Int Urol Nephrol (2009) 41:341–355 DOI 10.1007/s11255-009-9556-7
NEPHROLOGY - REVIEW
Direct renin inhibitors: ONTARGET for success? Yasmin Pasha Æ Paul Gusbeth-Tatomir Æ Adrian Covic Æ David Goldsmith
Received: 23 February 2009 / Accepted: 27 February 2009 / Published online: 19 March 2009 Ó Springer Science+Business Media, B.V. 2009
Abstract Direct renin inhibitors are the first new class of antihypertensive to emerge since angiotensin II receptor blockers. We discuss their reno- and cardioprotective potential, based on extrapolation from animal models and phase three trials that are currently ongoing. This paper reviews the potential benefits of direct renin inhibitors (DRIs), the only new anti-hypertensive class developed in the last decade, as compared to pre-existing classes of drug inhibiting more downstream, such as Angiotensin Converting Enzyme inhibitors (ACEI), Angiotensin 2 Receptor Blockers (ARBS). Keywords ACE-inhibitor Angiotensin II receptor blocker Aliskiren Chronic kidney disease Direct renin inhibitors Renin angiotensin system Renin inhibitors
Y. Pasha Chelsea and Westminster Hospital, Fulham Road, London, UK P. Gusbeth-Tatomir (&) A. Covic Nephrology Clinic, Parhon University Hospital, ‘‘Gr.T. Popa’’ University of Medicine and Pharmacy, Iasi, Romania e-mail:
[email protected] D. Goldsmith Renal Unit, Guy’s Hospital, London, UK
Introduction The recently reported ONTARGET trial [1, 2] now conclusively show that for all practical purposes the two classes of agents (ACE inhibitors—ACEI and Angiotensin Receptor Blockers—ARB) are effectively clinically equivalent in terms of cardiovascular risk reduction. Surprisingly, there were significant side-effects for both classes of drugs, and the combination of telmisartan and ramipril, though lowering BP further, was not accompanied by any additional clinical benefit (and was accompanied by more renal impairment and other side-effects). This, although answering some important questions, now raises a further series of clinical questions, chief amongst which is whether an ACEI, or an ARB, could summate the more effectively with an orallyactive direct inhibitor of renin synthesis. Kidneys synthesize renin, which acts on a plasma substrate to produce Angiotensin 1 (AT1). AT1 is converted enzymatically to Angiotensin 2 (AT2). AT2 is a powerful vasoconstrictor. Drugs exploiting this pathway have traditionally either interfered with the utilisation or formation of AT2 (see Fig. 1). The renin-angiotensin-aldosterone system (RAAS) is one of the most powerful regulators of arterial blood pressure and sodium balance. Hypovolemia, hypotension, stress and injury stimulate the macula densa, the baroreceptor reflex and the sympathetic nervous system. Each of these independently triggers renin release from the juxtaglomerular apparatus.
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342 Fig. 1 The Renin Angiotensin Aldosterone System (RAAS) and site of actions of antihypertensive drugs
Int Urol Nephrol (2009) 41:341–355 Indicates points of blockade A. Site of action of a Direct renin inhibitor (e.g. Aliskiren) B. Site of action of an ACE inhibitor C. Site of action of an Angiotensin Receptor Blocker
↓ NaCI intake
↓ Arterial pressure
↓ ECF volume
Angiotensinogen
Stress traum a
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R
Angiotensinogen I Asp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu
Angiotensin Converting Enzyme Chymase (heart)
Macula densa mechanism Baroreceptor mechanism Sympathetic nervous system
B
Angiotensinogen II
A Juxtaglomerular apparatus Cytosolic Ca cAMP
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
Renin Release
Angiotensinases
C
AT1 AT2 AT?
Metabolites Angiotensinogen (1-7) Angiotensinogen (2-8) Angiotensinogen (3-8) Inactive fragments
Angiotensinogen, produced in the liver is hydrolysed by renin into AT1. AT1 is converted to AT2, by the angiotensin-converting-enzyme (ACE). AT2 acts on the adrenal glands (zona glomerulosa) to stimulate aldosterone release. The kidneys increase Na? resorption, vasoconstriction and water retention, resulting in increased blood pressure. It is also key player in development of renal injury capable of causing systemic and glomerular hypertension. It reduces renal perfusion by intrarenal vasoconstriction causing ischemic damage. It can also directly and indirectly induce mesangial and tubular cell proliferation. This may lead to tubulointerstitial fibrosis [3].
Why RAAS worth inhibiting? Renal and cardiovascular benefits Beneficial effects of ACEI and ARBs are well documented in terms of improving cardiovascular mortality post-myocardial infarction and in patients with heart failure. Studies on diabetic and non diabetic populations have shown evidence of retardation of progression of renal failure and regression of proteinuria.
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Receptor binding and biological actions
Do ACEI/ARBs have any benefit over antihypertensive action? A large meta-analysis conducted by Casas et al. [4] suggested that these benefits could be explained in terms of blood pressure rather than specific benefits of interrupting the RAAS. ACEI’s and ARB’s appear to have benefits at least partially independent of their antihypertensive action. These include reduction of albuminuria and improvement in histological appearance of glomeruli. However, the degree of improvement varies between patients and many trials comparing the efficacy of various antihypertensives have failed to show consistent results. Sarafidis et al. [5] suggest that ACEI do exert BPindependent reno-protective effects but only in the presence of advanced chronic kidney disease (CKD) stage III–IV and proteinuria. A prominent criticism of the Casas meta-study was that a third of the renal outcomes came from the ALLHAT trial, which did not study a representative sample, i.e. one that could be extrapolated to the European CKD population. The study excluded most high-renal risk patients, including all with a serum creatinine [177 mmol/l, concurrent heart failure, those already on ACEI/ARB, and all those on concurrent diuretics. Additionally, data on base-line
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microalbuminuria and proteinuria was not always provided. Indeed, when ALLHAT data was excluded form the meta-analysis then a clear benefit for RAAS inhibition, over and above BP control has been demonstrated [6].
