European Journal of Internal Medicine 25 (2014) 173–176
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: An emerging paradigm in diabetic nephropathy A systematic review Thomas A. Mavrakanas a,⁎, Karim Gariani a, Pierre-Yves Martin b a b
General Internal Medicine Division, Geneva University Hospitals, Geneva, Switzerland Nephrology Division, Geneva University Hospitals, Geneva, Switzerland
a r t i c l e
i n f o
Article history: Received 5 July 2013 Received in revised form 28 October 2013 Accepted 10 November 2013 Available online 4 December 2013 Keywords: Diabetic nephropathy Mineralocorticoid receptor blockade Albuminuria Glomerular filtration rate Blood pressure Hyperkalemia
a b s t r a c t Blockade of the renin–angiotensin–aldosterone system (RAAS) is a standard therapeutic intervention in diabetic patients with chronic kidney disease (CKD). Concomitant mineralocorticoid receptor blockade has been studied as a novel approach to further slow down CKD progression. We used PubMed and EMBASE databases to search for relevant literature. We included in our review eight studies in patients of at least 18 years of age, with a diagnosis of type 1 or type 2 diabetes mellitus and diabetic nephropathy, under an angiotensin converting enzyme inhibitor (ACEI) and/or an angiotensin II receptor blocker (ARB) as standard treatment. A subset of patients in each study also received a mineralocorticoid receptor blocker (MRB) (either spironolactone or eplerenone) in addition to standard treatment. Combined treatment with a mineralocorticoid receptor blocker further reduced albuminuria by 23 to 61% compared with standard treatment. Estimated glomerular filtration rate values upon study completion slightly decreased under combined treatment. Blood pressure levels upon study completion were significantly lower with combined treatment in three studies. Hyperkalemia prevalence increased in patients under combined treatment raising dropout rate up to 17%. Therefore, combined treatment by an ACEI/ARB and a MRB may further decrease albuminuria in diabetic nephropathy. This effect may be due to the specific properties of the MRB treatment. Clinicians should regularly check potassium levels because of the increased risk of hyperkalemia. Available evidence should be confirmed by an adequately powered comparative trial of the standard treatment (ACEI or ARB) versus combined treatment by an ACEI/ARB and a MRB. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Blockade of the renin–angiotensin–aldosterone system (RAAS) is a well-recognized strategy to slow down renal disease progression in diabetic patients with chronic kidney disease (CKD). An angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) is the recommended therapeutic intervention in these patients. Recently, concomitant mineralocorticoid receptor blockade has also been studied as a novel approach to further slow down CKD progression. Concomitant aldosterone blockade attracted more interest when Pitt described a rebound of aldosterone production in patients receiving an ACEI for heart failure [1]. The eventual benefit of aldosterone blockade was then studied in various experimental models of diabetic
nephropathy. Spironolactone, as well as the more selective eplerenone, showed beneficial effects in several animal models of type 1 and type 2 diabetes [2–7]. Despite the encouraging results from experimental studies, largescale randomized prospective trials testing the combined angiotensin– aldosterone blockade have not been conducted in patients with diabetic nephropathy, mainly because of concerns about hyperkalemia. However, smaller clinical studies are available with promising results. Mineralocorticoid receptor blockade emerges as a new paradigm in patients with diabetes and CKD. This paper reviews currently available studies in patients with diabetic nephropathy. 2. Material and methods
⁎ Corresponding author at: Division of General Internal Medicine, Geneva University Hospitals, 4, Rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland. Tel.: +41 79 553 43 24; fax: +41 22 372 91 16. E-mail address: [email protected] (T.A. Mavrakanas).
We used PubMed and EMBASE databases as well as the Cochrane Register of Clinical Trials to search for relevant literature (indexed up to October 2012). We searched for published clinical trials in English
0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.11.007
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language, including patients of at least 18 years of age, with a diagnosis of type 1 or type 2 diabetes mellitus and diabetic nephropathy (defined as at least 30 mg of albuminuria in a 24-h urine collection or an albumin to creatinine ratio of at least 30 mg/g of creatinine). They should have received an ACEI and/or an ARB at an adequate dose throughout the study as standard treatment. To evaluate the effect of concomitant mineralocorticoid receptor blockade, a subset of patients in each study should also receive a mineralocorticoid receptor blocker (MRB) (either spironolactone or eplerenone) in addition to standard RAAS blockade. We also checked the reference list of the retrieved articles. Two authors independently performed study selection and extracted information from each included trial. The key words used for literature research in Pubmed, EMBASE and the Cochrane Register were diabetic nephropathy and aldosterone blockade, mineralocorticoid receptor blockade, spironolactone or eplerenone. Discrepancies between authors' assessments were resolved by mutual discussion of each item in question. Our primary objective was to compare the albuminuria levels in each study group upon study completion, assessed either by 24-h urine collection or a urine spot with calculation of the albumin to creatinine ratio. The secondary efficacy outcome was estimated glomerular filtration rate (GFR) and blood pressure (BP) levels in each group at the end of the study. The safety outcome was the dropout rate due to hyperkalemia. All studies were of sufficient methodological quality as assessed by the Jadad score (Table 1). The small number of the included studies, the different presentations of the primary outcome, and the heterogeneous design do not permit to perform a meta-analysis on available data. Nevertheless, the three trials from the Steno Diabetes Center included the same patients in more than one study [8–10]. They should be considered together and do not have the impact of three independent studies. Therefore, results are presented in the form of a systematic review. 3. Results We initially retrieved 103 English-language papers on MRB in diabetic nephropathy. There were only 17 human studies addressing our research question (Fig. 1). After reviewing the full article, we further excluded 9 studies: four used spironolactone monotherapy or loop diuretics, two studies also included patients without diabetic nephropathy, one was conducted only in patients with documented elevated aldosterone levels (aldosterone rebound), one was actually a comment on an already published study, and for one study major remarks concerning the results accuracy were published. In Table 1, we summarize the characteristics of the eight selected studies [8–15]. Table 2 shows the albuminuria levels upon study completion in each group (standard treatment versus MRB combined to standard treatment) as well as the dropout cases due to hyperkalemia. Albuminuria values were either directly reported in the articles or calculated from the percentage of change and the available baseline levels. Combined treatment further reduced albuminuria by 23 to 61% compared with standard treatment. Creatinine values upon study completion were available in only five trials and were largely overlapping. Data on estimated GFR were available for both groups in all studies. GFR values in patients also receiving
MRBs were inferior to GFR values in patients on standard treatment. However, baseline values were significantly different in the studied groups due to the exclusion of patients with hyperkalemia. Therefore, direct comparison of GFR values at study completion would be of limited interest (Table 2). BP decreased significantly from baseline with standard and combined treatment in three studies [11,12,14]. A significant difference in BP levels upon study completion between the two treatment groups was identified in three studies [9–11]. Data are summarized in Table 2. Hyperkalemia prevalence increased in patients under combined ACEI/ARB and MRB treatment compared with patients receiving standard treatment. Dropout significantly increased (up to 17%) under combined treatment in only two studies [11,14]. No deaths were reported secondary to hyperkalemia. No other serious side effects were reported.
4. Discussion In this systematic review, we used currently available evidence in order to compare standard treatment by an ACEI or an ARB with combined treatment by an ACEI/ARB and a MRB in patients with diabetic nephropathy. Short term combined treatment reduced urinary albumin excretion in all studies. Estimated GFR values upon study completion slightly decreased under combined treatment. However, hyperkalemia incidence increased in the combined treatment group necessitating MRB interruption in up to 17% of cases. Therefore, combined treatment by an ACEI/ARB and a MRB is effective in decreasing albuminuria in diabetic nephropathy but increases the risk of hyperkalemia. The antiproteinuric effect of ACEIs or ARBs is more prominent in patients on a low sodium diet or who are treated with diuretics because relative hypovolemia results in greater angiotensin-II dependence of the glomerular microcirculation [16]. Further reduction of proteinuria in patients on