Journal of Hypertension:
Can we use mineralocorticoid receptor blockade in diabetic patients with resistant hypertension? Yes we can! But it may be a double-edged sword
Azizi, Michela,b,c; Monge, Matthieuc; Lorthioir, Auréliena,b; Bobrie, Guillaumea; Amar, Laurencea,b
aAssistance Publique – Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit
cINSERM, Clinical Investigation Centre 9201, Paris, France
Correspondence to Professor Michel Azizi, Hypertension Unit, Hôpital Européen Georges Pompidou, 20–40, rue Leblanc, 75015 Paris, FranceTel: +33 1 56 09 29 11; fax: +33 1 56 09 29 29; e-mail: email@example.com
Primary resistant hypertension is defined as failure to reach target blood pressure (BP) in patients treated with an appropriate three-drug regimen, including a diuretic, with all administered at optimal doses [1,2]. Resistant hypertension prevalence ranges from 10 to 30% in surveys or tertiary centres and randomized trials [1,3–5]. It is frequently encountered in certain categories of patients, such as those with type 2 diabetes mellitus or chronic kidney disease in particular [1,6]. It is associated with a high prevalence of end-organ damage  and a high incidence of cardiovascular events .
The high frequency of resistant hypertension and its severity have led to the development of new treatment strategies based on the use of combinations of available drugs [1,2] or new device-based therapies, such as catheter-based endovascular renal denervation  and baroreflex activation therapy , the indications of which have yet to be clearly defined [10–12].
The frequent association of resistant hypertension with inappropriate volume retention [13,14] has led to international guidelines recommending principally a reduction in sodium intake and an increase in the intensity of diuretic therapy to treat this condition [1,2]. However, other pathophysiological systems, including the renin–angiotensin–aldosterone system (RAAS), the renal or central sympathetic nervous system and vasomotor systems (endothelin), may also influence BP [15–18]. An understanding of the relative contributions of each of these mechanisms to the BP level in individual patients with resistant hypertension would make it possible to tailor treatment to the individual, by selecting drugs or device-based therapies preferentially interfering with particular systems. However, it remains difficult to determine which patients are most likely to benefit from which treatment, the optimal drug doses to be used, the combinations and optimal order of drug initiation, and the optimal type and timing of device-based therapy. The problem is rendered even more complex by the presence of internal counter-regulation, which may limit the primary biological effect of each of these approaches, partially or fully neutralizing their BP-lowering effects. Finally, in addition to these internal pathophysiological factors, the care of patients with resistant hypertension is also rendered more difficult by problems of non-compliance with treatment, the prevalence of which is regularly reported to be as high as 40–50% in patients with resistant hypertension [19,20].
There is now a body of evidence to suggest that blocking the mineralocorticoid receptor, and hence, the multiple noxious effects of aldosterone in the kidney, vessels and heart , is one of the most effective ways of reducing BP in patients with resistant hypertension; indeed, this approach is now recommended by international guidelines [1,2]. There are multiple pathophysiological reasons for this efficacy. The primary mineralocorticoid hormone in humans, aldosterone, plays a major role in the homeostasis of sodium and potassium metabolism and BP control . In addition, aldosterone acts in conjunction with high sodium intake to stimulate inflammatory reactions, cellular hypertrophy, matrix formation and apoptosis in the vessels, heart and kidney [22–24], and is directly involved in causing target organ damage in various cardiovascular and renal disease states [22,25]. A series of observations over the past 10 years have confirmed that relative aldosterone excess is common in patients with hypertension [26–28], particularly in those with resistant hypertension and evidence of intravascular volume expansion [13,14], and in overweight normotensive individuals . It is also associated with insulin resistance . Blockade of the biological effects of aldosterone has mostly been achieved with two mineralocorticoid receptor antagonists, spironolactone and eplerenone [21,31]. Both are used to