Renoprotection: how is it measured? Microalbuminuria in hypertensive, diabetic or non diabetic is a recognised predictor of end-stage renal disease (ESRD), and early mortality as well as CV events [7]. Other markers used include doubling or trebling time of serum creatinine, years to dialysis or rate of decline of the glomerular filtration rate (GFR), time to transplantation or death. There is evidence to support the renoprotective benefits of RAAS inhibition in both diabetic and non diabetic disease. Two large meta-analyses consider the evidence. Cardiovascular (CV) benefits were demonstrated by the HOPE [8] trial, which showed reduced risk of cardiovascular events in diabetic patients with microalbuminuria, after treatment with ACE inhibitor. There was a significant reduction in the primary end point (MI/stroke/death) from 17.7% in placebo to 14.1% in the ramipril group, with a relative risk reduction of 22%. There was also a significant reduction in all-cause mortality (16% in the ramipril group). Similarly, the effects of the ARB losartan on CV mortality, studied in the LIFE trial [9] and extrapolation from the IDNT study [10] suggest that reduction of albuminuria during BP reduction reduces risk of CV events as well as development or progression of renal disease.
Trial data of RAAS inhibition in diabetics A meta-analysis of 12 placebo-controlled trials of ACE inhibition in type 1 diabetic patients, with normal BP and microalbuminuria demonstrated that ACEI were associated with a 62% reduction in risk of progression from micro to macroalbuminuria. There was a 300% increase in the probability of return to normo-albuminuria [11]. In Type I diabetics with overt proteinuria, captopril reduced the risk of progression of diabetic nephropathy by 48% compared to placebo, with a greater risk reduction at
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higher baseline creatinine levels. ACEI also reduced combined end-point of dialysis, transplantation or death by 50%. The IDNT study [9] high-lighted the relationship between reducing proteinuria in type II diabetics and risk of renal failure. Patients were randomised to placebo, irbesartan or amlodipine. Halving the proteinuria reduced risk of ESRD by 50%. The reduction of albuminuria was also associated with a reduction in risk of CV events. Comparative studies of ACEI and ARBs are rare; one such study [12] observed the effects of telmisartan and enalapril on microalbuminuria of Type 2 diabetics and concluded that ramipril was not inferior to telmisartan. The ABCD trial [13] was a study with a 5.3 follow-up of intensive vs. moderate BP control on diabetic complications. Patients were randomised to enalapril, nisoldipine or placebo. No differences were found between intensive and moderate arms, or between ACEI and calcium-channel blockers (CCB). In hypertensive patients there was no difference in the secondary endpoint of urinary albumin excretion between intensive and moderate groups. But enalapril significantly reduced urinary albumin excretion. In normotensives, intensive BP control reduced progression to microalbuminuria. A synthesis of the main studies on nephroprotection in diabetic nepropathy is presented in Table 1 [14].
Trial data of RAAS inhibition in non-diabetics A meta-analysis of 11 randomised ACEI trials in subjects with non-diabetic renal disease demonstrated a 30% reduction of risk of ESRD or combined endpoint ESRD or doubling of creatinine, in ACEI arms. Greater benefits were consistently found in patients with greater proteinuria [15]. The GISEN group [16] examined the effect of ramipril on normal to hypertensive patients with proteinuria unrelated to diabetes. This placebo controlled double-blind study showed equal incidence of CV events in both arms; BP was comparable in both as conventional antihypertensives were given in the non-ACEI arm. Ramipril significantly slowed the decline in GFR in patients with proteinuria over 3 g/24 h. Ramipril also halved combined endpoint of doubling creatinine or ESRD. There was also significant lowering of urinary protein excretion by 55% at
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Population
Study
123
ABCD
IRMA-2
MARVAL
IDNT
EUCLID
BENEDICT
n = 470
Type 2 DM and HTN
n = 590
Type 2 DM, HTN, microalbuminuria
n = 332
Type 2 DM and microalbuminuria ±HTN
n = 1,647
Type 2 DM, HTN, proteinuria, raised creatinine
n = 530
Type 1 DM, normomicroalbuminuria
n = 1,204
Type 2 diabetics with normoalbuminuria & HTN
n = 25,620
Persistent microalbuminuria
Composite; Death from cardiovascular causes, MI, CVA or admission for heart failure
Non inferior BP control
Primary endpoint
Randomised, blinded, 5.3 year mean follow up
Randomised, placebo, controlled, 2 year period
Randomised, double blind, 24 week trial
Change in 24 h creatinine clearance
Time to overt nephropathy
%change in UAER
The combination was associated with more adverse events without increase in benefit
Mean BP was lower in both the Telmisartan alone and combination groups than ramipril alone. Telmisartan alone was associated with less cough (1.1 vs. 4.2% P \ 0.001), less angioedema (0.1 vs. 0.3% P = 0.01), but more hypotensive symptoms (2.6 vs. 1.7%) than ramipril
Results
ACEI Lisinopril vs. Placebo
ARB reduced relative risk of diabetic nephropathy by 44% at low dose (150 mg/24 h) and by 68% at high dose (300 mg/24 h)
ARB reduced UAER by 44% compared to 8% with CCB, with similar BP in both groups
Enalapril vs. nisoldipine Intensive No difference in primary end-point BP control DBP aim 70 mmHg between ACEI and CCB. But fewer pts vs. mod 80–89 mmHg in the intensive BP group progressed from NA-MA (P = 0.012) and from MA to albuminuria (P = 0.028)
Irbesartan vs. placebo
Valsartan vs. amlodipine
ARB reduced relative risk of doubling creatinine by 33% compared to placebo and 37% vs. amlodipine
ACEI reduced UAER by 18.8% vs. placebo, treatment effect was far greater in microalbuminuric patients than normoalbuminuric patient