combined treatment may be due to the specific properties of the MRB treatment. Selective blockade at the mineralocorticoid receptor (MR) level has been demonstrated to reverse the changes in glomerular vascular barrier and reduce intraglomerular hydraulic pressure. Furthermore, MRB may prevent renal fibrosis, mesangial expansion and glomerulosclerosis via its action on TGF-β1, PAI-1, local oxidative stress and endothelial function [17,18]. Aldosterone rebound, i.e. a rebound in aldosterone plasma levels after a transient decrease, has been detected in 40% of patients with early diabetic nephropathy treated by an ACEI [19]. Therefore, pharmacological MR blockade may be of significant benefit in these patients. It must be noted that patients under standard treatment received either an ACEI or an ARB. These two drug classes do not have the same pharmacological properties. ACEI treatment reduces angiotensin II levels. On the other hand, ARBs significantly increase angiotensin II levels with subsequent stimulation of the type 2 angiotensin II receptor (AT2). ACEIs and ARBs also do not share the same characteristics concerning their effect on bradykinin catabolism and nitric oxide levels [20]. Unfortunately, the six studies with patients on either an ACEI or an ARB upon inclusion do not provide any sub-group analysis according to the standard treatment [8–11,13,15]. Therefore, the differences between standard
Table 1 Characteristics of the 8 selected studies. N, number of patients randomized in the study; MRB, mineralocorticoid receptor blocker; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker. Reference
Standard treatment
Studied MRB
Design
N
Duration
Jaddad score
Schjoedt et al. [8] Rossing et al. [9] Schjoedt et al. [10] van den Meiracker [11] Epstein et al. [12] Saklayen et al. [13] Mehdi et al. [14] Nielsen et al. [15]
ACEI or ARB ACEI or ARB ACEI or ARB ACEI or ARB Enalapril Lisinopril-losartan Lisinopril 80 mg ACEI or ARB
Spironolactone 25 mg Spironolactone 25 mg Spironolactone 25 mg Spironolactone 50 mg Eplerenone 50–100 mg Spironolactone 25–50 mg Spironolactone 25 mg Spironolactone 25 mg
Cross-over Cross-over Cross-over Cluster-randomized Cluster-randomized Cross-over Cluster-randomized Cross-over
22 21 20 59 177 30 54 21
2 months (each phase) 2 months (each phase) 2 months (each phase) 1 year 12 weeks 3 months (each phase) 48 weeks 2 months (each phase)
5 5 5 5 3 4 5 5
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175
Fig. 1. Search results and studies selection.
and combined treatment may be interpreted with caution, as an MRB may not have the same effect when added to an ACEI or an ARB. Concerning the impact on GFR, decreased GFR levels in patients receiving an MRB may be due to a drop in intra-glomerular pressure. In such a case, the fall in GFR would turn out to be a favorable event heralding better preservation of renal glomeruli over time. However, GFR was not measured by creatinine clearance in 24-hour urine collection but derived from plasma creatinine values using empiric formulas. No conclusion on the combined treatment effect on renal function can be drawn, as none of these studies was adequately powered for this endpoint. Eight studies met our inclusion criteria; three cluster randomized studies and five crossover trials. However, the number of included
patients was small with the studies being more inclined to report a positive effect [21,22]. Follow-up was rather of limited duration (2–3 months) with only two studies following the patients for 48– 52 weeks. The three studies from the Steno diabetes center may have included at least in part the same patients as acknowledged by the authors [8–10]. The absence of negative studies may be due to a publication bias effect. Heterogeneity was significant between the different studies (diverse degree of proteinuria, renal function, different drugs and treatment duration) making it difficult to generalize our results to all diabetic nephropathy patients. Data on albuminuria is clouded by the different presentations (geometric means in some, true means in others, and spot urine determination of the albumin to creatinine ratio versus 24 hour urine collection).
Table 2 Albuminuria levels, estimated glomerular filtration rate (eGFR, in ml/min), blood pressure (BP) levels (24 h values when available, in mm Hg) and dropout percentage due to hyperkalemia upon study completion in each group. UACR, urine albumin to creatinine ratio; UPCR, urine protein to creatinine ratio; N/A, not available. Reference
Albuminuria assessment
Standard treatment Albuminuria
Schjoedt et al. [8] Rossing et al. [9] Schjoedt et al. [10] van den Meiracker [11] Epstein et al. [12] Saklayen et al. [13] Mehdi et al. [14] Nielsen et al. [15] a
mg/24 h (geometric mean) mg/24 h (geometric mean) mg/24 h (geometric mean) UACR: mg/g (geometric mean) UACR: mg/g (median) UPCR: mg/g (mean) UACR: mg/g (geometric mean) mg/24 h (geometric mean)
831
Combined treatment c
eGFR 85
BP 144/72
Dropout % a
5
a
Albuminuria 584
c
Combined to standard treatment albuminuria ratio
eGFR
BP
Dropout %
81
136/69
5a
0.70
a
1566
74
138/71
5
1067
71
132/67
5
0.68
3718
64
143/81
0
2510
62
137/77
0
0.68
769 259 1570 691 90
74 72 55 64 78
S.d N.S.e 149/78 N.S.e 135/65
3 2 N/A 0 0
318 124b 790 529 35
59 66b 54 52 72
S.d N.S.e 142/77 N.S.e 133/64
17 8b N/A 7 0
0.41 0.48 0.50 0.77 0.39
