Abstract
During a meeting of the American Society of Hypertension, an expert panel was convened to discuss the use of renin inhibitors in the management of hypertension. Marvin Moser, MD, of the Yale University School of Medicine, New Haven, CT, moderated the panel, which included Domenic A. Sica, MD, Virginia Commonwealth University Health System, Richmond, VA, and Joseph L. Izzo Jr, MD, State University of New York, Buffalo, NY. This expert panel discussion was supported by Novartis and each author received an honorarium from Novartis for time and effort spent participating in the discussion and reviewing the transcript for important intellectual content prior to publication. The authors maintained full control of the discussion and the resulting content of this article; Novartis had no input in the choice of topic, speakers, or content.
DR MOSER:
Dom, we've heard a great deal in the past few months about prorenin and renin and how important these are in the pathogenesis of hypertension. There has also been a great deal of interest in the concept that inhibiting renin is important in the treatment of hypertension. I have a little trouble with this concept and need some clarification. For the past 15 to 20 years, we have been using angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in treatment. These have proved effective in reducing blood pressure (BP) and in reducing morbidity and mortality. In patients who take their medication, renin levels are elevated. Benefit occurs because the product of stimulation of the renin system (ie, angiotensin II), is either not elaborated or its action blocked. Now we are being told that elevated renin levels are deleterious, that the best way to treat hypertension may be by blocking the generation of renin. I have another problem with the concept of prorenin and renin. Would you first describe what prorenin and renin are? Does prorenin just lead to the generation of renin or is there another pathway that leads to vessel or target organ damage?
DR SICA:
The origin of renin dates back a little more than 110 years ago. Early experiments involved pulverized kidneys being injected into a jugular vein, with BP rising significantly within 80 seconds.
DR MOSER:
In rabbits. Tigerstedt's original data.
DR SICA:
Yes, rabbits were injected and because BP rose, it was presumed that a pressor substance existed in the kidney. Over the next several decades, there was a refinement of this concept. Investigators were able to establish that renin, present predominantly in the kidney, was capable of elevating BP. Eventually it was established that renin, which was not a vasopressor substance per se, interacted with angiotensinogen, an action that eventually resulted in formation of the potent vasoconstrictor angiotensin II, which has proven to be very potent in its ability to increase BP.
DR MOSER:
Is prorenin just a precursor of renin?
DR SICA:
Renin itself has predecessor components, including preprorenin and prorenin. It was originally thought that these precursor forms and, in particular, prorenin were “inactive”; however, the recent discovery of a renin receptor that can be activated by both renin and prorenin has led to a rethinking of this concept. This receptor binds renin and prorenin equally well.
DR MOSER:
Is there a separate prorenin pathway that has another function that doesn't progress through renin, or is the renin‐angiotensin‐aldosterone cascade dependent on prorenin as an initial step?
DR SICA:
There is not a separate prorenin pathway that is directly involved in generating angiotensin II, other than what occurs as prorenin is converted to renin; however, prorenin is able to generate angiotensin II by its direct interaction with the renin receptor, a process independent of renin per se.
DR MOSER:
I am still somewhat confused.
DR SICA:
Well let me restate what I have tried to say. We routinely produce significant amounts of prorenin, which is constitutively released by the kidney. Prorenin concentration in plasma is 10‐fold higher than that of renin. Prorenin can be further processed to form renin and the renin so formed can ultimately lead to the formation of angiotensin II. Alternatively, prorenin can bind to a “renin receptor” and, in stimulating this receptor, generate angiotensin II. Prorenin is nonproteolytically activated by way of a conformational change as it binds to the renin receptor.
DR MOSER:
So there is a separate pathway for prorenin.
DR SICA:
Yes, there's a separate pathway.
DR MOSER:
And the other pathway is through renin.
DR SICA:
Yes, from prorenin to renin. Relative to the renin receptor that is acted on by prorenin, although there is experimental evidence to suggest that its stimulation can have adverse consequences, we, as yet, do not know that to be the case in man.
DR MOSER:
What percentage of the prorenin goes into the traditional cascade of renin to angiotensin I to angiotensin II, etc?
DR SICA:
Probably most of it. This has not been specifically quantified. There is, however, the concept of total renin concentration. This is a term reflecting the quantity of renin and prorenin in the blood. Prorenin, as it turns out, is about 9 times more common than renin, so if you look at the absolute amount of total renin concentration, a large majority of it is prorenin.
DR MOSER:
So when we talk about the plasma concentration of renin, we're talking about the concentration of prorenin and renin.
DR SICA:
Right, however, the terminology can get confusing. As a clinician, you need to realize that there is a term, plasma renin concentration, which quantifies the amount of prorenin and renin. The term plasma renin activity describes the actual activity under test tube conditions of renin. So there are aspects of this which reflect activity and other considerations that simply relate to the mass amount or concentration. One of the things about renin inhibitors is that they do not block the production of renin. They block renin activity. Plasma renin concentration, predominantly prorenin, not unexpectedly increases with the administration of a direct renin inhibitor by virtue of the short feedback loop being blocked.
