from outcome trials comparing treatment regimens based on angiotensin-receptor blockers with control regimens.20 Reproduced with permission from Turnbull.20

Figure 1

Meta-analysis by the Blood Pressure Lowering Treatment Trialists' Collaboration of data from outcome trials comparing treatment regimens based on angiotensin-receptor blockers with control regimens.20 Reproduced with permission from Turnbull.20

Reduction in the incidence of new-onset diabetes with ARB therapy has been shown consistently in three large, long-term trials (Table 1). In the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study, losartan therapy was associated with a 25% reduction in the incidence of diabetes compared with atenolol in patients with essential hypertension and left ventricular hypertrophy.21 In the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity Program (CHARM) trial in patients with heart failure, the risk for new-onset diabetes was reduced by 22% compared with placebo.22 And in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, which enrolled patients at high risk for cardiovascular events, the risk for developing diabetes was 23% lower with valsartan compared with amlodipine.23

Table 1

Effect of angiotensin II receptor blockers on the incidence of new-onset diabetes21–23

Study Population Mean follow-up Incidence of type 2 diabetes 
LIFE 9193 patients with essential hypertension and left ventricular hypertrophy (55–80 years) 4.8 years Losartan (6.0%) vs. atenolol (8.0%), RR = 0.75 (95% CI 0.63–0.88) 
CHARM 7601 patients from 26 countries NYHA II–IV (≥18 years) ≥2 years Candesartan (6.0%) vs. placebo (7.4%), RR = 0.78 (95% CI 0.64–0.96) 
VALUE 15 245 patients of high risk of cardiovascular events (≥50 years) ≥4.2 years Valsartan (13.1%) vs. amlodipine (16.4%), RR = 0.77 (95% CI 0.69–0.86) 
Study Population Mean follow-up Incidence of type 2 diabetes 
LIFE 9193 patients with essential hypertension and left ventricular hypertrophy (55–80 years) 4.8 years Losartan (6.0%) vs. atenolol (8.0%), RR = 0.75 (95% CI 0.63–0.88) 
CHARM 7601 patients from 26 countries NYHA II–IV (≥18 years) ≥2 years Candesartan (6.0%) vs. placebo (7.4%), RR = 0.78 (95% CI 0.64–0.96) 
VALUE 15 245 patients of high risk of cardiovascular events (≥50 years) ≥4.2 years Valsartan (13.1%) vs. amlodipine (16.4%), RR = 0.77 (95% CI 0.69–0.86) 

CI, confidence interval; RR, relative risk.

Prevention of diabetes via renin–angiotensin system inhibition

The mechanisms by which RAS inhibition using ACE inhibitors and ARBs prevent the development of diabetes are not fully understood. Some of the ‘classic’ effects of RAS inhibition may promote insulin sensitivity: improved muscle blood flow, decreased sympathetic activity, and promotion of favourable ionic changes (K+ and Mg++). Other proposed mechanisms include beneficial effects on muscular fibre composition, effects on adipose tissue (reductions in free fatty acids, adiponectin, and adipogenesis), enhanced insulin signalling, and in the case of some of the ARBs, partial peroxisome proliferator-activated receptor (PPAR)-gamma activity (although for telmisartan, there is evidence that this PPAR-gamma-inducing activity is independent of its AT1-receptor-blocking action). Improvements in ionic balance and improved pancreatic islet blood flow may have beneficial effects on insulin secretion.24

Combination therapy: angiotensin-converting enzyme inhibitor plus angiotensin II receptor blocker

Combination therapy with different classes of antihypertensive agents having complementary mechanisms of action has been shown in numerous studies to provide greater blood pressure reductions than either agent alone.25 Although ACE inhibitors and ARBs both target the RAS, their mechanisms of action are complementary and have been shown to lower blood pressure to a greater extent when used in combination.26,27 Adding an ARB to ACE inhibitor therapy may counter reactivation of angiotensin II and aldosterone escape during ACE inhibitor therapy by specifically blocking the AT1 receptor.3,28 Findings from the Valsartan-Heart Failure Trial (Val-HeFT) study support this view: plasma aldosterone concentrations were significantly lower in patients with CHF receiving an ACE inhibitor plus valsartan compared with those receiving an ACE inhibitor plus placebo (P < 0.001).29

