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79th Scientific Sessions of the American Heart Association

Chicago, Illinois / November 12-15, 2006

Reviewed by: Richard Z. Lewanczuk, MD, PhD, FRCPC

Professor of Medicine Division of Endocrinology and Metabolism University of Alberta Edmonton, Alberta

In the treatment of hypertension, control of elevated blood pressure (BP) is essential, but similar antihypertensive effects of agents in the different antihypertensive drug classes have not yielded the same target organ protection. ACE inhibitors and angiotensin receptor blockers (ARBs) have been associated with protection from end-stage renal disease and progressive cardiovascular (CV) diseases such as heart failure. Both inhibit the effects of an upregulated renin angiotensin system (RAS). The importance of this mechanism of action has been validated in trials that have found RAS agents superior to a comparator for hard end points, such as myocardial infarction or CV death, even when the therapies are matched for BP control. Direct renin inhibitors (DRIs), a new class of drug acting on this same pathway, have the potential to build on the benefits of ACE inhibitors and ARBs through a mechanism of action much more specific to the pathophysiologic effects of upregulated RAS.

The first step in the development of a new antihypertensive class of drug is to demonstrate BP control. In a review at the American Heart Association (AHA) of clinical trials data with aliskiren, the DRI has demonstrated an antihypertensive effect at least comparable to other RAS agents. In one of the earliest dose-ranging studies, which randomized 226 hypertensive patients to one of four doses of aliskiren or losartan 100 mg, all but the lowest dose of aliskiren achieved BP control that was not significantly different from the ARB (Stanton et al. Hypertension 2003;42:1137-43).

According to Dr. Michael Weber, SUNY Downstate College of Medicine, Brooklyn, who conducted the review of antihypertensive data at the AHA, subsequent studies have not only confirmed antihypertensive activity but have also demonstrated additive BP control when aliskiren is combined with other types of antihypertensive agents, including RAS agents. Of the studies cited by Dr. Weber, one evaluated aliskiren in combination with the diuretic hydrochlorothiazide (HCTZ) while another studied the combined effects of aliskiren and the ACE inhibitor ramipril. Both associated the combination with superior BP control relative to either compound alone. In the study of the DRI and the ACE inhibitor, for example, ramipril 10 mg reduced systolic BP by 12.0 mm Hg, aliskiren 300 mg produced a 14.7-mm Hg reduction, and the combination produced a 16.6-mm Hg reduction (P<0.001 vs. ramipril alone).

While the BP reductions achieved with DRIs are an anticipated result, the expectations surrounding these agents are generated by their potential protective effect on target organs. In a review of the importance of renin as a target of therapy, Dr. Bradford Berk, University of Rochester Medical Center, New York, explained that renin, through its effect on RAS, is involved in the regulation of arterial pressure, cardiac and vascular function, and blood volume. Renin release is a key initial step in the series of events culminating in production of angiotensin II, which promotes vasoconstriction, vascular and cardiac hypertrophy, upregulation of prothrombotic factors, and platelet aggregation. Inhibiting the effects of angiotensin II is the putative mechanism of action of ACE inhibitors and ARBs, but ACE inhibitors block only one of the pathways that convert angiotensin I to angiotensin II, while ARBs block the actions of angiotensin II only after circulating levels have been increased. By inhibiting renin, DRIs block a rate-limiting step in the pathway—conversion of angiotensinogen to angiotensin I—that blocks all downstream events (Figure 1).

Figure 1. Renin Inhibition

Oral DIRECT RENIN INHIBITORS: NEW DRUG CLASS

The potential of DRIs to slow or halt pathology in the kidney and the heart is not a recent development. Dr. Berk noted that the early work with this class of drug was conducted more than a decade ago with agents developed for intravenous (i.v.) administration. As such formulations are impractical for a chronic disease, their clinical utility was not fully tested until orally active agents were successfully synthesized. While the promise of this class of drug is supported by work with aliskiren, the agent most advanced in the trajectory toward regulatory approval, other compounds at earlier stages of development have substantiated renin inhibition as a practical target.

When compared to ACE inhibitors and ARBs, DRIs hold an advantage with their ability to inhibit renin without a counterproductive stimulation of PRA. In a pooled analysis of four randomized, double-blind clinical trials presented here at the 2006 AHA scientific sessions (Gradman et al. Circulation 2006;114(suppl 2):II-773, Abs. 3620), PRA was increased by more than 70% in individuals who received HCTZ 25 mg and by more than 110% in those who received ramipril 10 mg or irbesartan 150 mg. In contrast, aliskiren was associated with a 70% reduction in PRA from baseline (P<0.0001). The senior author of that study, Dr. Alan Gradman, Chief, Division of Cardiovascular Sciences, The Western Pennsylvania Hospital, Pittsburgh, cited an earlier analysis that showed that PRA was maintained at 65% below baseline when aliskiren was combined with the ARB valsartan (Azizi et al. J Am Soc Nephrol 2004;15:3126-33).

So far, evidence that DRIs may have the potential to exert renoprotective and cardioprotective effects is derived primarily from experimental studies. According to Prof. A.H. Jan Danser, PhD, Professor of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands, this has been a rapidly evolving area which was recently advanced by the isolation of a pro-renin receptor on the surface of cells in target organ tissues, such as the kidney and heart. These pro-renin receptors, which can be stimulated when renin is upregulated, have been implicated in a variety of potentially pathogenic activities, including some that may not be directly related to upregulation of angiotensin II.