DR MOSER:
So you decrease renin activity but have an increase in plasma concentration of renin—most of which is prorenin.
DR SICA:
Right. Back to your original comments about an ACE inhibitor or an ARB. With these agents, both renin concentration and renin activity increase. Yet in the case of renin inhibitors, prorenin levels and plasma renin concentration increase, but plasma renin activity decreases. With each of the 3 classes, a direct renin inhibitor, an ACE inhibitor, and an ARB, plasma renin concentrations and prorenin levels increase; however, the rise in prorenin levels with a direct renin inhibitor appear to be greater than with either an ACE inhibitor or an ARB.
DR MOSER:
Do you have any trouble then with the concept that the benefits of ARBs and ACE inhibitors occur in the presence of high plasma renin activity?
DR SICA:
No, I don't. The successes with those drugs are evident to all and range to a varying degree from BP control to cardiac, renal, and stroke protection. If direct renin inhibitors are going to prove better than ACE inhibitor or ARB therapy, it has to be proved in clinical trials. I for one think that the clinical trial data we have with ACE inhibitors and ARBs are convincing, but it has been a little difficult to conclusively show that these drugs offer benefit beyond what would be seen with BP reduction alone, except in the instance of heart failure and renal disease. It's going to be quite difficult to find a dramatic outcomes difference with a direct renin inhibitor compared with an ACE inhibitor or an ARB.
DR MOSER:
Joe, we've been talking about renin inhibition and whether this is a real advance, whether it's important, whether the generation of angiotensin II is less with renin inhibition than it is with ACE inhibition, and whether vasoconstriction will be less when you block the renin‐angiotensin system (RAS) cascade at its beginning. What's your take on this?
DR IZZO:
I would start with the results, such as heart failure, kidney disease, or myocardial infarction. Blocking the RAS at the level of the converting enzyme or at the angiotensin I receptor yields consistent outcome benefits for the heart and kidney. In the former case, angiotensin II levels decrease and in the latter case angiotensin II levels increase. In both cases, renin levels increase. Thus, it does not appear that the organ benefits are adversely affected by increases in any one component of the RAS, as long as the impact of the system as a whole is blocked somewhere along the way. With renin inhibitors, I would expect at least the same levels of benefit as we have identified for ACE inhibitors and ARBs.
DR MOSER:
Whether you block the RAS at the ACE level or prevent effects of angiotensin II at the vascular level?
DR IZZO:
If you block the angiotensin I receptor, plasma renin concentration, plasma renin activity, and plasma angiotensin II increase, but there is still a benefit. As far as I am aware, renin itself has no direct effect on disease mechanisms, although some investigators believe that “overstimulation” of the renin receptor may have adverse consequences. The evidence, however, for that contention is lacking at this time.
DR SICA:
Other than, perhaps, an ill‐defined effect at the renin receptor.
DR IZZO:
As I said, you can see various patterns of increases or decreases in the precursors or in angiotensin II itself, but it doesn't seem to matter because at the end of the day, there is net inhibition of the entire RAS, whether it's from a renin inhibitor, an ACE inhibitor, or an angiotensin I receptor blocker.
DR MOSER:
So would you envision much difference in outcome with these different agents?
DR IZZO:
There may be one other important difference: duration of action. So far, the data suggest greater persistence of effect with a renin inhibitor over a longer period of time. But we don't have any outcome data. Renin inhibitors persist in the tissue for long periods of time, perhaps days to weeks. My guess is that these drugs are going to teach us some physiology that we don't yet understand, just as has been true with the ACE inhibitors and ARBs.
DR MOSER:
Joe, is this other pathway that Dom talked about, the prorenin pathway leading to angiotensin II, significant?
DR IZZO:
You'll find differences of opinion. So far I haven't found compelling evidence that it will be important in human disease prevention.
DR SICA:
I would agree. Just to add to that, there is a fair amount of β‐blocker data that would suggest that you prevent the generation of renin with these agents. I don't think that the mechanistic differences between the direct renin inhibitors, ACE inhibitors, or ARBs will amount to much, but I do think the pharmacologic features of this first avalable renin inhibitor, aliskiren, including its very long half‐life will have some play in whether there are outcomes differences. Of interest, discontinuation of the drug is followed by a slow recovery to baseline BP, and plasma renin activity, a marker of drug action, remains suppressed for several days after drug discontinuation. We have never had a drug with a residual effect as prolonged as this.
DR MOSER:
We have had drugs like the diuretics, for example, where BP stays down after the effects of the medication have worn off.