However, the results for the cardiac effects of adding an ARB to ACE inhibitor therapy in patients with CHF have been conflicting. In Val-HeFT, ACE inhibitor plus valsartan therapy was associated with significant reductions in hospitalizations and slowing of left ventricular remodelling, but no effects on mortality were observed.29 In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), which enrolled patients with acute MI complicated by left ventricular dysfunction, combining captopril with valsartan did not improve survival.30 In contrast, the CHARM-Added trial demonstrated significantly reduced risk for cardiovascular death or hospitalization due to CHF (adjusted hazard ratio of 0.85; P = 0.010; Figure 2).31

Figure 2

Reduction in mortality with combination angiotensin receptor blocker plus angiotensin converting-enzyme inhibitor therapy in (A) the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity-Added (CHARM-Added)31 and (B) the Valsartan in Acute Myocardial Infarction Trial (VALIANT).30 Reproduced with permission from Pfeffer et al.30 and McMurray et al.31

Figure 2

Reduction in mortality with combination angiotensin receptor blocker plus angiotensin converting-enzyme inhibitor therapy in (A) the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity-Added (CHARM-Added)31 and (B) the Valsartan in Acute Myocardial Infarction Trial (VALIANT).30 Reproduced with permission from Pfeffer et al.30 and McMurray et al.31

Telmisartan

Telmisartan is an ARB with a high degree of lipophilicity, tissue penetration, and high affinity for the AT1 receptor.32,33 Direct comparative, randomized, double-blind studies of blood pressure lowering in patients with mild-to-moderate essential hypertension have shown telmisartan was as effective at decreasing trough blood pressure as the ACE inhibitors lisinopril or enalapril,34,35 the calcium channel blocker amlodipine,36 and the beta-blocker atenolol.37

Telmisartan is notable for its long half-life, which is ∼24 h, and its long duration of action. One randomized, double-blind study using ambulatory blood pressure monitoring (ABPM) directly compared the efficacy of telmisartan with amlodipine, also noted for a long half-life (≥30 h) and duration of action. During the 24 h dosing interval, telmisartan 40–120 mg and amlodipine 5–10 mg were associated with similar mean changes in systolic and diastolic blood pressure. However, blood pressure reduction during the night and the last 4 h before dosing was significantly greater with telmisartan than with amlodipine (P < 0.05).37

Randomized, double-blind studies using ABPM have been conducted to directly compare the 24 h blood pressure control with telmisartan and the ARBs losartan and valsartan. Telmisartan 40 and 80 mg was associated with significantly greater mean reductions in systolic and diastolic blood pressure during the 24 h dosing period and during the last 6 h of the dosing interval compared with losartan 50 mg (P = 0.05).38 A combined analysis of two studies comparing 24 h blood pressure control with telmisartan 80 mg and valsartan 160 mg found that telmisartan was associated with greater reductions in 24 h systolic and diastolic blood pressure during normal daily dosing and in 24 h systolic blood pressure after a missed dose (P = 0.0004). Significantly greater changes in systolic and diastolic blood pressure were observed with telmisartan compared with valsartan during the last 6 h before dosing during normal dosing and after a missed dose (P = 0.0066 for normal dosing and P = 0.0004 after a missed dose).39

The efficacy of telmisartan 80 mg and ramipril 10 mg for providing 24 h blood pressure control were recently compared in two prospective, randomized, open-label 14-week trials enrolling a total of >1600 patients.40,41 Patients received telmisartan 80 mg or ramipril force-titrated to 10 mg. Both trials found that, compared with ramipril, telmisartan provided significantly lower mean 24 h blood pressure, greater mean reductions from baseline in 24 h blood pressure (P < 0.0001), and significantly greater reductions in systolic and diastolic blood pressure during the last 6 h of the dosing interval (P < 0.01). Both treatments were generally well tolerated, but the incidence of cough was consistently higher in the ramipril arms compared with the telmisartan arms (5.7 and 10.1% for ramipril vs. 0.5 and 1.5% for telmisartan).

