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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2736-2740
Copyright © 2004 by The Endocrine Society

Distinguishing the Antihypertensive and Electrolyte Effects of Eplerenone

D. G. Levy, R. Rocha and J. W. Funder

Pfizer Inc. (D.G.L., R.R.), Peapack, New Jersey 07977; and Prince Henry’s Institute of Medical Research (J.W.F.), Clayton 3168, Victoria, Australia

Address all correspondence and requests for reprints to: Prof. J. W. Funder, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton 3168, Victoria, Australia. E-mail: John.Funder{at}phimr.monash.edu.au.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In two clinical trials on the antihypertensive effects of the mineralocorticoid receptor antagonist eplerenone 397 essential hypertensives were dose titrated (50, 100, and 200 mg/d) over successive 4-wk periods until they reached target blood pressure levels. Of the total, 44% reached target on 50 mg/d, 17% on 100 mg/d, and 19% on 200 mg/d, with 20% failing to do so despite stepwise dose increases. At each dose level, those who reached target (responders) were compared with those who did not (nonresponders), with three major findings. First, at each dose level, the blood pressure fall in responders (systolic, 16–20 mm Hg; diastolic, ~15 mm Hg) was markedly more than mean values in nonresponders (systolic, 2–5 mm Hg; diastolic, 1–3 mm Hg). Second, sensitivity to eplerenone varied widely across the population studied in terms of blood pressure reduction. Third, there was no difference in plasma [K+] levels between responders and nonresponders at any dose level. We interpret these data as evidence for the major antihypertensive effect of eplerenone being via mechanisms other than those involving epithelial electrolyte and fluid transport. The modest (<=0.2 mEq/liter at 200 mg/d) mean elevation in plasma [K+] suggests that titration to effect rather than forced titration may minimize the risk of hyperkalemia, even where relatively high (100–200 mg/d) doses of the specific mineralocorticoid receptor antagonist eplerenone may ultimately be required.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE MINERALOCORTICOID ALDOSTERONE is the primary hormonal regulator of sodium and potassium metabolism and thus a major determinant of extracellular fluid volume. Aldosterone has long been known to act on epithelial tissues such as kidney and colon to promote sodium retention and potassium excretion. Classically, aldosterone was considered to raise blood pressure (BP) by its actions on such epithelia to retain salt and water, and thus to increase blood volume and cardiac output, with cardiac output then normalized by a reflex increase in peripheral resistance. It is now known that aldosterone may also act directly on nonepithelial tissues, including blood vessels and brain, with these effects mediated via mineralocorticoid receptors located in these tissues (1).

Eplerenone is a highly selective mineralocorticoid receptor antagonist recently approved in the United States for the treatment of both hypertension and heart failure after myocardial infarction. In initial dose-ranging studies, eplerenone was shown effective in reducing BP both as monotherapy and in combination with other agents (2). In additional titration-to-effect trials, using doses from 50–200 mg/d, eplerenone was shown to reduce both systolic BP (SBP) and diastolic BP (DBP) with no effect on heart rate (3). In postmyocardial infarction heart failure, the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study trial showed eplerenone to have a substantial effect in improving survival, when added to standard of care, at an average dose of 43 mg/d (4). Eplerenone acts by competitively inhibiting binding to mineralocorticoid receptors, in both epithelial and nonepithelial tissues (5).

By inhibiting the effect of aldosterone in the renal epithelium, eplerenone causes an increase in renal sodium excretion and a decrease in potassium excretion (6). We performed a secondary analysis of two titration-to-effect clinical trials with similar study designs to determine whether the antihypertensive effects of eplerenone were related to major changes in serum potassium concentration ([K+]), a marker of the diuretic/natriuretic action of eplerenone. If the antihypertensive effect of eplerenone were due primarily to blocking the renal epithelial actions of aldosterone, we would expect the magnitude of the BP response to show a relationship with measured changes in serum [K+].