DR SICA:
Marv, you make an important point. When you do short‐term studies and BP normalizes, it returns to baseline fairly soon after the medication is stopped. If you do long‐term studies and reset mechanisms that may have adjusted, BP may stay lower longer upon discontinuation of treatment.
DR MOSER:
Like resetting baroreceptors.
DR SICA:
In studies with renin inhibitors, these findings have actually been both short term and long term. There is a very slow recovery to baseline on discontinuation in both cases.
DR MOSER:
So mechanistically there is a difference in the physiology of this drug compared with ACE inhibitors and ARBs in terms of renin activity.
DR SICA:
I believe the available data suggest that rather strongly.
DR MOSER:
Joe, you've got a drug or a group of drugs that may have more persistent activity. What about effects on BP? Are they more dramatic than with ACE inhibitors, ARBs, diuretics, or calcium channel blockers, or are they about the same?
DR IZZO:
Monotherapy with a renin inhibitor looks a lot like an ACE inhibitor or an ARB in the magnitude of response and the differential response in subpopulations with low overall activity of the RAS. As you know, there are some people with hypertension who are more sensitive to RAS‐blocking drugs, younger white patients for example, and then there are those who are less sensitive.
DR MOSER:
Like blacks and the elderly, who may be less responsive.
DR IZZO:
Right. So those groups who do not respond as readily to ACE inhibitors or ARBs do not seem to respond vigorously to renin inhibitors either. Let's be careful to note that lower responses do not mean they don't respond at all, just less, to monotherapy. It is also important to understand that there is tremendous variation in responsiveness within all subpopulations. That is why we should not use race or age to preclude the use of a RAS blocker in therapy.
DR MOSER:
So you believe that the BP responses to renin inhibition are equivalent to other agents that block the RAS?
DR IZZO:
Yes. I strongly suspect that will be the case. RAS blockers all appear to be similar in efficacy as monotherapy. They also look similar when combined with either a thiazide diuretic or a calcium antagonist. It is the combinations that most of us now recommend; not only do you get better efficacy over time but you also get more predictability of responses in hypertensive subpopulations. Racial or age groups all respond vigorously and predictably to the combination of any RAS blocker and a vasodilator (calcium channel blocker or thiazide). While there has been some debate over whether it might be useful to combine a renin inhibitor with an ARB, the much more advantageous combination is a one of drugs with complementary mechanisms of action. In this regard, RAS blockers are the perfect complements for a thiazide diuretic or calcium channel blocker, whether you base your judgment on cell‐signaling mechanisms, physiologic control mechanisms, or BP efficacy.
DR MOSER:
So at the moment, at least, you don't see this as a major advance over what we've had before just in terms of BP regulation?
DR IZZO:
Probably not in BP terms, but some questions remain. Are there disease mechanisms that may be better handled either by keeping BP down longer or by more adequately blocking renin activity in the kidney? Possibly.
DR SICA:
We simply do not have sufficient data at this point to answer that question and we only have one direct renin inhibitor available, which is the drug aliskiren. The long pharmacologic half‐life with this particular compound provides for an extended pharmacodynamic effect, and this feature may open up a range of new issues. All of us would say that this is an interesting property in that if you miss a dose, there appears to be a substantial residual effect the next day. The overall effects on tissue protection with most every antihypertensive compound relates to the durability of the effect. A separate thought with aliskiren is that if its pharmacodynamic half‐life is prolonged, the issue of hyperkalemia in patients with kidney disease may be important; however, the degree to which this compound differentially affects serum potassium values (compared with an ACE inhibitor or an ARB) remains to be determined with appropriate clinical trials.
DR MOSER:
Well, what about the adverse effects? How about cough and angioedema?
DR IZZO:
It doesn't look like there's any intrinsic cough mechanism to speak of or any specific angioedema mechanism with use of a renin inhibitor. The only things that show up at higher doses of aliskiren are gastrointestinal complaints such as diarrhea. But aliskiren appears to be a well‐tolerated drug, at the dosages of 150 to 300 mg/d.
DR SICA:
Let me add a point to what Joe was saying. A lot of the drugs we use are used indiscriminately. The presumption is if a little is good, more is better, particularly if dose escalation does not increase the frequency of adverse effects per se. So there's been a prescribing position that has arisen of late to say if you give an ARB dose beyond the maximal recommended dose on the label, you can get an additional antiproteinuric effect. If you were to do this with aliskiren and went up from 300 to 600 mg, there is a substantial increase in the diarrhea rate.
DR MOSER:
And no further BP benefit?
DR SICA:
No further benefit for BP, but the diarrhea rate is higher, so one has to caution the clinician not to go higher than 300 mg/d, presuming that it is an innocuous process. In fact, the Food and Drug Administration made that point and delayed approval of the compound for a short period to investigate the basis for the diarrhea rate. They still haven't come up with a mechanistic basis for the dose‐dependent diarrhea seen with aliskiren.