ACEI trandolapril vs. ACEI plus Both arms prevented microalbuminuria CCB (verapamil) vs. CCB alone 5.7% of MA prevented in combination arm vs. 6% in ACEI only arm, 11.9% in CCB only arm compared with 10% in placebo
Ramipril 10 mg vs. Telmisartan 80 mg vs. the combination
Intervention
Randomised, double blind Doubling time of creatinine, ARB Irbesartan vs. CCB ESFR, all cause mortality amlodipine or placebo
Randomised, doubleRate of change in urine blind, 2 year follow up albumin excretion rate
Randomised, double blind, placebo control 3.6 year follow up
ONTARGET Patients with high risk Randomised, double diabetes/vascular blind, non-inferiority disease without heart study, median follow failure up 56 months
Trial/Study
Table 1 Data on RAAS inhibition in Diabetic Renal Disease
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Time to 1st event of Losartan vs. placebo (both added composite doubling of on to conventional BP creatinine, ERSF or death treatment)
ARB reduced relative risk of doubling of creatinine by 25% and risk of ESRD by 28%. No effect on all cause mortality
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n = 1,513
Type 2 DM, nephropathy RENAAL
Randomised, double blind, placebo controlled, 3.4 year follow up
Enalapril vs. nisoldipine Intensive No difference in primary end-point BP control 10 mmHg below between ACEI and CCB. No difference baseline vs. mod control 80– in progression from NA-MA or MA89 mmHg albuminuria. Subjects with albuminuria at base-line continued to show a decline in renal functions at both levels of BP control Change in 24 h creatinine clearance Type 2 DM and normotension n = 470 ABCD
Randomised, blinded, 5.3 year, mean follow up
Population Trial/Study
Table 1 continued
Study
Primary endpoint
Intervention
Results
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36 months. This effect was greater than would be expected by BP control alone. The AASK study [17] compared effects of an ACEI, a beta-blocker (BB) and a CCB on African-American patients with hypertension-related decline in GFR. There was no association between the BP level and the endpoints reached. However, ramipril was significantly found to reduce risk of ESRD by 22% compared to metoprolol and by 38% compared to amlodipine. Both ramipril and metoprolol reduced the risk of ESRD alone and risk of ESRD or death, compared to amlodipine. At 3 years, the mean decline in GFR was 36% slower in patients on ramipril compared to amlodipine. A synthesis of the main studies on nephroprotection in non-diabetic CKD is presented in Table 2 [14].
Antiproteinuric activity of non-RAAS drugs Calcium channel blockers (CCB) cause dilatation of the afferent arterioles (in contrast to ACEI/ARB’s). In the presence of systemic hypertension, this may cause intraglomerular hypertension. The PREVEND study [18] looked at the incidence of microalbuminuria in non-diabetic renal patients on various antihypertensive agents, elevated urinary albumin was found in patients on dihydropyridine CCBs, but not in non-dihydropyridine CCBs. Of note, the same study showed that ACEI were only superior in protecting against microalbuminuria, when combined with a diuretic. Other classes such as diuretics, beta-blockers, and hydralazine do not induce efferent dilatation and are theoretically less likely to reduce intraglomerular hypertension. Non-selective beta-blockers—BB (e.g. propranolol) reduce GFR and renal perfusion by reducing cardiac output. A reflex rise in sympathetic activity results in raised systemic and renovascular resistance, via alpha-receptors. A few studies [19] have shown that selective BBs (e.g. metoprolol and atenolol), while reducing hypertension, do not reduce GFR or renal blood flow (RBF), although renovascular resistance increases. In patients with renovascular hypertension, treating with metoprolol has been shown to reduce plasma renin activity (PRA). A study using atenolol in diabetics with microalbuminuria showed also that BB may retard usual progression to renal failure [20]. However, all BBs cause sympathetic nervous system (SNS) and RAAS stimulation, resulting in increased levels of renin and noradrenaline.
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Table 2 Data on RAAS inhibition in non diabetic renal disease Trial/Study
Population
GISEN group Normohypertensive pt with proteinuria
Study
Primary endpoint Intervention
Double blind, Rate of decline of ACE-I vs. placebo ie placebo GFR standard BP control controlled (non ACE/ARB agents used)
n = 117
AASK
African American 18–70 year with hypertensive renal disease
Results Ramipril significantly reduced decline in GFR in pts with[3 g/ 24 h of proteinuria. Ramipril also halved combined endpoint of doubling creatinine or death. Significant lowering of urinary protein excretion by 55% at 36 months
Randomised, double blind, placebo control
Rate of change in Amlodipine vs. ramipril No difference in MAP goal and GFR vs. metoprolol ±other usual goal in terms of decline in (secondary agents to reach MAP of GFR. Ramipril reduced relative composite) \92 or 102–107 mmHg risk of composite clinical endpoint by 22% metoprolol and by 38% vs. amlodipine
Randomised, controlled, 36 month follow up
Time to ESRD
Randomised, double blind 2.9 year follow up
Combined time to ARB losartan or ACEI doubling or trandolapril or creatinine or combination ESRD
Randomised, doubleblind, 24 weeks
Microalbuminuria Eplerenone vs. amlodipine Eplerenone significantly reduced urine albumin: creatinine ratio vs. amlodipine
Randomised, double blind, 8 months
Change in proteinuria
n = 1094 REIN-2
Non diabetic proteinurics n = 338
COOPERATE Non diabetic renal disease Cr133-398, GFR2070 ml/min
Ramipril (moderate BP control) or Ramipril ? felodipine (intensive BP control)
Despite better BP reduction in intensive group, cumulative incidence of ESRD, GFR decline and residual proteinuria was similar in both arms Combination treatment reduced relative risk of creatinine doubling/ESRD by 62% vs. trandolapril alone and by 60% vs. losartan alone
n = 263 White et al.
