Direct Renin Inhibition— Commonly Asked Questions

There have been numerous attempts to bring renin inhibitors to market, with most such efforts failing because of limited compound bioavailability and/or potency.1 Recently, the direct renin inhibitor aliskiren has become available. This compound is a highly specific in vitro inhibitor of both human and primate renin with an IC50 of 0.6 nmol/L. The capacity of this drug to reduce blood pressure (BP) in patients with hypertension is similar to (or slightly better) than what is seen with standard therapeutic doses of various angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).2,3 Opinions vary considerably on the utility of aliskiren, ranging from enthusiasm for an antihypertensive with a “new” mechanism of action to a “so what?” attitude derived, in part, from a cost profile that goes unjustified by the absence of outcomes data distinguishing this compound from either ACE inhibitors or ARBs. Pending availability of specific cardiovascular and renal outcomes data with aliskiren, there still remains the need to better understand how this compound fits in the management of hypertension. This compound has been available since 2007 and is typically the case for a compound with expanding clinical usage questions arise as to compound-specific pharmacology, efficacy, and tolerance. Herein, perspective on several of the more commonly asked questions about aliskiren is provided. There have been frequent attempts to bring renin inhibitors to market, with all such efforts stymied by the limited bioavailability and/or potency of the available compounds.1 Aliskiren, an octanamide, is the first of a new class of nonpeptide, low-molecular-weight, orally active transition-state renin inhibitors with sufficient absorption and potency to give good reason for its being brought to market.4 Aliskiren is fairly rapidly absorbed, with its maximum plasma concentration (Cmax) reached 1 to 3 hours following its administration. The absolute bioavailability of aliskiren is in the order of 2% or 3%, as determined in healthy male patients, with an interindividual variability of 40% to 70% for area under the curve (AUC) and 30% to 50% for Cmax.5 There is a modest food effect with aliskiren (300 mg) when administered with a standard US Food and Drug Administration high-fat meal given 30 minutes prior with 71% and 85% reductions in AUC and Cmax, respectively.5 This food effect is without a significant effect on aliskiren’s inhibition of plasma renin activity (PRA), which is a reflection of this compound’s potency. Of note, limited or variable compound bioavailability will not adversely affect drug action if the amount of drug absorbed still reaches and sustains the blood level required for the sought-after pharmacologic effect. Aliskiren’s potency and specificity for human renin inhibition effectively offsets its low absolute bioavailability.6 Drugs that interfere with renin-angiotensin system (RAS) activity, such as ARBs and ACE inhibitors, are commonly used in the setting of chronic kidney disease (CKD). The use of drugs in this class, or for that matter any drug in the renally compromised patient, should raise consideration of the impact of renal disease on the systemic elimination of the compound. For example, the majority of ACE inhibitors, with the exception of fosinopril and trandolapril, are predominantly renally eliminated. Consequently, they are subject to systemic accumulation when dosed to steady state in the setting of stage 3 to 5 CKD, and dosing guidelines recommend graded dose reduction.7 Alternatively, all compounds making up the ARB class undergo significant hepatic elimination (at least 40%–50%); thus, in the patient with renal failure, they are not subject to relevant degrees of systemic accumulation upon repetitive dosing. Aliskiren systemic elimination has been studied in patients with mild (creatinine clearance [Clcreat], 50–80 mL/min), moderate (Clcreat, 30–49 mL/min), or severe renal insufficiency (Clcreat <30 mL/min) following 7 consecutive days of aliskiren (300 mg/d) dosing. In these studies, AUC and Cmax values for aliskiren were 1.5 to 2.0 times higher than values in matched healthy patients and showed no correlation with the severity of renal failure. Aliskiren accumulation (ratio of AUC0–24 hours on day 7 vs day 1) was no different in each category of renal failure (range, 1.35–1.99) vs a pooled group of healthy persons (1.79). These data indicate that renal failure does not alter the accumulation profile of aliskiren.8 Therefore, aliskiren does not require dose adjustment in renal failure on the basis of its pharmacokinetic pattern; rather, dose reduction should be an empiric process dictated by BP having fallen below target values. When interpreting the results of clinical trials with aliskiren, a distinction should be made between the mean reduction in BP, which is typically significant (compared with placebo) and the percentage of individuals who have poor to average (<10-mm Hg diastolic BP reduction) and excellent (>10-mm Hg diastolic BP reduction) responses. Unfortunately, the BP response data with aliskiren is mainly reported as mean reductions in BP; thus, patients cannot be assigned to one or the other of these response categories (poor, average, and excellent). As such, “average” response rates/change in BP reduction can vary significantly from study to study.2,3,9 The established dosage range for aliskiren (150–300 mg/d) is a function of various developmental and tolerance issues. For example, in the early phase of aliskiren development, the dosage range studied was 75 to 600 mg/d; however, an inconsistent BP lowering at the 75-mg dose and unacceptable gastrointestinal adverse effects with the 600-mg dose led to the abandonment of both doses. The contour of the dose-BP response curve for aliskiren depends on the response category into which a patient falls: for example, a “poor” response has a very flat dose-BP response curve, whereas an “excellent” response has a steep response curve at low doses with a flattening of the curve thereafter at higher doses. The duration of therapy is also likely to influence the dose-BP response curve in that recognition of the full BP response to aliskiren will require weeks to months.10 Although there are fundamental differences in how ACE inhibitors, ARBs, direct renin inhibitors, such as aliskiren, work, they should all reduce BP similarly if given separately to the same patient. When patients are given either an ACE inhibitor or an ARB, there can be considerable heterogeneity in the response; however, the magnitude of the difference in absolute BP reduction—one class vs the other—is not large.11,12 When a between-class difference in response exists, it likely reflects, at least in part, dissimilar pharmacologic characteristics (differing half-lives) of the compounds being compared. Nonresponse (or partial response) to either an ACE inhibitor or an ARB occurs in a patient with phenotypic (and possibly genotypic) characteristics that would limit the response to any agent that lowers RAS activity.13 Patients in whom there is nonresponse (or partial response) to either an ACE inhibitor or an ARB should not have a response to aliskiren in a “meaningfully” different manner unless the very long half-life of aliskiren translates into a more sustained effect and thereby greater efficacy. Within the African American population, the BP reduction observed with ACE inhibitors and ARBs may be less than what is seen with diuretics and calcium channel blockers14,15; however, this is not an all-or-none differentiation, with many African Americans still exhibiting a discernable response to RAS interruption.16 Differences in response to ACE inhibitors or ARBs in African Americans compared with Caucasians diminish when diuretics are coadministered but not when an ACE inhibitor is combined with an ARB.14,15 Based on the mechanism of action of aliskiren and the phenotypic characteristics of many African American patients with hypertension, there is little reason to believe that this compound would work under circumstances in which an ACE inhibitor or ARB has failed. Available monotherapy treatment experience with aliskiren in African Americans shows the magnitude of BP reduction to be significantly smaller in African Americans compared with Caucasians for both systolic and diastolic BP.17 There has been no published information concerning end-organ protection with aliskiren in African Americans, and final judgment on this facet of aliskiren action awaits such studies. ACE inhibitors and ARBs are regularly prescribed for the management of hypertension. Both of these drug classes have also been proven to improve the morbidity and mortality that ordinarily attends heart failure, proteinuric CKD, and/or a high cardiac risk profile. The individual gains seen with each of these drug classes has fueled speculation that their use in combination might offer additive outcomes benefits. The foundation of this hypothesis, although biologically possible, has thus far not been sufficiently well proven to support the everyday use of these 2 drug classes together for the treatment of hypertension, proteinuric renal disease, or high cardiac risk.18–20 Although aliskiren is an effective monotherapy for BP reduction, its use as first-step therapy will be influenced by cost and the lack of outcomes data; thus, an add-on philosophy has been tested for aliskiren, with studies examining its effect in combination with either an ACE inhibitor or an ARB (as well as other drug classes) for BP reduction and with the ARB losartan for its antiproteinuric effect in diabetic nephropathy.21–23 In the studies with maximal dosages of aliskiren (300 mg/d) and valsartan (320 mg/d), the incremental benefit for systolic BP reduction was approximately 5 mm Hg.22 Such a reduction in BP does not warrant this compound being used as either the second or third agent in an antihypertensive regimen that began with an RAS inhibitor. In that regard, diuretics and calcium channel blockers are clearly superior in how much they further reduce BP when added to an RAS inhibitor. Aliskiren would seem to be best situated as the fourth drug in multidrug regimens for BP reduction; however, the competition for designation as the preferred fourth-line therapy has spironolactone emerging as the lead candidate in most clinical circumstances. The role of combination ARB and aliskiren therapy in diabetic nephropathy treatment, with 300 mg of aliskiren daily (in addition to losartan 100 mg/d) as compared with losartan 100 mg/d and placebo, reduced the urinary albumin/creatinine ratio by 20%. Moreover, the urinary albumin/creatinine ratio was reduced by ≥50% in approximately 25% of patients receiving combination therapy compared with 12.5% of patients receiving losartan and placebo.23 Although these are interesting data, it is unclear whether this level of reduction in the urinary albumin/creatinine ratio exceeds that seen with a combination of an ACE inhibitor and an ARB.18 Angiotensin II has a tonic negative feedback effect on renin release; thus, as aliskiren reduces angiotensin II levels, more renin is released. In the process, there is a significant increase in both prorenin and plasma renin concentration (renin mass); however, this occurs without any untoward consequences, since aliskiren curtails enzymatic renin activity by way of its primary mechanism of action.24,25 Of note, the prorenin receptor, whose stimulation (by either prorenin or renin) is associated with end-organ damage, is not blocked by aliskiren.26 The increase in renin mass with aliskiren does not limit its inhibitory action on the activity of renin (PRA)—a finding that persists even when the increase