DR MOSER:
One of the reasons that people say ACE inhibitors still have an advantage is because of the effect on bradykinin. What does this drug do to bradykinin levels?
DR IZZO:
I don't know of any direct data where it's been measured. Dom, do you?
DR SICA:
No, there's no effect on ACE so it should not have any direct effect on bradykinin. As far as drug‐drug interactions, there is evidence that there is reduction in furosemide absorption with aliskiren; however, these data need to be carefully looked at and a determination made as to whether this is an interaction between aliskiren and all loop diuretics and, moreover, whether this interaction is of clinical relevance in heart failure and renal disease patients.
DR MOSER:
Is there a problem with thiazides?
DR SICA:
I know that there has been a pharmacokinetic study with hydrochlorothiazide and aliskiren given together, and there was a small change in the area under the curve for hydrochlorothiazide. The degree of change probably was not clinically relevant.
DR MOSER:
There have been treatment studies with a combination of the renin inhibitor and hydrochlorothiazide.
DR SICA:
Yes, I would infer that there is nothing negative in giving hydrochlorothiazide and aliskiren together, since there is nothing on the label. Again, changes in absorption are an interesting issue. We don't have many drugs in the US market that specifically reduce the absorption of coadministered drugs.
DR MOSER:
Many of them work the other way.
DR IZZO:
In this case, if you are using furosemide in a patient who might be taking aliskiren, it implies that this person has kidney failure because we're not yet using renin inhibitors in heart failure. Small increases in the dose of furosemide rarely present a clinical problem. I might say that there is also an opportunity to combine a loop diuretic with a thiazide, which I often do in heart failure. This combination is very helpful in fluid management and in controlling potassium.
DR MOSER:
Let me summarize and then ask each of you for a final comment. We have a new class of drugs that act in a different way on the RAS than drugs that have been available. Renin inhibitors affect the cascade at its origin rather than through an enzymatic change, like the ACE inhibitors, or at the periphery, like the ARBs.
There are some theoretic advantages to this drug. First of all, aliskiren, the first available oral renin inhibitor, is longer acting and remains in tissues longer.
In terms of efficacy, as monotherapy, it is probably equivalent to ACE inhibitors and ARBs as an antihypertensive agent. In combination with a diuretic, for example, it is equal to an ACE inhibitor/diuretic or ARB/diuretic. I am unaware of studies comparing this combination to a calcium channel blocker/diuretic.
DR SICA:
I do not know of any, either.
DR MOSER:
So at the moment we have a theory that longer duration of action, and possibly the mechanism of action, may reduce target organ damage more than some of the other drugs, but we have to await long‐term clinical trials and further studies for the answer. Is that fair?
DR IZZO:
Yes, I think it's fair. In general, BP control should remain at the top of the list. If renin inhibitors are truly similar to ACE inhibitors and ARBs, the patient should be well served. The controversy over whether the prorenin increase with renin inhibitors is deleterious remains highly hypothetical right now. It would seem that this feature does not present a major stumbling block to the use of renin inhibitors, but we simply don't have enough information at this point. Outcome studies will be necessary in order for reasonable comparisons to be made; the results of such studies are pending.
DR SICA:
We have embraced the notion of a pleiotropic effect for certain medications over the last several years. Increasingly, we've recognized that this effect often represents no more than just good BP control that has gone unrecognized. For aliskiren, separating the benefits from a pleiotropic effect compared with a more primary and long‐lived BP‐lowering effect probably will not matter if the outcomes are better. I think that the very long half‐life in the serum, the prolonged half‐life in the tissues, and the demonstrable evidence of prolonged deactivation of renin are attractive features of aliskiren. Yet we still need to proceed further to more complex experiments than just simply BP reduction if we are truly going to recognize the merits of this compound.
I'll close with one final statement. If you lower BP with a renin inhibitor like aliskiren to a degree comparable to that of an ACE inhibitor or an ARB, it is a rather pure experiment. If you try to change the rate of progression of end organ disease, it is a very complicated experiment with multiple contributing factors. I think the likelihood of showing a major difference with aliskiren compared with other therapies is probably not great. We have to look no further than the Prevention of Events With Angiotensin‐Converting Enzyme Inhibition (PEACE) trial to appreciate this perspective. The PEACE study with trandolapril (4 mg vs placebo) was conducted in high‐risk coronary artery disease (CAD) patients. At the end of the day, 4 mg of trandolapril compared with a placebo, with both in addition to conventional therapy, did no better for CAD event rate reduction. Why? Well, the patients in the placebo group did so well with contemporary therapies that it was hard to improve upon the favorable outcomes; thus, the difficulty for aliskiren is going to be that the bar is set so high right now because there are a lot of solid therapies invariably used that, in their own right, improve outcomes.
DR MOSER:
Thank you very much.