Values are overall dropout levels (given the cross-over design of the trials) not permitting the comparison of the two groups. In the eplerenone 100 mg group. Differences in eGFR levels should be interpreted with caution (significant differences in baseline levels due to the exclusion of patients with hyperkalemia). d Raw data were not available. Systolic but not diastolic blood pressure was significantly lower in the combined treatment group. e Raw data were not available. BP levels decreased significantly from baseline. However, difference in BP levels upon study completion is reported to be nonsignificant between the treatment groups. b c
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The impact on proteinuria and GFR may just be attributed to better BP control under dual blockade with reduced transmission of the elevated systemic pressure to the glomeruli. Impaired autoregulation of GFR in diabetic nephropathy may enhance the downstream transmission of BP reduction [8]. BP levels were modestly reduced throughout several of the studies but a significant difference upon study completion between treatment groups was identified in only three of them [9–11]. However, small differences in ambulatory BP could be biologically important, albeit not statistically significant [14]. A simple dose effect in patients under combined treatment cannot be excluded too. Previous studies on dual RAAS blockade (combined ACEI and ARB administration or association of aliskiren with ACEI or ARB) have demonstrated that further decrease in albuminuria levels is not associated with a better outcome in diabetic patients. Indeed, the dual RAAS blockade group exhibited increased incidence of cardiovascular events and acute kidney injury [23,24]. Current studies on combined treatment with ACEI/ARB and MRB do not yet address this issue. Clinicians should be aware of the hyperkalemia risk and regularly check potassium levels when prescribing an MRB, always starting with a low dose (i.e., 12.5 mg per day for spironolactone). More prominent hyperkalemia is awaited in patients with diabetes mellitus and impaired renal function, concomitant use of non-steroidal anti-inflammatory drugs or potassium-sparing diuretics, and among the elderly [25]. Whether the benefits of combined treatment by an ACEI/ARB and an MRB exceed the risks of this association has to be confirmed by an adequately powered prospective comparative clinical trial. Conflicts of interests The authors have no competing interests to declare. Acknowledgments We thank Dr C. Combescure, PhD for his suggestions. References [1] Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin-converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 1995;9:145–9. [2] Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol 2006;17:1362–72. [3] Taira M, Toba H, Murakami M, Iga I, Serizawa R, Murata S, et al. Spironolactone exhibits direct renoprotective effects and inhibits renal renin–angiotensin–aldosterone system in diabetic rats. Eur J Pharmacol 2008;589:264–71. [4] Fujisawa G, Okada K, Muto S, Fujita N, Itabashi N, Kusano E, et al. Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int 2004;66:1493–502.
[5] Guo C, Martinez-Vasquez D, Mendez GP, Toniolo MF, Yao TM, Oestreicher EM, et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology 2006;47:5363–73. [6] Kang YS, Ko GJ, Lee MH, Song HK, Han SY, Han KH, et al. Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats. Nephrol Dial Transplant 2009;24:73–84. [7] Mavrakanas TA, Cheva A, Kallaras K, Karkavelas G, Mironidou-Tzouveleki M. Effect of ramipril alone compared to ramipril with eplerenone on diabetic nephropathy in streptozocin-induced diabetic rats. Pharmacology 2010;86:85–91. [8] Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Tarnow L, et al. Beneficial impacts of spironolactone in diabetic nephropathy. Kidney Int 2005;68:2829–36. [9] Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy. Diabetes Care 2005;28:2106–12. [10] Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 2006;70:536–42. [11] Van den Meiracker AH, Baggen RGA, Pauli S, Lindemans A, Vulto AG, Poldermans D, et al. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens 2006;24:2285–92. [12] 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 2006;1:940–51. [13] Saklayen MG, Gyebi LK, Tasosa J, Yap J. Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind, crossover trial. J Investig Med 2008;56:714–9. [14] 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 2009;20:2641–50. [15] Nielsen SE, Persson F, Frandsen E, Sugaya T, Hess G, Zdunek D, et al. Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo-controlled crossover study. Diabet Med 2012;29:e184–90. [16] Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989;36:272–9. [17] Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int 2004;66:1–9. [18] Bertocchio JP, Warnock DG, Jaisser F. Mineralocorticoid receptor activation and blockade: an emerging paradigm in chronic kidney disease. Kidney Int 2011;79:1051–60. [19] Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003;41:64–8. [20] Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995;47:25–49. [21] Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408–12. [22] Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in metaanalyses? Lancet 1998;352:609–13. [23] ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Pogue J, Dyal L, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547–59. [24] NOVARTIS Media Release: NOVARTIS announces termination of ALTITUDE study. Assessed at http://www.novartis.com/downloads/newsroom/product-related-infocenter/Altitude-Rasilez-Tekturna-press-release.pdf . [on 04.22.2013]. [25] Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensinconverting enzyme inhibitors. How much should we worry? Arch Intern Med 1998;158:26–32.