treat hypertension , particularly the forms of hypertension in which aldosterone is thought to play a major role, such as primary aldosteronism [32,33], low-renin hypertension , metabolic syndrome  and complicated hypertension with left-ventricular hypertrophy . They are also specifically used in patients with resistant hypertension. Indeed, in several studies of patients with resistant hypertension, spironolactone (25–100 mg/day) has been reported to yield additional decreases in BP when used in combination with other antihypertensive drugs [37–39]. However, most of these studies were uncontrolled, non-randomized, open-label, or included poorly characterized patients . The only randomized, double-blind, controlled study published to date, in which a dose of 25 mg of spironolactone was used in patients with resistant hypertension, reported a significant decrease in systolic/diastolic daytime ambulatory BP of 5.4/1.0 mmHg with respect to placebo (P = 0.024/0.358, respectively) . The percentage of patients with resistant hypertension achieving a target systolic office BP of less than 140 mmHg was 54.5% in the spironolactone group and 42.9% in the placebo group. Eplerenone is a short-acting mineralocorticoid receptor antagonist that is less potent than spironolactone [31,33,42]. However, it has the advantage of being more selective than spironolactone for the mineralocorticoid receptor. It does not interfere with progesterone or androgen receptors at the marketed doses (50–100 mg) and, therefore, does not have the sexual side-effects of spironolactone, such as impotence, gynaecomastia, breast tenderness and menstrual irregularities . Eplerenone (50–100 mg daily) was given as an add-on therapy to patients with resistant hypertension in an uncontrolled, non-randomized, open-label trial, in which it was found to control BP in about 40% of patients . However, eplerenone has not been approved for use in the treatment of hypertension in many European countries.
In this issue of the Journal of Hypertension, Oxlund et al. provide additional clinical evidence from the use of low-dose spironolactone for resistant hypertension treatment in another population of patients with type 2 diabetes, in which the balance between the benefits and the risk of this approach was needed to be evaluated in the light of the safety concerns reported in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints trial . Indeed, only 20–40% of the patients with resistant hypertension included to date in clinical trials or observational studies assessing the efficacy of spironolactone had type 2 diabetes [37,38,46]. The findings of this 16-week multicentre, double-blind, randomized, placebo-controlled study can be summarized as follows: 119 overweight or obese type 2 diabetic patients (mean age 63 years) with resistant hypertension defined as mean daytime ambulatory SBP of at least 130 mmHg and DBP of at least 80 mmHg (mean 146/79 mmHg), or either of the above conditions, despite treatment with three or more antihypertensive drugs (range 3–5), including a diuretic and an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB), at appropriate doses, were included after a period of unmodified antihypertensive treatment of at least 1 month. A dose of 25 mg spironolactone or placebo was added to the previous treatment. The dose of spironolactone or placebo could be doubled, if a target BP of less than 130/80 mmHg was not achieved after 4 weeks, or halved, if BP was too low. After 16 weeks of treatment, 15% of the patients were taking a daily dose of 12.5 mg spironolactone, 41% were taking 25 mg and 44% were taking 50 mg (mean daily dose 34.9 ± 15.5 mg). The placebo-corrected decrease in mean daytime ambulatory BP was 8.9 (4.7; 13.2)/3.7 (1.5; 5.8) mmHg (P < 0.001) and that of night-time BP was 9.8 (4.0; 15.5)/3.2 (0.4; 6.7) mmHg (P < 0.001). The target daytime ambulatory BP (<130/80 mmHg) was achieved by 30% of the patients in the spironolactone group, versus only 9% in the placebo group (P = 0.019). The significant decrease in BP in the patients on spironolactone was associated with a significant decrease in urinary albumin excretion. Only about half the patients had microalbuminuria/macroalbuminuria at baseline. Small studies have shown that mineralocorticoid receptor blockade added to background ACE inhibition decreases proteinuria in patients with type 2 diabetes [47–49]. However, large clinical trials are required to demonstrate both the safety and the nephroprotective effects of such an approach in the long term .