in renin mass (with aliskiren) is compounded further by coadministration of a diuretic, an ACE inhibitor, or an ARB.2,3,24,25 Aliskiren is distinguished from other RAS-interrupting agents by this suppressive effect on PRA. For example, ACE inhibitors decrease angiotensin II levels but in so doing allow all upstream components of the RAS to reactively increase, including renin mass, PRA, and angiotensin I. Likewise, ARB therapy also allows for these same components of the RAS, as well as angiotensin II, to significantly rise. It is thought that the earlier the juncture at which the RAS is interrupted, the less the breaking of the short feedback loop will come into play. This “earlier” interruption of RAS cascade activity does not distinguish aliskiren from ACE inhibitors or ARBs in the efficiency with which BP is reduced. Whether earlier RAS-blocking activity translates into better outcomes (because of more complete blockade) may be resolved as results become available from a number of ongoing outcomes studies. The issue of how stimulation of the prorenin receptor, by way of the increase in renin mass with aliskiren, affects outcomes also remains to be determined.26 Rebound hypertension is best described as a sudden rise in BP following discontinuation of an antihypertensive agent. Such is the case with the central α-agonist clonidine, where BP can increase quickly and significantly, often exceeding baseline levels of hypertension, with missed doses or abrupt discontinuation. Rebound hypertension is not, however, a term that describes the expected rise in BP that occurs toward the end of a dose interval for an antihypertensive compound. Aliskiren is not associated with rebound hypertension, as is the case for ACE inhibitors and ARBs. Aliskiren is, however, distinguished from ACE inhibitors and ARBs in that >80% of the BP-lowering efficacy of aliskiren remains 4 days postdose and >80% of the PRA reduction with aliskiren is still present 4 weeks after stopping therapy. These sustained effects of aliskiren after stopping treatment are observed after durations of therapy anywhere from 8 to 48 weeks.27 This long duration of effect of aliskiren, which is well beyond its 40-hour half-life, may relate to sequestration of aliskiren in deep tissue compartments such as the kidney. In that regard, autoradiographic studies show localization of aliskiren in glomeruli, renal arteries, and capillaries.28 This question can be viewed in the context of drugs influencing the pharmacokinetics of aliskiren as well as the converse. In such drug-drug interaction studies, there is typically “pharmacokinetic noise”; thus, AUC and Cmax values of relevance are those in excess of a certain set point, which is typically 30% of similar values seen in normal healthy volunteers. For example, coadministration of the ARB irbesartan with aliskiren reduced its AUC and Cmax values by 18% and 27%, respectively—changes of little clinical significance.8 Alternatively, more substantive changes in aliskiren (300 mg/d) pharmacokinetics occur when either the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin (80 mg/d) or the azole antifungal agent ketoconazole (200 mg twice daily) are coadministered. The AUC and Cmax values for aliskiren increase by 47% and 50%, respectively, when atorvastatin is coadministered and 76% and 81%, respectively, when ketoconazole is given together with aliskiren. This interaction likely relates to aliskiren being a substrate (and not an inhibitor) for the P-glycoprotein efflux transporter; thus, when inhibitors of this transporter, such as atorvastatin and ketoconazole, are given, aliskiren absorption will increase in relation to the potency of the inhibiting compound.29 In that regard, the AUC value for aliskiren (75-mg single dose) increased by 430% when given together with the potent P-glycoprotein inhibitor cyclosporine (200-mg single dose).5 The drug-drug interactions in which aliskiren has an effect on another compound are for the most part minor, with the exception of the loop diuretic furosemide. The coadminstration of aliskiren with furosemide in healthy persons was associated with a 28% decrease in AUC and a 49% decrease in Cmax for furosemide.30 If this magnitude change in these pharmacokinetic parameters also occurs in the setting of either heart failure or CKD, it is likely that the net diuretic effect of furosemide would be lessened; therefore, the furosemide effect should be carefully monitored when it is given together with aliskiren. The basis for this decreased absorption is unclear, as is whether this drug-drug interaction occurs with other loop diuretics such as bumetanide and torsemide. Angioedema is a well-appreciated adverse effect of ACE inhibitor therapy. Over time, reports have also appeared describing the occurrence of angioedema in ARB-treated patients. In ARB-treated patients, angioedema has occurred in a range of patient types, including those not having previously been exposed to an ACE inhibitor or in those who previously received an ACE inhibitor with or without the development of angioedema.31 There has been a 0.06% angioedema rate with the direct renin inhibitor aliskiren in completed clinical studies. In that regard, there have been 2 confirmed episodes of angioedema, each with respiratory symptoms, and 2 possible cases of angioedema with periorbital edema and no respiratory involvement.9 Quite logically, these patients were not rechallenged, so a cause-and-effect relationship could not be definitively established. Moreover, aliskiren has been safely used in a patient who had experienced life-threatening angioedema (requiring intubation) with ACE inhibitor therapy.32 A conservative approach to this issue would be to consider aliskiren therapy in a patient with a history of ACE inhibitor– or ARB-related angioedema if there is a defensible clinical position for its use.