Twenty-four hour blood pressure control, including control during the last several hours before the next dose, is clinically important. At night-time, blood pressure normally decreases, and the absence of this night-time decrease has been associated with greater risk for target organ damage and cardiovascular events.42 During morning hours after awakening, there is a blood pressure surge that coincides with increases cardiovascular tone, platelet aggregability, and other cardiovascular processes believed to contribute to the rise in risk for cardiovascular events during this time of day.43

Telmisartan reduced the decline in glomerular filtration rate (GFR) in the Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study, a prospective, multicentre, double-blind, 5-year trial that randomized 250 patients with type 2 diabetes, mild-to-moderate hypertension, and early nephropathy to telmisartan 80 mg or enalapril 20 mg.44 The primary endpoint in the DETAIL study was the change in GFR from baseline to the last study visit. Secondary endpoints included the annual change in GFR, serum creatinine level, urinary albumin excretion, and blood pressure, the incidence of end-stage renal disease and cardiovascular events, and the all-cause mortality rate.

At the 5-year endpoint, the mean change in GFR was −17.9 mL/min/1.73 m2 in the telmisartan arm and −14.9 mL/min/1.73 m2 in the enalapril arm, for a treatment difference of −3.0 to 17.9 mL/min/1.73 m2 with a 95% CI of −7.6 to 1.6–17.9 mL/min/1.73 m2. As the predefined clinically relevant difference for change in GFR between the treatment arms was 10.0 mL/min/1.73 m2, telmisartan was not inferior to enalapril. The annual mean change in GFR was −18.7 mL/min/1.73 m2 for telmisartan and −15.8 mL/min/1.73 m2 for enalapril (95% CI of the treatment difference −9.2 to 3.4 mL/min/1.73 m2), also showing non-inferiority of telmisartan to enalapril. The other renal variables (change in serum creatinine and percentage change in urinary albumin excretion) did not differ significantly between telmisartan and enalapril. Overall, these findings showed that telmisartan was similar to enalapril for providing long-term renoprotection in patients with type 2 diabetes and early nephropathy.

The ONTARGET programme

The protective effects of ARBs on specific outcomes and in specific populations have been convincingly shown in a number of studies—stroke reduction with losartan in patients with hypertension and left ventricular hypertrophy in the LIFE study,21 reduced cardiovascular risk in patients with hypertension and cardiovascular risk in the VALUE study,45 reduced cardiovascular mortality and morbidity in patients with CHF with candesartan in the CHARM trial,46 and slowing the progression of diabetic nephropathy in the IDNT,47 RENAAL,48 and DETAIL studies.44

Prior to ONTARGET, however, no ARB trial had assessed efficacy in reducing cardiovascular outcomes with in a broad cross section of high-risk patients with or without hypertension in comparison with ramipril (a proven therapy in this group), or whether combination therapy with an ARB and an ACE inhibitor would provide added benefits.49,50 ONTARGET was a large, long-term study (25 620 patients, 5.5 years) that compared the benefits of telmisartan, ramipril, or the combination for preventing morbidity and mortality from cardiovascular causes.51 A separate study, the Telmisartan Randomized AssessmeNt Study in aCE-iNtolerant patients with cardiovascular Disease (TRANSCEND) was also conducted for patients who cannot tolerate ACE inhibitor therapy.49 The study gave a clear result: telmisartan provided equivalent efficacy to ramipril but with fewer discontinuations, whereas the combination was no more effective but was associated with worse tolerability. The results of ONTARGET are explored further elsewhere in this supplement.

Conflict of interest: T.U. has received speaker honoraria and consultancy fees from Boehringer Ingelheim.

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