Systolic HTN n = 269
VVANNTT
Non diabetic nephropathy n = 69
Why inhibit renin? What can it achieve that other classes cannot? Neither ACEIs nor ARBs alone can inhibit the RAAS completely. Renin catalyses the rate-limiting step of RAAS. Renin is unique in specificity and only appears to recognise one known substrate, angiotensinogen. ACE, by comparison, recognises other peptides in addition to angiotensin, such as bradykinins. However, renin receptor occupancy with renin/prorenin also stimulates specific protein kinases ERK1 and ERK-2, which are mitogen-activated, without affecting AT generation [21]. This supports a pro-fibrotic role for renin, independent of its angiotensin
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Trandolapril ? verapamil or amlodipine
Trandolapril alone significantly reduced proteinuria from baseline. Addition of CCB did not make any difference to proteinuria
generating effect. Recently, renin receptors have been identified in the glomerular mesangium and arterial sub-endothelium; this suggests potential additional advantages of renin inhibition, over and above ACE and angiotensin receptor blockade. Unlike ACEI and ARBs, renin inhibitors induce a marked and sustained reduction in PRA and consequently prevents the formation of both angiotensin 1 (AT1) and angiotensin 2 (AT2), consecutively reducing the levels of aldosterone—see Table 3 for a detailed comparison of ACEIs, ARBs and Direct Renin Inhibitors. ARBs usage leads to increased concentration of AT2. The therapeutic response achieved by both ACE and ARB may be attenuated by the reactive rise
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Table 3 Comparison between different classes of antihypertensives involved in RAAS inhibition Drug class
ACE inhibitor
Angiotensin 1 receptor blocker Direct renin inhibitors
Aldosterone antagonist
Mechanism
Retard conversion AT1–AT2
Inhibit AT2 at receptor level
Aldosterone antagonist
Direct renin inhibition
ACEI ? ARBs
Bradykinin levels Up
Up (but less than ace)
No change
Increased
Angiotensinogen levels
Decreased
Decreased
No change
Additive effect
Plasma ACE
Inhibited
Not inhibited
Not inhibited
Inhibited
AT1 levels
Up
Up
Down
Additive effect
AT2 levels
Down(but long term increase)A2 escape
Up
Down
Down/normal
AT1 receptor
Not stimulated
Blocked
Not stimulated
Not stimulated and blocked
AT2 receptor
Not stimulated
Stimulated
Not stimulated
Minor stimulation
Renin concentrations
Up
Up
Down
Plasma renin activity
Increases
Increases
Inhibited
Serum aldosterone
Lower initially (then aldosterone escape, normal to high levels)
Lower initially (then aldosterone escape, normal to high levels)
Lower
Lower
Lower
MAP
Lower
Lower
Lower
Lower
Lower
Renovascular response
Yes
Yes. Greater than ACEI
Yes. Greater than ARB and ACEI
Effect on GFR
Increase
Increase
Greater increase
Intra-glomerular Lower (dilates efferent blood pressure arteriole)
Lower (dilates efferent arteriole)
Lower (dilates efferent arteriole)
Effect on proteinuria
Reduces
Reduces
Reduces
Tissue RAAS
Inhibited
Blocked
Inhibited
of renin [22] and therefore of angiotensin peptides, which does not occur with direct renin inhibition. Inhibition of ACE leads to accumulation of AT1. This AT1 can then potentially be converted to AT2 by alternative pathways not blocked by ACE inhibition. There is data to suggest that up to 30–40% of AT2 formation in the healthy human, during RAAS activation, occurs through renin dependent, but ACEindependent pathways [23, 24]. Angiotensin break-through or escape is the name given to the tendency of AT2 to rise toward pretreatment levels [25]. Additionally, polymorphism within the ACE gene means up to 45% of congestive heart failure (CHF) patients on long-term ACEinhibition continue to have elevated AT2 levels [26].
Up
Additive Additive
Lower
Reduces
Reduces Additive effect
It is worth noting that aldosterone independently contributes to renal injury as well. Pathways shown to promote this include inflammatory cytokines, generation of oxygen free radicals and up-regulation angiotensin II (type 1) receptors, which potentiate the damaging effects of ATII [27, 28].
Aldosterone escape ACE and ARBs initially reduced aldosterone levels, but in the longer term they lead to incomplete aldosterone suppression or aldosterone escape [29]. There is evidence to suggest that direct renin inhibitors (DRIs) such as aliskiren can reduce AT2
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reactivation in ACE inhibition and aldosterone escape by ACEI or ARB, at least in RAAS-dependent aldosterone production. For RAAS-independent aldosterone production, DRIs and drugs such as eplerenone may be beneficial [29].