We studied a total of 397 patients who responded or did not respond to eplerenone therapy (50–200 mg/d) over three sequential 4-wk periods of observation. At no dose did the extent of change in serum [K+] predict the antihypertensive response to eplerenone therapy. These findings suggest that the major antihypertensive actions of eplerenone reflect effects on nonepithelial, rather than epithelial, electrolyte transporting aldosterone target tissues.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Data from patients who participated in two studies (016, 020) of the eplerenone Phase III hypertension development program with similar study designs were included in the present secondary analysis. Both studies were double-blind, randomized, multicenter, placebocontrolled, lead-in, parallel group, titration-to-effect studies. Study 016 included patients with mild to moderate (DBP, >=90 and <110 mm Hg) or newly diagnosed hypertension. Study 020 included patients with mild to moderate established (DBP, >=95 and <110 mm Hg; SBP, <180 mm Hg) or newly diagnosed hypertension.

After a 4-wk placebo run-in period, patients were given 50 mg eplerenone. If after 4 wk any study subjects did not meet BP goals (study 016, DBP <= 90; study 020, DBP <= 90 or SBP <= 140), they were up-titrated to 100 mg. Subjects were further up-titrated to 200 mg at wk 8 if necessary. BP and serum [K+] assessments were made at wk 4, 8, and 12.

The eplerenone-treated patients from both studies were pooled for analysis. Antihypertensive response status was defined by DBP < 90 (responders) vs. DBP >= 90 mm Hg (nonresponders). The mean of BP changes from baseline at the end of each titration interval and the corresponding mean changes in [K+] were calculated for responders and nonresponders.

There was a combined total of 424 subjects in study 016 (250 subjects) and study 020 (174 subjects). However, the total was reduced to 408 because 16 subjects were excluded due to: 1) one subject from study 020 (2142) had a baseline DBP of 83.5 and should not have been entered into the trial; and 2) 15 subjects did not have any serum [K+] measurements recorded.

The total was further reduced to 398 because 10 subjects were determined to be "under-dosed": 1) at wk 4, six subjects had DBP >= 90, yet their dose was not up-titrated to 100 mg; and 2) at wk 8, four subjects had DBP >= 90, yet their dose was not up-titrated to 200 mg.

One subject had measurements at baseline and wk 8 and 12, but not at wk 4. This subject was also excluded from analysis, bringing the total number of subjects included in the analysis to 397.

There was a total of 20 subjects that were also not dosed according to protocol in that their DBP was <90, yet their doses were incorrectly increased to 100 mg (12 subjects) or 200 mg (8 subjects). Because these subjects were considered as responders and would not contribute to the analysis estimates beyond the time they were inappropriately up-titrated, it was decided to leave them in the analysis.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographics and baseline characteristics of the 397 patients studied are shown in Table 1Go. The patients were almost equally divided between male and female, with over 70% Caucasian and spanning a substantial range of ages with a mean of 53 yr. On average, patients were moderately hypertensive, with initial DBPs, on average, 10 mm Hg above target (<90 mm Hg), on which basis subsequent allocation into responder and nonresponder groups was made. Baseline serum [K+] was 4.3 mEq/liter, again with a SD of ±10% around this mean value.


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  		TABLE 1. Demographics and characteristics at baseline

 
Table 2Go details the changes from baseline in BP and serum [K+] for patients stratified by DBP response after 4, 8, and 12 wk of treatment with eplerenone. After 4 wk of treatment with 50 mg once daily, 44% of patients achieved target DBP levels of <90 mm Hg. The magnitude of the response is different in responders and nonresponders: in responders, SBP fell almost three times as far from baseline (15.9 vs. 5.6 mm Hg), and diastolic over four times (14.5 vs. 3.3 mm Hg).


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  		TABLE 2. Changes from baseline ({Delta}) for BP and serum [K+] for patients stratified by DBP response

 
The 222 nonresponders at 4 wk were evaluated at 8 wk, 4 wk after their dose had been increased to 100 mg eplerenone daily. At 8 wk, 30% of the initial nonresponders (to 50 mg eplerenone daily) had responded to 100 mg/d. In responders, SBP fell 19.9 mm Hg, compared with the nonresponders’ 4.6 mm Hg, and a similar pattern was seen for diastolic pressure (14.8 vs. 3.2 mm Hg).