RENAL PROTECTION

In one of several models reviewed by Prof. Danser, a comparison of aliskiren to valsartan indicated that the DRI, at equieffective antihypertensive doses, was as effective as valsartan was for halting progression of renal disease (Pilz et al. Hypertension 2005;46:569-76). Mice transgenic for human renin and angiotensinogen genes received one of two doses of aliskiren, one of two doses of valsartan, or were left untreated after matching for albuminuria. Untreated mice developed elevated systolic BP, progressive albuminuria, and increased serum creatinine. The higher dose of valsartan (10 mg/kg/day), which had been previously associated with protection against end-organ damage, was more effective than the lower dose (1 mg/kg/day) for reducing BP and albuminuria. Similarly, the higher dose of aliskiren (3 mg/kg/day) was more effective than the lower dose (0.3 mg/kg/day) in reducing BP and albuminuria and normalizing serum creatinine. Reduction of BP and albuminuria for the highest dose of the ARB and aliskiren were in a similar range. At the study end, mortality was 100% in the untreated mice, 26% in the mice receiving the lowest dose of valsartan, and 0% in the groups receiving either dose of aliskiren or the higher dose of valsartan.

Another example of target organ protection in an animal model was presented at the 2006 AHA (Lu et al. Circulation 2006;114(suppl II):II-215, Abs. 1154). Male mice negative for a LDL receptor received one of two doses of aliskiren or its vehicle. All mice received a lipid-rich diet. While BP rose in the vehicle-treated mice, it fell in those receiving aliskiren. The DRI was not associated with a change in total cholesterol concentration or in oxidant stress. No atherosclerosis was observed in the actively treated mice but significant atherosclerosis developed in the vehicle-treated mice. Although the authors noted that other RAS agents have also prevented atherosclerotic lesions in similar models, this is the first experimental evidence of a direct renin effect. Unlike the effects of ACE inhibitors, which might be confounded by their ability to increase bradykinin levels, or ARBs, which might exert protection by stimulating the AT2 receptor, the renin inhibitors do not have known effects on other pathways.

These studies not only illustrate the potential advantages of DRIs over other compounds, but they are also generating new insight into the pathophysiology of CV and renal diseases. RAS upregulation is among the pathological states that appear to link impaired vascular function with clinical disease propelled not only by elevated BP but dyslipidemias and impaired glucose metabolism as well. Dr. Thomas Giles, Tulane University School of Medicine, New Orleans, Louisiana, emphasized this interrelationship in his review of efforts to seek better control of hypertension. Based on this interrelationship, a new definition of hypertension was proposed last year by the American Society of Hypertension (ASH) Writing Group (Giles et al. J Clin Hypertens (Greenwich)2005;7:505-12) that no longer depends on any specific BP level. In this definition, the ASH Writing Group contends that “hypertension cannot be classified solely by discrete BP thresholds”; rather, “progression is strongly associated with functional structural cardiac and vascular abnormalities that damage the heart, kidneys, brain, vasculature, and other organs that lead to premature morbidity and death.”

PREVENTING TARGET ORGAN DAMAGE: THE ULTIMATE GOAL

DRIs are a welcome tool both for their ability to contribute a new mechanism to antihypertension treatment and for their potential to improve outcomes independent of BP control. According to Dr. Giles, new drug development is very important in the context of the continuing unmet need to bring all hypertensive patients to goal. He cautioned that control to target levels remains below 50% among treated patients despite the fact that established targets may not represent optimal BP levels. He indicated that epidemiologic data suggest that the level at which CV morbidity begins to climb is somewhere between 115/75 and 125/80 mm Hg, particularly among patients with multiple risk factors (Lewington et al. Lancet 2002;360:1903-13). In Canada we do no better; for example, in one estimate, only 16% of patients are at BP targets (Khan et al. Can J Cardiol 2002;18:657-61). With multiple agents across six classes of antihypertensive agents, it is widely assumed that failure to bring patients under control is a question of inadequate doses or adherence. While these are important problems, Dr. Giles suggested that better strategies of combining agents with complementary mechanisms of action are needed. The expanding number of well tolerated therapeutic options is an important step toward increasing the opportunities for safe and effective combinations, particularly because both inadequately aggressive therapy and poor adherence may stem from problems of tolerability. DRIs, in addition to their potent antihypertensive effect, have yet to be associated with any significant adverse events in clinical trials.

SUMMARY

The most important obstacle to reducing the risk of progressive renal and CV diseases is simply achieving tight control of modifiable risks factors, including hypertension. Drug potency is not the only issue. Treatments must also be convenient and well tolerated. The attributes of DRIs, which are on track to constitute the next class of antihypertensive drugs, include antihypertensive potency, compatibility with other antihypertensive agents, and a low risk of adverse events. In addition, they have the potential to expand options that have benefits independent of BP control. Acting along the same pathway as ACE inhibitors and ARBs, both of which have been shown to inhibit renal and CV disease progression independent of their antihypertensive effects, DRIs act at a more fundamental point in RAS upregulation but do not increase PRA. As the DRI most advanced in clinical testing, aliskiren has demonstrated potent antihypertensive effects with a placebo-like safety profile in initial clinical trials. The next step is to determine whether drugs in this class can more directly inhibit the pathophysiology induced by upregulated RAS.