Plasma renin level and plasma renin activity (PRA) To measure the effect of various agents on renin concentration either the plasma renin activity or the plasma renin concentration can be used. Plasma renin activity (PRA) measures the enzymatic activity of renin and quantifies the amount of angiotensin I generated from renin activity. Hypertensive patients demonstrate a wide spectrum of plasma renin activity (PRA). Studies have shown the association between occurrence medium to high PRA in hypertensive and future cardiovascular events [30]. PRA is also a predictor of response to various antihypertensives. Lowering PRA is believed to be important in endorgan protection. PRA is an independent risk factor and direct surrogate marker for several cardio-renal diseases, such as myocardial infarction (MI) and chronic kidney disease (CKD). Direct renin inhibitors lower PRA, whereas most current anti-hypertensive drug classes such as ACE-Is and ARBs increase PRA levels (See Table 3 for a comparison of the actions ACEI, ARBs and DRIs). Currently aliskiren is the only orally-active DRI that has passed Phase III trials, despite drug development commencing some thirty years ago. This highly lipophilic formulation, aliskiren, has a half life of 24 h, improved bioavailability and undergoes under 1% metabolism by the liver negating the need for renal dosing in renal impairment and is unaffected by the p450 enzyme system. Aliskiren is able to inhibit PRA by up to 65% from baseline [31]. This is in contrast to ACE inhibitors and ARBs that interrupt feedback regulation by AT2, causing increased renin levels and increased PRA. When aliskiren is added to an ARB or ACE inhibitor, PRA is lower than with the ARB or ACE inhibitor alone and higher than with aliskiren monotherapy [32, 33]. Additionally, it can counteract the hydrochlothiazide (HCZ)-induced rise in PRA if used in combination [31, 34]. Aliskiren-induced inhibition of PRA persists for 3–6 h with lower doses (40–80 mg/day)
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and 10–48 h with higher doses (160–640 mg/day). PRA is reduced in a dose-relatedly manner, with the greatest reductions occurring at the highest doses. On cessation of aliskiren, PRA does not return to pretreatment levels for up to 2 weeks. In contrast, both ACE inhibitors and ARBs have been observed to increase PRA to a greater extent than placebo. This occurs within a few hours of ACE inhibitor or ARB being administered. PRA remains elevated throughout therapy. The other method of quantifying renin is the measurement of plasma active renin, also known as active renin concentration (ARC). Measurement of ARC allows quantification of the amount of renin present, regardless of its activity. ARC is elevated early after treatment with aliskiren and remains elevated with repeated dosing. ARC does not return to pre-treatment levels until 2 weeks after withdrawal, suggesting that long-term protective effects could be derived at tissue level. Aliskiren causes a greater elevation in ARC than with valsartan [32]. ARC is likely to be increased because the amounts of both angiotensin I and angiotensin II are reduced by aliskiren for at least 24 h after treatment administration. A feedback loop signalling the kidneys to release more renin is triggered by low levels of angiotensin II; therefore, an increase in ARC is a marker of RAAS suppression. The higher ARC observed with aliskiren compared with that of ACE inhibitors or ARBs suggests that aliskiren provides more complete suppression of the RAAS. Although ARBs inhibit the action of angiotensin II at the level of the AT1 receptor and ACE inhibitors prevent the generation of angiotensin II, ARBs also increase both AT I and II, whereas ACE inhibitors increase AT I. Increased angiotensin I could lead to increased generation of angiotensin II by alternative pathways, and more angiotensin II could lead to increased stimulation of AT2 receptors, which are not blocked by ARBs. There are data [23] to suggest that up to 30–40% of AT2 formation in the healthy human, during RAAS activation, occurs through rennin-dependent but ACE-independent pathways. ARC may be higher with DRIs, because these inhibit the RAAS before these alternative pathways and targets the only known pathway for conversion of angiotensinogen to angiotensin I.
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Direct renin inhibitors currently available As the initial and rate limiting step of the RAAS cascade, direct renin inhibition was expected to be the most effective means of inhibiting the RAAS. Earlier technical problems for drug development included low potency, poor bioavailability related to minimal gastro-intestinal absorption, substantial first-pass metabolism, weak antihypertensive ability and limited duration of action. Aliskiren is currently the only orally active DRI that has passed phase III clinical trials. However, others such as enalkiren and remikiren are under study. In healthy adults, with oral administration of aliskiren in doses of 40–640 mg/24 h, plasma concentration increased in a dose-dependant fashion. Peak concentrations were achieved within 3–6 h. Aliskiren plasma steady state concentrations were achieved in 5–8 days of treatment. Mean plasma half life was 23.7 h [35], allowing once daily dosing regimens. Pharmacokinetics deviate from dose linearity [36]. Oral bioavailability is 2.6% and food intake reduces the maximum concentration cmax by 19% and the area under the curve by 38% [37]. Elimination is primarily via the biliary route; the drug is excreted in unmetabolised form. Under 1% undergoes urinary excretion, this means there is no need for adjustment of the starting dose in patients with renal impairment [36, 38]. It is also not affected by cytochrome P450 system [39, 40].