The 156 nonresponders at wk 8 were evaluated again at 12 wk, 4 wk after their dose had been doubled once more to 200 mg/d. At this dose, 48% of this group responded by lowering their DBP below target (<90 mm Hg). Once again, differences were observed between responders and nonresponders in both systolic (mean, 17.4 vs. 2.0 mm Hg) and diastolic (mean, 14.6 vs. 1.4 mm Hg) BP decrement.

The right column of Table 2Go shows the mean and 95% confidence limits for the change in serum [K+] for each of the six groups. At each of the three dosage levels, mean changes in serum [K+] (all <0.2) are consistent with the modest effect of eplerenone on serum [K+] previously found in a variety of studies (7, 8, 9). Moreover, at all doses the change in serum [K+] for responders was less than or equal to that for nonresponders. In all groups, some subjects had BP measured but no blood taken per value recorded for [K+]; only in the final, nonresponder to 200-mg group does this represent a substantial loss.

Figure 1Go is a graphical representation of the data in Table 2Go to illustrate the differences in BP between responders and nonresponders at each successive dose level.



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  		FIG. 1. Change in SBP by change in serum [K+] for responder and nonresponders at each time/dose interval.

 
Figure 2Go illustrates the relationship of changes in serum [K+] and the changes in BP for responders and nonresponders at each dose. The regression lines are uniformly near horizontal, indicating no association between the two variables.



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  		FIG. 2. Change in SBP by change in serum [K+] for responder and nonresponders at each time/dose interval.

 
When differences are sought across the patient sample stratified by response in a variety of other parameters, no confounding findings emerge. Table 3Go shows data for responders and nonresponders at each dose for age, ethnicity, and baseline SBP and DBP. No correlation was seen between responder/nonresponder status and age or ethnicity, or with baseline serum Na+, {Delta} Na+, baseline or {Delta} plasma renin concentration, baseline body weight, {Delta} body weight, gender, or heart rate (data not shown). Not surprisingly, the patients responding to 50 or 100 mg/d eplerenone showed marginally lower baseline SBP and DBP than nonresponders, consistent with attaining a target DBP of <90 mm Hg. The dimensions of the difference in baseline SBP (5–6 mm Hg) and DBP (3–4 mm Hg) are, however, much less than the BP differences between responders and nonresponders (SBP, 10–15 mm Hg; DBP, 12–13 mm Hg). At the 200 mg/d eplerenone dose, no differences in baseline SBP or DBP were seen between responders and nonresponders.


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  		TABLE 3. Comparison of various parameters between responder and nonresponder groups

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
There are two major findings of the present analysis, neither of which was anticipated. First, in a group of unselected patients with moderate essential hypertension, there seems to be a wide variation in response to mineralocorticoid receptor blockade, essentially unrelated to any variable. Second, although changes in serum potassium also seem widely distributed at each dose level, and in general rise with increasing eplerenone dosage, responders in terms of BP at each dose show elevations in serum [K+] equal to or less than those seen in nonresponders. At all doses, there is no evidence for responders showing a more marked change in serum [K+] and thus no evidence for a relationship between the "potassium-sparing diuretic" effects of eplerenone and BP change. Each of these two findings will be discussed in terms of the (patho)physiological mechanisms involved, as will the implications for the role of mineralocorticoid receptor blockade in the treatment of hypertension and vascular protection.

Although the present study covered only a 4-fold range of doses, it is likely that the effective dose range for eplerenone is closer to 10-fold. At the lowest of the three doses used, 44% of the patients responded with substantial falls in both systolic (15.9 mm Hg) and diastolic (14.5 mm Hg) BP; on the basis that almost half of the patient sample responded to the 50 mg dose, it would seem reasonable to suggest that perhaps up to half of this responder group might also achieve goal DBP values on 25 mg eplerenone per day. Such an interpretation is supported by considering the proportion of the treated population responding at each dose level, net of dropouts. If half of the responders at 50 mg also would have responded at 25 mg, the percentage of responder values would be 22% at 25 mg, 22% at 50 mg, 17% at 100 mg, and 19% at 200 mg, with 20% residual nonresponders at the highest dose used.