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: An emerging paradigm in diabetic nephropathy A systematic review Thomas A. Mavrakanas a,⁎, Karim Gariani a, Pierre-Yves Martin b a b
General Internal Medicine Division, Geneva University Hospitals, Geneva, Switzerland Nephrology Division, Geneva University Hospitals, Geneva, Switzerland
a r t i c l e
i n f o
Article history: Received 5 July 2013 Received in revised form 28 October 2013 Accepted 10 November 2013 Available online 4 December 2013 Keywords: Diabetic nephropathy Mineralocorticoid receptor blockade Albuminuria Glomerular filtration rate Blood pressure Hyperkalemia
a b s t r a c t Blockade of the renin–angiotensin–aldosterone system (RAAS) is a standard therapeutic intervention in diabetic patients with chronic kidney disease (CKD). Concomitant mineralocorticoid receptor blockade has been studied as a novel approach to further slow down CKD progression. We used PubMed and EMBASE databases to search for relevant literature. We included in our review eight studies in patients of at least 18 years of age, with a diagnosis of type 1 or type 2 diabetes mellitus and diabetic nephropathy, under an angiotensin converting enzyme inhibitor (ACEI) and/or an angiotensin II receptor blocker (ARB) as standard treatment. A subset of patients in each study also received a mineralocorticoid receptor blocker (MRB) (either spironolactone or eplerenone) in addition to standard treatment. Combined treatment with a mineralocorticoid receptor blocker further reduced albuminuria by 23 to 61% compared with standard treatment. Estimated glomerular filtration rate values upon study completion slightly decreased under combined treatment. Blood pressure levels upon study completion were significantly lower with combined treatment in three studies. Hyperkalemia prevalence increased in patients under combined treatment raising dropout rate up to 17%. Therefore, combined treatment by an ACEI/ARB and a MRB may further decrease albuminuria in diabetic nephropathy. This effect may be due to the specific properties of the MRB treatment. Clinicians should regularly check potassium levels because of the increased risk of hyperkalemia. Available evidence should be confirmed by an adequately powered comparative trial of the standard treatment (ACEI or ARB) versus combined treatment by an ACEI/ARB and a MRB. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Blockade of the renin–angiotensin–aldosterone system (RAAS) is a well-recognized strategy to slow down renal disease progression in diabetic patients with chronic kidney disease (CKD). An angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) is the recommended therapeutic intervention in these patients. Recently, concomitant mineralocorticoid receptor blockade has also been studied as a novel approach to further slow down CKD progression. Concomitant aldosterone blockade attracted more interest when Pitt described a rebound of aldosterone production in patients receiving an ACEI for heart failure [1]. The eventual benefit of aldosterone blockade was then studied in various experimental models of diabetic
nephropathy. Spironolactone, as well as the more selective eplerenone, showed beneficial effects in several animal models of type 1 and type 2 diabetes [2–7]. Despite the encouraging results from experimental studies, largescale randomized prospective trials testing the combined angiotensin– aldosterone blockade have not been conducted in patients with diabetic nephropathy, mainly because of concerns about hyperkalemia. However, smaller clinical studies are available with promising results. Mineralocorticoid receptor blockade emerges as a new paradigm in patients with diabetes and CKD. This paper reviews currently available studies in patients with diabetic nephropathy. 2. Material and methods
⁎ Corresponding author at: Division of General Internal Medicine, Geneva University Hospitals, 4, Rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland. Tel.: +41 79 553 43 24; fax: +41 22 372 91 16. E-mail address: [email protected] (T.A. Mavrakanas).
We used PubMed and EMBASE databases as well as the Cochrane Register of Clinical Trials to search for relevant literature (indexed up to October 2012). We searched for published clinical trials in English
0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.11.007
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language, including patients of at least 18 years of age, with a diagnosis of type 1 or type 2 diabetes mellitus and diabetic nephropathy (defined as at least 30 mg of albuminuria in a 24-h urine collection or an albumin to creatinine ratio of at least 30 mg/g of creatinine). They should have received an ACEI and/or an ARB at an adequate dose throughout the study as standard treatment. To evaluate the effect of concomitant mineralocorticoid receptor blockade, a subset of patients in each study should also receive a mineralocorticoid receptor blocker (MRB) (either spironolactone or eplerenone) in addition to standard RAAS blockade. We also checked the reference list of the retrieved articles. Two authors independently performed study selection and extracted information from each included trial. The key words used for literature research in Pubmed, EMBASE and the Cochrane Register were diabetic nephropathy and aldosterone blockade, mineralocorticoid receptor blockade, spironolactone or eplerenone. Discrepancies between authors' assessments were resolved by mutual discussion of each item in question. Our primary objective was to compare the albuminuria levels in each study group upon study completion, assessed either by 24-h urine collection or a urine spot with calculation of the albumin to creatinine ratio. The secondary efficacy outcome was estimated glomerular filtration rate (GFR) and blood pressure (BP) levels in each group at the end of the study. The safety outcome was the dropout rate due to hyperkalemia. All studies were of sufficient methodological quality as assessed by the Jadad score (Table 1). The small number of the included studies, the different presentations of the primary outcome, and the heterogeneous design do not permit to perform a meta-analysis on available data. Nevertheless, the three trials from the Steno Diabetes Center included the same patients in more than one study [8–10]. They should be considered together and do not have the impact of three independent studies. Therefore, results are presented in the form of a systematic review. 3. Results We initially retrieved 103 English-language papers on MRB in diabetic nephropathy. There were only 17 human studies addressing our research question (Fig. 1). After reviewing the full article, we further excluded 9 studies: four used spironolactone monotherapy or loop diuretics, two studies also included patients without diabetic nephropathy, one was conducted only in patients with documented elevated aldosterone levels (aldosterone rebound), one was actually a comment on an already published study, and for one study major remarks concerning the results accuracy were published. In Table 1, we summarize the characteristics of the eight selected studies [8–15]. Table 2 shows the albuminuria levels upon study completion in each group (standard treatment versus MRB combined to standard treatment) as well as the dropout cases due to hyperkalemia. Albuminuria values were either directly reported in the articles or calculated from the percentage of change and the available baseline levels. Combined treatment further reduced albuminuria by 23 to 61% compared with standard treatment. Creatinine values upon study completion were available in only five trials and were largely overlapping. Data on estimated GFR were available for both groups in all studies. GFR values in patients also receiving
MRBs were inferior to GFR values in patients on standard treatment. However, baseline values were significantly different in the studied groups due to the exclusion of patients with hyperkalemia. Therefore, direct comparison of GFR values at study completion would be of limited interest (Table 2). BP decreased significantly from baseline with standard and combined treatment in three studies [11,12,14]. A significant difference in BP levels upon study completion between the two treatment groups was identified in three studies [9–11]. Data are summarized in Table 2. Hyperkalemia prevalence increased in patients under combined ACEI/ARB and MRB treatment compared with patients receiving standard treatment. Dropout significantly increased (up to 17%) under combined treatment in only two studies [11,14]. No deaths were reported secondary to hyperkalemia. No other serious side effects were reported.
4. Discussion In this systematic review, we used currently available evidence in order to compare standard treatment by an ACEI or an ARB with combined treatment by an ACEI/ARB and a MRB in patients with diabetic nephropathy. Short term combined treatment reduced urinary albumin excretion in all studies. Estimated GFR values upon study completion slightly decreased under combined treatment. However, hyperkalemia incidence increased in the combined treatment group necessitating MRB interruption in up to 17% of cases. Therefore, combined treatment by an ACEI/ARB and a MRB is effective in decreasing albuminuria in diabetic nephropathy but increases the risk of hyperkalemia. The antiproteinuric effect of ACEIs or ARBs is more prominent in patients on a low sodium diet or who are treated with diuretics because relative hypovolemia results in greater angiotensin-II dependence of the glomerular microcirculation [16]. Further reduction of proteinuria in patients on combined treatment may be due to the specific properties of the MRB treatment. Selective blockade at the mineralocorticoid receptor (MR) level has been demonstrated to reverse the changes in glomerular vascular barrier and reduce intraglomerular hydraulic pressure. Furthermore, MRB may prevent renal fibrosis, mesangial expansion and glomerulosclerosis via its action on TGF-β1, PAI-1, local oxidative stress and endothelial function [17,18]. Aldosterone rebound, i.e. a rebound in aldosterone plasma levels after a transient decrease, has been detected in 40% of patients with early diabetic nephropathy treated by an ACEI [19]. Therefore, pharmacological MR blockade may be of significant benefit in these patients. It must be noted that patients under standard treatment received either an ACEI or an ARB. These two drug classes do not have the same pharmacological properties. ACEI treatment reduces angiotensin II levels. On the other hand, ARBs significantly increase angiotensin II levels with subsequent stimulation of the type 2 angiotensin II receptor (AT2). ACEIs and ARBs also do not share the same characteristics concerning their effect on bradykinin catabolism and nitric oxide levels [20]. Unfortunately, the six studies with patients on either an ACEI or an ARB upon inclusion do not provide any sub-group analysis according to the standard treatment [8–11,13,15]. Therefore, the differences between standard
Table 1 Characteristics of the 8 selected studies. N, number of patients randomized in the study; MRB, mineralocorticoid receptor blocker; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker. Reference
Standard treatment
Studied MRB
Design
N
Duration
Jaddad score
Schjoedt et al. [8] Rossing et al. [9] Schjoedt et al. [10] van den Meiracker [11] Epstein et al. [12] Saklayen et al. [13] Mehdi et al. [14] Nielsen et al. [15]
ACEI or ARB ACEI or ARB ACEI or ARB ACEI or ARB Enalapril Lisinopril-losartan Lisinopril 80 mg ACEI or ARB
Spironolactone 25 mg Spironolactone 25 mg Spironolactone 25 mg Spironolactone 50 mg Eplerenone 50–100 mg Spironolactone 25–50 mg Spironolactone 25 mg Spironolactone 25 mg
Cross-over Cross-over Cross-over Cluster-randomized Cluster-randomized Cross-over Cluster-randomized Cross-over
22 21 20 59 177 30 54 21
2 months (each phase) 2 months (each phase) 2 months (each phase) 1 year 12 weeks 3 months (each phase) 48 weeks 2 months (each phase)
5 5 5 5 3 4 5 5
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175
Fig. 1. Search results and studies selection.
and combined treatment may be interpreted with caution, as an MRB may not have the same effect when added to an ACEI or an ARB. Concerning the impact on GFR, decreased GFR levels in patients receiving an MRB may be due to a drop in intra-glomerular pressure. In such a case, the fall in GFR would turn out to be a favorable event heralding better preservation of renal glomeruli over time. However, GFR was not measured by creatinine clearance in 24-hour urine collection but derived from plasma creatinine values using empiric formulas. No conclusion on the combined treatment effect on renal function can be drawn, as none of these studies was adequately powered for this endpoint. Eight studies met our inclusion criteria; three cluster randomized studies and five crossover trials. However, the number of included
patients was small with the studies being more inclined to report a positive effect [21,22]. Follow-up was rather of limited duration (2–3 months) with only two studies following the patients for 48– 52 weeks. The three studies from the Steno diabetes center may have included at least in part the same patients as acknowledged by the authors [8–10]. The absence of negative studies may be due to a publication bias effect. Heterogeneity was significant between the different studies (diverse degree of proteinuria, renal function, different drugs and treatment duration) making it difficult to generalize our results to all diabetic nephropathy patients. Data on albuminuria is clouded by the different presentations (geometric means in some, true means in others, and spot urine determination of the albumin to creatinine ratio versus 24 hour urine collection).
Table 2 Albuminuria levels, estimated glomerular filtration rate (eGFR, in ml/min), blood pressure (BP) levels (24 h values when available, in mm Hg) and dropout percentage due to hyperkalemia upon study completion in each group. UACR, urine albumin to creatinine ratio; UPCR, urine protein to creatinine ratio; N/A, not available. Reference
Albuminuria assessment
Standard treatment Albuminuria
Schjoedt et al. [8] Rossing et al. [9] Schjoedt et al. [10] van den Meiracker [11] Epstein et al. [12] Saklayen et al. [13] Mehdi et al. [14] Nielsen et al. [15] a
mg/24 h (geometric mean) mg/24 h (geometric mean) mg/24 h (geometric mean) UACR: mg/g (geometric mean) UACR: mg/g (median) UPCR: mg/g (mean) UACR: mg/g (geometric mean) mg/24 h (geometric mean)
831
Combined treatment c
eGFR 85
BP 144/72
Dropout % a
5
a
Albuminuria 584
c
Combined to standard treatment albuminuria ratio
eGFR
BP
Dropout %
81
136/69
5a
0.70
a
1566
74
138/71
5
1067
71
132/67
5
0.68
3718
64
143/81
0
2510
62
137/77
0
0.68
769 259 1570 691 90
74 72 55 64 78
S.d N.S.e 149/78 N.S.e 135/65
3 2 N/A 0 0
318 124b 790 529 35
59 66b 54 52 72
S.d N.S.e 142/77 N.S.e 133/64
17 8b N/A 7 0
0.41 0.48 0.50 0.77 0.39
Values are overall dropout levels (given the cross-over design of the trials) not permitting the comparison of the two groups. In the eplerenone 100 mg group. Differences in eGFR levels should be interpreted with caution (significant differences in baseline levels due to the exclusion of patients with hyperkalemia). d Raw data were not available. Systolic but not diastolic blood pressure was significantly lower in the combined treatment group. e Raw data were not available. BP levels decreased significantly from baseline. However, difference in BP levels upon study completion is reported to be nonsignificant between the treatment groups. b c
176
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The impact on proteinuria and GFR may just be attributed to better BP control under dual blockade with reduced transmission of the elevated systemic pressure to the glomeruli. Impaired autoregulation of GFR in diabetic nephropathy may enhance the downstream transmission of BP reduction [8]. BP levels were modestly reduced throughout several of the studies but a significant difference upon study completion between treatment groups was identified in only three of them [9–11]. However, small differences in ambulatory BP could be biologically important, albeit not statistically significant [14]. A simple dose effect in patients under combined treatment cannot be excluded too. Previous studies on dual RAAS blockade (combined ACEI and ARB administration or association of aliskiren with ACEI or ARB) have demonstrated that further decrease in albuminuria levels is not associated with a better outcome in diabetic patients. Indeed, the dual RAAS blockade group exhibited increased incidence of cardiovascular events and acute kidney injury [23,24]. Current studies on combined treatment with ACEI/ARB and MRB do not yet address this issue. Clinicians should be aware of the hyperkalemia risk and regularly check potassium levels when prescribing an MRB, always starting with a low dose (i.e., 12.5 mg per day for spironolactone). More prominent hyperkalemia is awaited in patients with diabetes mellitus and impaired renal function, concomitant use of non-steroidal anti-inflammatory drugs or potassium-sparing diuretics, and among the elderly [25]. Whether the benefits of combined treatment by an ACEI/ARB and an MRB exceed the risks of this association has to be confirmed by an adequately powered prospective comparative clinical trial. Conflicts of interests The authors have no competing interests to declare. Acknowledgments We thank Dr C. Combescure, PhD for his suggestions. References [1] Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin-converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 1995;9:145–9. [2] Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol 2006;17:1362–72. [3] Taira M, Toba H, Murakami M, Iga I, Serizawa R, Murata S, et al. Spironolactone exhibits direct renoprotective effects and inhibits renal renin–angiotensin–aldosterone system in diabetic rats. Eur J Pharmacol 2008;589:264–71. [4] Fujisawa G, Okada K, Muto S, Fujita N, Itabashi N, Kusano E, et al. Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int 2004;66:1493–502.
[5] Guo C, Martinez-Vasquez D, Mendez GP, Toniolo MF, Yao TM, Oestreicher EM, et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology 2006;47:5363–73. [6] Kang YS, Ko GJ, Lee MH, Song HK, Han SY, Han KH, et al. Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats. Nephrol Dial Transplant 2009;24:73–84. [7] Mavrakanas TA, Cheva A, Kallaras K, Karkavelas G, Mironidou-Tzouveleki M. Effect of ramipril alone compared to ramipril with eplerenone on diabetic nephropathy in streptozocin-induced diabetic rats. Pharmacology 2010;86:85–91. [8] Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Tarnow L, et al. Beneficial impacts of spironolactone in diabetic nephropathy. Kidney Int 2005;68:2829–36. [9] Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy. Diabetes Care 2005;28:2106–12. [10] Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 2006;70:536–42. [11] Van den Meiracker AH, Baggen RGA, Pauli S, Lindemans A, Vulto AG, Poldermans D, et al. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens 2006;24:2285–92. [12] 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 2006;1:940–51. [13] Saklayen MG, Gyebi LK, Tasosa J, Yap J. Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind, crossover trial. J Investig Med 2008;56:714–9. [14] 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 2009;20:2641–50. [15] Nielsen SE, Persson F, Frandsen E, Sugaya T, Hess G, Zdunek D, et al. Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo-controlled crossover study. Diabet Med 2012;29:e184–90. [16] Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989;36:272–9. [17] Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int 2004;66:1–9. [18] Bertocchio JP, Warnock DG, Jaisser F. Mineralocorticoid receptor activation and blockade: an emerging paradigm in chronic kidney disease. Kidney Int 2011;79:1051–60. [19] Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003;41:64–8. [20] Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995;47:25–49. [21] Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408–12. [22] Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in metaanalyses? Lancet 1998;352:609–13. [23] ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Pogue J, Dyal L, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547–59. [24] NOVARTIS Media Release: NOVARTIS announces termination of ALTITUDE study. Assessed at http://www.novartis.com/downloads/newsroom/product-related-infocenter/Altitude-Rasilez-Tekturna-press-release.pdf . [on 04.22.2013]. [25] Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensinconverting enzyme inhibitors. How much should we worry? Arch Intern Med 1998;158:26–32.