What do we expect DRIs to do? Extrapolation from animal models The main biochemical difference between direct renin inhibitors and ACEIs or ARBs is that DRIs dramatically inhibit renin activity without altering angiotensinogen expression, indicated by decreases in both AT1 and AT2. In animal studies specifically, in the double-renin transgenic rat (developed to overexpress renin and angiotensin genes), aliskiren has demonstrated attenuation of cardiac and renal end organ damage in a similar fashion to valsartan. In addition to BP and microalbuminuria reduction, normalisation of the serum creatinine, and regression of LVH, aliskiren treated rats also showed improved overall survival [41]. ACE-inhibitors also block the proteolytic inactivation of bradykinin and substance P, leading to two
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side-effects: dry cough (common) and angioedema (occasionally). While AII-antagonists show limited receptor subtype activity, several cases of angioedema have been reported; the mechanism remains unclear but may be due to the observation that ARBs can induce tissue, but not serum increase in bradykinin levels [42]. Because renin is upstream from these events, a therapeutic approach which targets this enzyme should be free from these side-effects and limitations; indeed, no cases of angioedema with aliskiren treatment have been reported so far. Increased levels of bradykinin, a vasodilatory peptide, after ACE inhibition are likely to be at least in part responsible for its superior antihypertensive properties of ACEI over both ARBS and potentially DRIs. But in addition to the irritating cough, it is possible that accumulating bradykinin (during ACE inhibition) may counteract the beneficial effects on end-organs of reducing AT2. The accumulating AT1 may be susceptible to conversion to AT2 by ACE-independent processes. This would not occur with direct DRIs. Therefore, it is possible that DRIs may offer better cardio- and renoprotection. This also suggests that DRIs maybe usefully in combination with ACEIs. Given the action of ACEIs, it was expected that ACEI should produce a more profound renovascular responses than DRI, as ACE leads to kinin degradation and induces vasodilator prostaglandin formation or activation of NO release. However, vasodilatation with enalkiren was superior to captopril [43]. In a follow up study, enalkiren and captopril were compared in a placebo-controlled randomised doubleblind trial. Captopril and enalkiren both led to striking renal vasodilatation, whereas placebo had no effect. The response to enalkiren was significantly larger than the response to captopril [44]. In fact, a meta-analysis suggested that the renal vasodilator response to DRI exceeds that of ACEI by up to 50% in healthy adults [24]. The magnitude of the responses confirmed a more recent study by the same authors (Fisher and Hollenberg) [45], with another direct renin inhibitor, zankiren, that induced a larger renal vasodilator response than could have been anticipated from the ACE inhibitor experience. These data suggest that a renin-dependant, ACE-independent pathway for AT2 generation maybe implicated. Similar results were obtained in the guinea-pig study by El-Amrani et al. [46], which examined the renovascular responses to
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ACE lisinopril, ARB losartan and the DRI RO425892 in guinea pigs. Despite similar BP reduction, the increase in renal plasma flow, GFR, diuresis and natriuresis were significantly greater with DRIs. One explanation offered for the superiority of the DRI-induced vasodilatation over ACEI is ACE independent AT2 formation, another is better tissue penetration of the DRI. The new agents are highly lipophilic, which means they may have enhanced renal tissue penetration, perhaps allowing more effective local (renal) AT2 formation blockage.
Intrarenal AT2 formation in humans Sustained vascular activity of the DRI enalkiren in humans was noted to continue despite discontinuation of the drug. As expected, plasma concentrations fell sharply after end of the infusion, approximating a half-life of 90 min, but renal plasma flow continued to rise. This suggests that enalkiren exerts its main influence outside of the plasma compartment [47]. It is possible that enalkiren is interrupting local intrarenal AT2 formation and this accounts for both the sustained vasodilator response but also for the observation that it exceeds the response of ACE inhibition. In support of DRIs long-term effects being at tissue level, it is noted aliskiren concentrations in the kidneys are particularly high and persist for up to 3 weeks after discontinuation of the drug [48]. A recent study [34] looked at effects of aliskiren versus aliskiren ? hydrochlorothiazide on renin concentration and PRA specifically at the effects of drug withdrawal. After six months, on-treatment renin concentration rose in the aliskiren arm, but was even higher in the combination group. During withdrawal, some patients switched to placebo and the remainder continued on aliskiren. PRA remained suppressed in those who continued, but in the group switched to placebo, PRA remained over 50% below baseline at 4 weeks after withdrawal, although renin concentration had reduced to baseline by then. This again suggests continued renin inhibition beyond the drug’s half life.
What are the expected cardiac effects of DRIs? In rats, dogs and sheep with left ventricular failure, DRI treatment is associated with reduced left
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ventricular end-diastolic pressure. Regression of LVH comparable to that achieved with by ACEI and ARBs has also been demonstrated [41]. Like ACEIs, DRIs induce vasodilatation, offering potential to improve arterial wall elasticity. Currently, there is not much (human) data for cardiovascular effects. Novartis is now recruiting for Phase III trials looking at aliskiren in hypertensive patients with LVH (the ALLAY trial). This trial will be comparing effects of aliskiren with losartan and combination of both over 9 months in LVH patients, the end-point being MRI assessment of LVH mass [49, 50]. In the ALOFT study by Recio-Mayoral et al. [51], aliskiren was added to optimum standard therapy in NYHA class II–IV heart failure. One hundred and fifty-six patients had aliskiren 150 mg or placebo added to an ACEI or ARB. Interim results of surrogate markers are positive; in the aliskiren arm, serum BNP was five times more reduced compared to standard therapy, where BNP levels are a surrogate measure of heart failure severity. In addition, tolerability of aliskiren was similar to placebo and there were no cases of worsening of heart failure on treatment, in contrast to recognised worsening of failure with some BB and CCB therapies.
What are the expected side effects of DRIs? Cough, one of the major side effects of ACE inhibition, was predicted to be unlikely, as renin inhibition does not affect bradykinin formation. The incidence of cough with aliskiren is slightly increased when compared with placebo, but still much lower than with ACEI. Angio-oedema occurs less often than with placebo. When hyperkalaemia [5.5 was reported this was usually in diabetics on concurrent ACE inhibition. Published safety data include Oh et al.’s [52] randomised double-blind multicenter placebo-controlled study, analysing the dose dependent efficacy and tolerability of aliskiren in patients with mild-tomoderate hypertension. Aliskiren was well tolerated with an adverse event profile similar to placebo at up to 300 mg. There was a higher rate of diarrhoea at 600 mg (11.4 vs. 1.2%, 1.8 and 1.2% for aliskiren 150, 300 and placebo respectively). There were four severe adverse events and no deaths. BP was lowered
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in a dose-dependant manner. These were sustained over the 24 h dosing interval [52]. Weir et al.’s pooled analysis [53] examined the adverse event profile of DRI from seven randomised control trials, five of which were placebo-controlled. A total of 7,060 patients (50.2–72.5% male, 77.4% white, age range 50.2–59.8 year) with mild-to-moderate hypertension. DRIs showed similar tolerability to placebo. With doses of 75–600 mg of aliskiren, 39.8% complained of any side-effects, compared with 40.2% of placebo. The most common adverse events reported by over 2% of patients on aliskiren were headache, nasopharyngitis and diarrhoea. Headache was shown to reduce at higher doses. Diarrhoea was more frequent in all groups of aliskiren overall— 2.6% compared with placebo (1.2%). This was due mainly to higher frequency of diarrhoea—9.5% at higher (600 mg) dose. Overall, over 95% of adverse events with study drug were mild-moderate severity. However, there are limitations with estimating side effects of DRI therapy with the available data. Subjects are usually healthy volunteers or patients with mild disease. Higher-risk patients that are older, have renal failure etc are unlikely to be included. Study groups are also under more rigorous follow up. In addition, the numbers under study are too small to identify all side-effects that can occur with wider usage of the drug. As a class, DRIs are likely to have similar effects and contraindications to ACEI and ARBs. No lifethreatening complications of therapy have been reported thus far, but the possibility of hyperkalaemia and deterioration of already impaired renal function remain. DRIs should be avoided in renal artery stenosis and pregnancy. No information about teratogenicity is currently available. Total RAAS inhibition is another area where safety studies are needed; this may be achievable if aliskiren is used with another RAAS inhibitor. Special circumstances include elderly or salt deplete patients and patients with renal artery stenosis.
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nephroprotection [54]. Synergistic antihypertensive effects with ACEI and ARBs have been demonstrated in both animal and human models. Combination of ACEI and ARB therapy has also been shown to have an increased anti-proteinuric effect and have been demonstrated to slow kidney disease progression more than either agent alone. The COOPERATE study [55] looked at the use of maximum doses of ACE1 and ARB used alone or in combination (still at maximal dose) in non-diabetic patients. Of those on combination treatments, 11% reached the endpoints of creatinine doubling or ESRD, compared with 23% of the patients on the trandolapril-only arm and 23% on the losartanonly arm. A further prospective randomised crossover study by Campbell et al. [56] examined a combination of sub-maximal doses of benazepril and valsartan, in one arm, compared with maximal doses of each agent alone, in the other two. The population treated were non-diabetic CKD patients. After 8 weeks of therapy, superior reduction in proteinuria was achieved by the half-dose combination, compared to both full dose agents alone, for equivalent changes in BP and GFR. ONTARGET has now shown us that we can achieve maximal blockade of the RAAS using an ACE inhibitor or an ARB, but that both is not necessarily better [1]. In practice, we now need to know which combination of an ACEI, or an ARB, with a drug such as aliskiren could bring additional cardioprotective benefit. Antihypertensive actions of diuretics are potentiated by targeting the compensatory increase in AT2 and aldosterone by coadministration of an ACE inhibitor [22]. This also allows greater tolerance and reduced side effects. Additional antihypertensive value of ACEI and ARBs, over and above single agent use, can also be achieved by adding in eplerenone, a selective aldosterone inhibitor, in patients resistant to monotherapy [57].
DRIs as synergistic agents In addition to a thiazide or versus thiazides
Synergy? Does more inhibition of the RAAS mean more renoprotection? Neither ACEI nor ARBs alone can completely suppress RAAS activity, this supports the possibility that DRIs are likely to provide more complete
Aliskiren (75 mg, 150 mg or 300 mg/day) has been evaluated both individually and in combination with hydrochlorothiazide (6.25 mg, 12. 5 mg or 25 mg/day) in a single-blind Phase II trial. Aliskiren was superior to placebo and combination treatment was superior to each monotherapy, alone. Renin inhibition also
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managed to neutralise the compensatory increase in PRA induced by HCZ. This study also suggested there is a less risk of patients developing hypokalaemia as a result of diuretic treatment in this combination [31]. In addition to a calcium channel blockers In a Phase III trial, patients with a mean BP over 90 mmHg after 4 weeks of amlodipine 5 mg/day, entered a 6-week double-blind trial and were randomised to amlodipine 10 mg, amlodipine 5 mg with aliskiren 150 mg or to continue with amlodipine 5 mg/day. Mean systolic and diastolic BP reductions after 6 weeks were significantly greater than with 5 mg of amlodipine alone, for both the amlodipine 10 mg and CCB/DRI combination. Incidence of oedema in the combination group was also much less than high-dose CCB [58].
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37.5 mg, 75 mg, 150 mg or 300 mg of aliskiren or 100 mg of losartan. After 1 month of therapy, ambulatory BP readings were performed. Mean reductions in systolic pressure were not significantly different between losartan 100 mg and aliskiren 150 mg and 300 mg [59]. Another double-blind phase 2 study compared irbesartan 150 mg with placebo and aliskiren 150 mg, 300 mg or 600 mg, once daily for 8 weeks. The endpoint was sitting-office BP. Aliskiren 150 mg was comparable to irbesartan 150 mg. Higher dose aliskiren had a significantly greater effect on DBP than 150 mg irbesartan [60]. A placebo controlled study (n = 1,123) of aliskiren 75–300 mg vs. valsartan 80–320 mg concluded that aliskiren and valsartan alone and in combination showed doserelated reduction in DBP and SBP. The combination had greater antihypertensive effect and was welltolerated [61].