Whereas the extent of this spread of responsiveness to mineralocorticoid receptor blockade in terms of BP was not anticipated, what it underlies is the multiplicity of mechanisms involved in the maintenance of BP in essential hypertension. In the present titration-to-effect studies, it is, by definition, not possible to know to what extent (if any) BP in responders might have fallen to further doubling or redoubling the eplerenone dose. From forced-titration clinical studies of eplerenone, however, there would seem to be little, if any, additional BP decrement: the measured values at each dose in the present study are clearly comparable with those seen when all patients are force-titrated to 200 mg/d. Our interpretation of the present data then is that mineralocorticoid receptor-mediated actions may account for the 16–18 mm Hg elevation in SBP, and 14–15 mm Hg in DBP, in essential hypertension, but that to block these actions requires up to an order of magnitude range of mineralocorticoid receptor antagonist. Whereas this possible 10-fold range in responsiveness may, in part, reflect differences in eplerenone metabolism and clearance, or differences in mineralocorticoid receptor expression in different tissues between patients, a substantially greater source of variation may be in the levels of endogenous steroid against which eplerenone competes at the mineralocorticoid receptor.

If response in terms of BP does not correlate with changes in serum [K+], then presumably eplerenone is acting largely at sites other than epithelial sites of electrolyte transport to lower BP. Candidate sites are the blood vessels themselves and the AV3V region of the brain where mineralocorticoid receptor activation has been shown to elevate BP. Fifteen years ago, in studies in mesenteric vascular arcades from adrenalectomized rats, it was shown that the vascular smooth muscle cells are physiological aldosterone target tissues (10). In terms of physiology, an aldosterone-responsive vasculature is presumably an evolutionary advantage in the context of volume depletion, to act in concert with catechols and angiotensin II to maintain BP. Both rapid, presumably nongenomic (11, 12) and more conventional, presumably genomic effects of aldosterone (13) on vascular smooth muscle have been shown, consistent with a physiological role for the steroid in the control of vascular tone and thus BP. The subcellular mechanisms involved in the direct effects of aldosterone on vascular smooth muscle cells remain to be established.

In some (rat, dog) but not all (sheep) experimental animals, intracerebral ventricular infusion of aldosterone, at levels totally without effect when infused peripherally, has been shown to raise BP (for review see Ref. 14). Conversely, intracerebral ventricular infusion of the mineralocorticoid receptor antagonist RU28318, into animals receiving a peripheral infusion of aldosterone, has been shown to block the hypertensive response otherwise seen: interestingly, the direct cardiac effects of peripheral aldosterone infusion (hypertension, fibrosis) remain equivalent in doubly infused, normotensive animals (15). The present studies do not address which of these (or other) sites of eplerenone action are responsible for the observed fall in BP; they do, however, suggest that fluid and electrolyte changes do not play a dominant role. Although clearly serum [K+] is an imperfect index of potassium status, particularly of intracellular potassium, it is of major importance in monitoring the course of therapy in clinical practice. For a more complete description of the patients’ fluid and electrolyte status, balance studies and measures of 24-h aldosterone production would be necessary. On the other hand, from what data were collected at each visit, there is no suggestion that the measured plasma [K+] is misleading in terms of fluid and electrolyte status.

In the absence of data on circulating hormone levels, it is possible but unlikely that the wide variation in apparent sensitivity to eplerenone reflects an equally wide variation in aldosterone levels. It is also possible that it reflects variable mineralocorticoid receptor activation by cortisol rather than aldosterone, under conditions of altered intracellular redox state and/or the presence of reactive oxygen species, as has been shown previously in experimental studies (16, 17, 18, 19). Whatever the underlying molecular and cellular mechanisms involved, the present studies may be of use in the clinical application of eplerenone, used as monotherapy in primary aldosteronism or perhaps more commonly in combination with other agents in heart failure, and for lowering BP in African-Americans, isolated systolic hypertension, and (by definition) resistant hypertension. Under the latter circumstances, the present studies would suggest that eplerenone dosage should be titrated to effect, as monitored (20) by BP response, and that even at levels of 200 mg/d, in those patients who need it for BP reduction, the effects of serum [K+] should be monitored but not expected to be a cause of concern in patients without other factors (e.g. renal insufficiency, K+ supplementation) predisposing to hyperkalemia.


   Footnotes
 
This work was presented at the annual meetings of the American Society of Hypertension (May 2003) and the European Society for Hypertension (June 2003).

