Renin inhibitors are unique in their effects on the RAAS. Both ACE inhibition and angiotensin receptor blockade lead to a reactive rise in plasma renin activity (PRA) and thus to an increase in the angiotensin peptides, both angiotensin I and angiotensin II in the case of angiotensin receptor blockers (ARBs) and angiotensin I with ACE inhibitors. Renin inhibitors, operating at the first and rate-limiting step of the cascade, render the entire pathway quiescent. Because renin is specific for the substrate angiotensinogen, renin inhibitors do not cause stimulation of bradykinin or prostaglandins. In addition, renin inhibitors reduce angiotensin II formed by non-ACE pathways.
Renin inhibitors may also confer benefit by inhibiting activation of the proenzyme prorenin, long thought to be inactive. Prorenin can be activated by conversion to renin through cleavage of a 43-amino acid segment from the N-terminal end. Importantly, when it binds to the (pro)renin receptor it can also undergo nonproteolytic activation via conformational change and exposure of the active site. The discovery and identification of this receptor, primarily on glomerular mesangial cells and vascular smooth muscle cells, has offered new insights into possible pathophysiology.1 With the binding of renin to this receptor, its catalytic efficiency of converting angiotensinogen to angiotensin I increases 4-fold. As impressive, prorenin was found to bind the receptor, and when bound, is as active as renin in causing a biologic response. Either renin or prorenin occupation of the receptor results in intracellular signaling processes accompanied by activation of mitogen-activated protein kinases, transforming growth factor β, and plasminogen activator inhibitor-1, independent of angiotensin generation. If prorenin contributes to pathophysiology, as data in diabetics have suggested,2 then renin inhibitors possess an expanded potential for therapy compared with ACE inhibitors or ARBs (Figure). Aliskiren has a steady-state half-life in plasma of 23 to 36 hours3; its tissue half-life is even more prolonged.
Figure FIGURE. Pro(renin) receptor–binding initiates intracellular signaling 1 of 3 mechanisms to activate prorenin to renin. AGT indicates angiotensinogen; ANG I, angiotensin I; MAP, mitogen-activated protein; PAI, plasminogen activator inhibitor; PRS, prorenin segment; TGF, transforming growth factor.
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To date, aliskiren is the sole oral renin inhibitor approved for use in humans. Earlier molecules, peptide analogs including remikiren and enalkiren, had potency only with parenteral administration given severely limited oral bioavailability. Several laboratories have new orally effective molecules, produced by x-ray crystallographic procedures, in the pipeline.
Indications and Outcome Studies
Aliskiren is indicated for the treatment of hypertension, either as monotherapy or in combination. Clinical trials in more than 12,000 people have demonstrated that once-daily aliskiren is effective in treating mild to moderate hypertension, with reductions in blood pressure similar to other agents.
Early placebo-controlled trials evaluated the impact of aliskiren as monotherapy; a dose-response relationship was demonstrated up to 300 mg/d.4–6 No significant further blood pressure (BP) lowering was seen with the 600-mg dose, which was accompanied by increased gastrointestinal side effects. A series of subsequent clinical trials evaluated the impact of aliskiren against other agents, including hydrochlorothiazide (HCTZ) and ACE inhibitors. These included studies in elderly hypertensive patients7,8 and patients with severe hypertension.9 They have generally demonstrated a very favorable safety and tolerability profile together with equivalent degrees of BP lowering.
Most hypertensive patients require combination therapy to lower their BP. Aliskiren has been studied in combination with thiazide diuretics, calcium channel blockers (CCBs), ACE inhibitors, and ARBs, and was found to be more effective in combination with each than alone.10–15 Several long-term combination therapy trials demonstrated a similar efficacy and safety profile with additive BP-lowering effects when aliskiren was combined with HCTZ (including one study in obese hypertensives).11,12 Combining aliskiren with thiazides, as with ACE inhibitors and ARBs, blocks the rise in PRA otherwise seen. Aliskiren has also been shown to have additive efficacy with amlodipine.15,16 Interestingly, initial use of combined aliskiren and amlodipine over 24 weeks achieved superior BP reduction and tolerability when compared with sequential add-on treatment with the same drugs.15 Dual blockade of the RAAS with aliskiren and ramipril has resulted in lower BP than with either alone.13 After 6 months of randomized treatment, there was a slower return to median BP level <140/90 mmHg with the aliskiren based regimen (4 weeks) than with ramipril (1 week) following withdrawal of therapy.13 This sustained BP-lowering effect has been replicated and is attributed to the long half-life of the drug.17 Another study of dual blockade in 1797 patients with mild to moderate hypertension also demonstrated that the combination of aliskiren 300 mg and valsartan 320 mg resulted in a significantly greater BP reduction than either aliskiren or valsartan alone (−17.2/−12.2 mm Hg vs −13/−9 mm Hg and −12.8/−9.7 mm Hg, respectively; P<.0001).10
The benchmark for selecting antihypertensive therapy in clinical practice has shifted during the past decade. While the primary goal continues to be controlling BP, there is an ever-increasing burden to show added benefit in terms of improvement in surrogate markers of disease progression, target organ damage, and ultimately in clinical events.
Four cardiorenal surrogate end point studies have been published with aliskiren. The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial demonstrated that the addition of aliskiren to ARB therapy with losartan in patients with hypertension and type 2 diabetic nephropathy for 6 months resulted in a 20% reduction in mean urinary albumin-to-creatinine ratio (UACR) (P<.001), when compared with losartan alone.18 There was a 2/1-mm Hg (P<.07) greater fall in BP at study end with the renin inhibitor. After adjustment, the reduction in UACR with aliskiren was still 18% greater than with placebo. There was no difference in the overall incidence of adverse events between the two groups. The publication of the AVOID study has raised considerable debate. Therapy with an ARB (or an ACE inhibitor) is considered standard of care in patients with proteinuria and type 2 diabetes mellitus, with many practitioners using the combination to reduce proteinuria. However, reports from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) question the utility and safety of dual RAAS blockade.19 The AVOID study comes at a time when alternative approaches to dual RAAS blockade are being sought. Of note, data from the secondary prevention Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) (Table) are awaited to ascertain whether direct renin inhibition with aliskiren reduces cardiovascular and renal morbidity and mortality in patients with type 2 diabetes.20
Table TABLE. Summary of Completed BNP Surrogate End Point Studies and Ongoing Clinical End Point Trials
|Study Acronym||Patient Population||Outcome Measure|
|ALLAY||Hypertensive with LV hypertrophy||LV mass|
|ALOFT||Hypertensive with class II to IV heart failure||BNP + NT-proBNP|
|AVOID||Hypertensive type II diabetes with proteinuria||UACR|
|ASPIRE||Post-MI with systolic dysfunction||LV remodeling|
|ALTITUDE||Type II DM with CVD and/or DM nephropathy||Time to first event—CV death/MI|
|Doubling serum creatinine|
|APOLLO||Normal and hypertensive elderly patients||Prevention of CV end points|
|ASTRONAUT||Acute heart failure||Time to first event—CV death|
|ATMOSPHERE||Chronic systolic heart failure||Time to first event—CV death|
The Aliskiren Left Ventricular Assessment of Hypertrophy (ALLAY) trial demonstrated that aliskiren was as effective as losartan in reducing left ventricular mass index (LVMI; P<.001 for noninferiority). However, the combination of aliskiren and losartan was no more effective in reducing LVMI than losartan monotherapy in an obese hypertensive population with documented LV hypertrophy (P=.52).20 BP was significantly and similarly reduced in all groups, and no added toxicity was reported for the combination. The Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) trial evaluated the impact of aliskiren on left ventricular (LV) remodeling when added to standard therapy with an ACE inhibitor or an ARB in high-risk post-myocardial infarction patients with LV systolic dysfunction.22 The study demonstrated that the addition of aliskiren to standard therapy (that included either an ACE inhibitor or an ARB) provided no further attenuation of LV remodeling and was associated with increased hypotension, hyperkalemia, and elevation in creatinine. The combined results of ALLAY and ASPIRE show that there is no positive impact on LV hypertrophy or LV remodeling with combined aliskiren and ARB or aliskiren and ACE inhibitor therapy.
The addition of aliskiren to standard of care in patients with heart failure, examined in the Aliskiren Observation of Heart Failure Treatment (ALOFT) trial demonstrated a reduction of neurohumoral activation (BNP and NT-pro-BNP), previously linked to adverse outcome in patients with heart failure.23 The rationale for such an approach was supported by the known deleterious impact of activation of RAAS in patients with heart failure and the additional knowledge that while ACE inhibitors and ARBs have proven efficacy in this patient population, sustained increases in PRA persist despite therapy. These data, however encouraging, are not definitive. Wide ranges in standard deviations raise obvious questions regarding reproducibility, and it remains to be proven whether such improvements in neurohumoral activation can be sustained over time and are correlated with a reduction in cardiovascular events. The Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure (ATMOSPHERE) and rationale and design of the multicenter, randomized, double-blind, placebo-controlled Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) studies designed to evaluate the impact of aliskiren on heart failure are underway.24,25 Finally the Aliskiren in Prevention of Later Life Outcomes (APOLLO) trial will address elderly patients with a systolic BP 130 to 159 mm Hg, no overt cardiovascular disease, and a high cardiovascular risk profile, in order to test the efficacy of the drug in reducing the risk of major cardiovascular end points.
Ultimately, determination of the impact of direct renin inhibition on clinical end points is essential to delineate the most appropriate use of this approach in clinical practice. Results from studies designed to answer this question are expected in 2012 and beyond.26