In addition to an ACEI and versus ACEI therapy
What are DRIs intrarenal effects?
In a phase III double-blind study of hypertensive (both type 1 and 2) diabetics, patients were randomised (double-blinded) to either ramipril 5 mg, aliskiren 150 mg or the combination 150/5 mg/day. After 4 weeks, doses of each were increased to either ramipril 10 mg, aliskiren 300 mg or 300/10 mg for the combination. Aliskiren monotherapy was noninferior to ramipril monotherapy for diastolic BP reduction. Aliskiren was statistically superior to ramipril for systolic BP control. Combination therapy was superior to ramipril monotherapy. Renin concentration increased in all groups: aliskiren (115%), ramipril (68%), but greatest in combination (315%). PRA increased by 111% in ramipril arm, reduced to 68% in aliskiren group; the greatest overall reduction was with combination to 44% [33]. Nussberger et al. [36], in a well-done trial in healthy normotensive males, concluded 160 mg of aliskiren had an equivalent hormonal effect to enalapril 20 mg in terms of PRA inhibition—which was dose-dependant. There was no significant difference in BP or HR and aliskiren was well tolerated.
Animal studies using the DRI ciprokiren in the canine kidney demonstrated both prevention of the reduction of RBF and prevention of the increase of renal arterial resistance in response to decreased perfusion pressure [62]. Correspondingly, in sodium-depleted monkeys and normotensive guinea pigs, enalapril and the DRIs enalkiren and remikiren reduced renovascular resistance and increased renal perfusion with or without a rise in GFR [62]. In healthy hypertensive, sodium-depleted men, the renal circulation was studied in response to AT2 challenge, in the presence of placebo, enalkiren or captopril. Both agents significantly increased renal blood flow during AT2 infusion, compared with placebo [47]. A trial of once-daily remikiren 600 mg given to 14 hypertensive subjects with normal to impaired renal function, reduced mean BP from baseline by 11.2% at peak plasma concentration and 6.0% at trough. Renal vascular resistance and filtration fraction was reduced by 15 and 10%, without change in GFR. Proteinuria in six patients with abnormal renal function was reduced by 27% from a baseline of 5.8 g/day [63]. Two new trials report positive results of the antiproteinuric effect of aliskiren in diabetics. The first (open-label study) looked at type 2 diabetics with urine albumin/creatinine ratio (UACR) [30 mg/g,
Versus ARBs treatment Hypertensive patients were randomised (in a phase II trial) to the following double-blind treatment groups,
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before and after aliskiren therapy with 300 mg/day. Outcome measures included BP and morning UACR. Systolic BP was significantly lower at 7 days with no further reduction after 28 days, returning to baseline within 7 days after cessation of treatment. Significant reductions in UACR were found at after 2–4 and 7 days, by 17%. There was further reduction in UACR after 28 days to 44% which continued for a week after withdrawal, without significant change in eGFR [64]. The AVOID [65] double blind randomised trial evaluated the benefit of combining aliskiren 150 mg or placebo with losartan 100 mg in 599 hypertensive type 2 diabetics. After 3 months, the aliskiren arm was up-titrated to 300 mg/day. Primary outcome measure was decline in early morning UACR. Aliskiren reduced UACR by 20% and UAER by 18% compared to placebo. 24.7% of aliskiren patients (compared with 12.5% of placebo) underwent a C50% reduction of UACR. GFR remained unchanged and as in the previous study changes in BP did not correlate well with reduction in albuminuria. These data suggest that aliskiren-induced renoprotection is independent of its antihypertensive effects in type 2 diabetics already on recommended ARB losartan, with acceptable BP control. ALTITUDE [49] is a much larger scale prospective study of type 2 diabetics that aims to determine whether aliskiren therapy can delay diabetic complications in diabetic nephropathics.
Conclusions. At what level and what combination and what criteria should we be judging it by? Current data suggest that DRIs are at least as effective as ARBs and ACEIs for short-term BP reduction. They also have fewer side effects. Obviously, these drugs are much more expensive than the alternatives, most of which are generically available. Long-term data is needed with regard to renal and cardiovascular protection. Until this is available, DRIs are likely to be used as add-on therapy in hypertensive patients who are failing on existing combinations. They might be particularly useful in combination with agents that cause a reactive increase in plasma renin activity such as diuretics, ARBs and ACEIs. DRIs may prove more useful in high-renin hypertensives such as young and Caucasian patients who have more active renin system
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than blacks and older populations. However, pooled analysis of monotherapy efficacy studies demonstrates antihypertensive benefit of aliskiren 150 mg or 300 mg regardless of age, gender or race [53]. DRIs maybe useful in patients unable to tolerate ACE-inhibition. They may become important in diseases where AT2 activity is pathological. DRIs maybe indicated for patients requiring dual blockade of RAAS eg diabetics with albuminuria or in fibrotic renal diseases. The ONTARGET trial has now shown us that to all intents and purposes we can achieve maximal blockade of the RAAS using an ACE inhibitor or an ARB, but that both is not necessarily better. In practice, we now need urgently to know whether the combination of an ACEI, or an ARB, with a drug such as aliskiren could bring additional cardioprotective benefit. Conflict of interest statement Dres. Goldsmith and Covic received honoraria and speaker fees from Novartis.
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