Present address for R.R.: Novartis Corporation, New Hanover, New Jersey 01770.

Present address for D.G.L.: Hoffman-La Roche Inc., Nutley, New Jersey 07936.

Abbreviations: BP, Blood pressure; DBP, diastolic BP; SBP, systolic BP.

Received December 15, 2003.

Accepted February 23, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Rocha R, Funder JW 2002 The pathophysiology of aldosterone in the cardiovascular system. Ann NY Acad Sci 970:89–100[Abstract/Free Full Text]
  2. White WB, Duprez D, St Hillaire R, Krause S, Roniker B, Kuse-Hamilton J, Weber MA 2003 Effects of the selective aldosterone blocker eplerenone versus the calcium antagonist amlodipine in systolic hypertension. Hypertension 41:1021–1026[Abstract/Free Full Text]
  3. Flack JM, Oparil S, Pratt JH, Roniker B, Garthwaite S, Kleiman JH, Yang Y, Krause SL, Workman D, Saunders E 2003 Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients. J Am Coll Cardiol 41:1148–1155[Abstract/Free Full Text]
  4. Pitt B, Remme W, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M 2003 Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348:1309–1321[Abstract/Free Full Text]
  5. Basile J 2003 Analysis of recent papers in hypertension: efficacy of eplerenone, a new aldosterone antagonist. J Clin Hypertens 5:80–82
  6. Weber MA 2002 Clinical implications of aldosterone blockade. Am Heart J 144:S12–S18
  7. Weinberger MH, Roniker B, Krause SL, Weiss RJ 2002 Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens 15:709–716[CrossRef][Medline]
  8. Krum H, Nolly H, Workman D, He W, Roniker B, Krause S, Fakouhi K 2002 Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension 40:117–123[Abstract/Free Full Text]
  9. White WB, Carr AA, Krause S, Jordan R, Roniker B, Oigman W 2003 Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension. Am J Cardiol 92:38–42[CrossRef][Medline]
  10. Funder JW, Pearce PT, Smith R, Campbell J 1989 Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology 125:2224–2226[Abstract]
  11. Alzamora R, Michea L, Marusic ET 2000 Role of 11beta-hydroxysteroid dehydrogenase in nongenomic aldosterone effects in human arteries. Hypertension 35:1099–1104[Abstract/Free Full Text]
  12. Romagni P, Rossi P, Guerrini L, Quirini C, Santiemma V 2003 Aldosterone induces contraction of the resistance arteries in man. Atherosclerosis 166:345–349.[CrossRef][Medline]
  13. Kornel L, Smoszna-Konaszewska B 1995 Aldosterone (ALDO) increases transmembrane influx of Na+ in vascular smooth muscle (VSM) cells through increased synthesis of Na+ channels. Steroids 60:114–119[CrossRef][Medline]
  14. Gomez-Sanchez EP, Funder JW, Central nervous actions of mineralocorticoids. Curr Opin Nephrol Hypertens, in press
  15. Young MJ, Funder JW 1996 The renin-angiotensin-aldosterone system in experimental mineralocorticoid-salt induced cardiac fibrosis. Am J Physiol 271:E883–E888
  16. Ward MR, Kanellakis P, Ramsey D, Funder JW, Bobik A 2001 Eplerenone suppresses constrictive remodeling and collagen accumulation after angioplasty in porcine coronary arteries. Circulation 104:467–472[Abstract/Free Full Text]
  17. Young MJ, Moussa L, Dilley R, Funder JW 2003 Early inflammatory responses in experimental cardiac hypertrophy and fibrosis: effects of 11ßhydroxysteroid dehydrogenase inactivation. Endocrinology 144:1121–1125[Abstract/Free Full Text]
  18. Funder JW, Aldosterone, mineralocorticoid receptors and vascular inflammation. Mol Cell Endocrinol, in press
  19. Funder JW, Is aldosterone bad for the heart? Trends Endocrinol Metab, in press
  20. Sica DA 2002 Current concepts of pharmacotherapy in hypertension. Eplerenone: a new aldosterone receptor antagonist—are the FDA’s restrictions appropriate? J Clin Hypertens 4:441–445



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