The frequency of adverse events was low in this population of highly selected diabetic patients, from which patients with an estimated glomerular filtration rate (eGFR) below 50 ml/min per 1.73 m2 and previous intolerance to spironolactone were excluded. The patients were exposed to a low dose of spironolactone for only a short period of time (16 weeks). Consequently, no sexual adverse effects were reported. However, despite the dose-dependent nature of the sexual side-effects of spironolactone , longer-term exposure to even low doses of spironolactone has been associated with gynaecomastia/breast tenderness, leading to treatment discontinuation in patients with heart failure . As expected, given the combination of a blockade of the renal tubular effects of aldosterone and the background blockade of the renin–angiotensin system (RAS) by ACEI or ARBs, plasma potassium concentration was 0.3 (±0.3) mmol/l higher in the treated patients than in the controls. Mild hyperkalaemia was the most common adverse event, leading to a decrease in spironolactone dose in three patients and treatment cessation in one case, consistent with the findings of other studies (see for review ). The risk of hyperkalaemia is of concern and should not be underestimated in patients with resistant hypertension and type 2 diabetes. Indeed, most of these patients are already on RAS inhibitor treatment and may have diabetes-induced hyporeninic hypoaldosteronism or associated conditions, such as diabetic nephropathy, with a low GFR, potentially increasing the risk of hyperkalaemia . However, the risk of hyperkalaemia should not be stressed too strongly either, because it might decrease the rate of prescription of spironolactone in this setting. Careful monitoring of plasma potassium and creatinine concentrations in patients on spironolactone treatment, especially in those with low GFR values, should make it possible to detect hyperkalaemia early, if it occurs, and to adopt appropriate preventive measures , including the tapering of spironolactone dose and the avoidance of co-prescription with hyperkalaemic drugs, for example.
Are there other alternatives to the administration of low-dose spironolactone in patients with resistant hypertension? New potent dihydropyridine-based third-generation and fourth-generation mineralocorticoid receptor antagonists  and aldosterone synthase inhibitors  are currently being tested as new tools for antagonizing the effects of aldosterone. However, both these approaches are likely to entail the same risk of adverse events as the first generation of steroidal mineralocorticoid receptor antagonists, including electrolyte disorders, hypotension, renal insufficiency and severe hypoaldosteronism, depending on residual aldosterone effects, initial renal function, dehydration, general anaesthesia, comorbidities (diabetes mellitus) and co-prescriptions (cyclooxygenase inhibitors, RAS blockers, heparin, trimethoprim-sulphamethoxazole, etc.). Another possible way to control BP in patients with resistant hypertension is sequential nephron blockade , based on the use of low doses of diuretics operating on different nephron segments to neutralize the effects of intra-renal counter-regulatory mechanisms triggered by the use of diuretics acting at a single site, particularly when used at high doses.
In conclusion, this new study by Oxlund et al. adds grist to the mill of those stressing the pathophysiological role of aldosterone in patients with resistant hypertension and an additional condition, type 2 diabetes mellitus. Indeed, diabetes and obesity are known to be independent predictors of the development of resistant hypertension, but the long-term benefit–risk balance of mineralocorticoid receptor blockade in patients with diabetes in ‘real life’ remains to be determined.
Conflicts of interest
There is no conflict of interest.
1. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation
2. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens
3. Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension
4. Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation
5. de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension
6. Gupta AK, Nasothimiou EG, Chang CL, Sever PS, Dahlof B, Poulter NR. Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J Hypertens
7. Cuspidi C, Macca G, Sampieri L, Michev I, Salerno M, Fusi V, et al. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens
8. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet
9. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol
10. Azizi M, Steichen O, Frank M, Bobrie G, Plouin PF, Sapoval M. Catheter-based radiofrequency renal-nerve ablation in patients with resistant hypertension. Eur J Vasc Endovasc Surg
11. Persu A, Renkin J, Thijs L, Staessen JA. Renal denervation: ultima ratio or standard in treatment-resistant hypertension. Hypertension
12. De Leeuw PW, Kroon AA. Clinical end points in baroreflex activation therapy: what do we need to know? Expert Rev Cardiovasc Ther
13. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension
14. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, Calhoun DA. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med
15. Laragh JH, Sealey JE, Buhler FR, Vaughan ED, Brunner HR, Gavras H, Baer L. The renin axis and vasoconstriction volume analysis for understanding and treating renovascular and renal hypertension. Am J Med
16. Hall JE, Guyton AC, Mizelle HL. Role of the renin-angiotensin system in control of sodium excretion and arterial pressure. Acta Physiol Scand Suppl
17. Dibona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol
18. Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, et al. Hypertension: physiology and pathophysiology. Compr Physiol
19. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ
20. Jung O, Gechter JL, Wunder C, Paulke A, Bartel C, Geiger H, Toennes SW. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens
21. Jansen PM, Danser AH, Imholz BP, van den Meiracker AH. Aldosterone-receptor antagonism in hypertension. J Hypertens
22. Connell JM, MacKenzie SM, Freel EM, Fraser R, Davies E. A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function. Endocr Rev
23. Brown NJ. Aldosterone and end-organ damage. Curr Opin Nephrol Hypertens
24. Funder JW, Mihailidou AS. Aldosterone and mineralocorticoid receptors: clinical studies and basic biology. Mol Cell Endocrinol
25. Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, et al. Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension
26. Newton-Cheh C, Guo CY, Gona P, Larson MG, Benjamin EJ, Wang TJ, et al. Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample. Hypertension
27. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med
28. Meneton P, Galan P, Bertrais S, Heudes D, Hercberg S, Menard J. High plasma aldosterone and low renin predict blood pressure increase and hypertension in middle-aged Caucasian populations. J Hum Hypertens
29. Bentley-Lewis R, Adler GK, Perlstein T, Seely EW, Hopkins PN, Williams GH, Garg R. Body mass index predicts aldosterone production in normotensive adults on a high-salt diet. J Clin Endocrinol Metab
30. Garg R, Hurwitz S, Williams GH, Hopkins PN, Adler GK. Aldosterone production and insulin resistance in healthy adults. J Clin Endocrinol Metab
31. Menard J. The 45-year story of the development of an antialdosterone more specific than spironolactone. Mol Cell Endocrinol
32. Lim PO, Young WF, MacDonald TM. A review of the medical treatment of primary aldosteronism. J Hypertens
33. Parthasarathy HK, Menard J, White WB, Young WF JJr, Williams GH, Williams B, et al. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens
34. Hood SJ, Taylor KP, Ashby MJ, Brown MJ. The spironolactone, amiloride, losartan, and thiazide (SALT) double-blind crossover trial in patients with low-renin hypertension and elevated aldosterone-renin ratio. Circulation
35. Briet M, Schiffrin EL. The role of aldosterone in the metabolic syndrome. Curr Hypertens Rep
36. Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, et al. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation
37. Chapman N, Dobson J, Wilson S, Dahlof B, Sever PS, Wedel H, Poulter NR. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension
38. de Souza F, Muxfeldt E, Fiszman R, Salles G. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension
39. Alvarez-Alvarez B, Abad-Cardiel M, Fernandez-Cruz A, Martell-Claros N. Management of resistant arterial hypertension: role of spironolactone versus double blockade of the renin-angiotensin-aldosterone system. J Hypertens
40. Colussi G, Catena C, Sechi LA. Spironolactone, eplerenone and the new aldosterone blockers in endocrine and primary hypertension. J Hypertens
41. Vaclavik J, Sedlak R, Plachy M, Navratil K, Plasek J, Jarkovsky J, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension
42. Weinberger MH, Roniker B, Krause SL, Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens
43. Calhoun DA, White WB. Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension. J Am Soc Hypertens
44. Oxlund CS, Henriksen JH, Tranow L, Schousboe K, Gram J, Jacobsen IA. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens
45. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med
46. Bobrie G, Frank M, Azizi M, Peyrard S, Boutouyrie P, Chatellier G, et al. Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. J Hypertens
47. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension
48. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol
49. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol
50. Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int
51. Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVries C, Plouin PF, et al. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol
52. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med
53. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med
54. Fagart J, Hillisch A, Huyet J, Barfacker L, Fay M, Pleiss U, et al. A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule. J Biol Chem
55. Azizi M, Amar L, Menard J. Aldosterone synthase inhibition in humans. Nephrol Dial Transplant
© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins