Role of Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease
Abstract
:1. Introduction
2. Pleiotropic Effects of Aldosterone in Diabetic Kidney Disease
2.1. Physiological Role of Aldosterone and Mechanisms of Ligand-Specific Activation of Mineralocorticoid Receptors
2.2. Aldosterone Breakthrough and Potential Mechanisms of Aldosterone-Induced Diabetic Kidney Disease and Cardiac Damage
3. Clinical Studies of Mineralocorticoid Receptor Antagonism in Diabetic Kidney Disease
3.1. Effect of Mineralocorticoid Receptor Antagonists in Albuminuria/Proteinuria and Kidney-Related Outcomes
3.1.1. Spironolactone
3.1.2. Eplerenone
3.1.3. Finerenone
3.1.4. Canrenone
3.1.5. Esaxerenone
3.1.6. Apararenone
Study | Study Design | Follow UP | Nr of Patients | Patient Characteristics | Active Treatment | Comparator | Back- Ground Treatment | Main Results |
---|---|---|---|---|---|---|---|---|
Fogari et al., 2014 [57] | Open-label, parallel- group RCT | 24 weeks | 120 | T2DM and UACR 60–300 mg/g | Canrenone | Hydrochlorothiazide | Valsartan | ↓ UACR −45.3% for canrenone; −20.3% for hydrochlorothiazide (p < 0.01) |
Derosa et al., 2018 [90] | Double-blind, parallel-group RCT | 12 months | 182 | T2DM and hypertension | Canrenone | Hydrochlorothiazide | ARB | Significant ↓ K only for hydrochlorothiazide (p < 0.05); neutral effect for canrenone Significant ↓ eGFR for hydrochlorothiazide (p < 0.01) Significant ↑ eGFR for canrenone (p < 0.05) |
Ito et al., 2019 [91] | Double-blind, parallel-group RCT | 12 weeks | 365 | T2DM, UACR 45–300 mg/g, eGFR ≥ 30 mL/min/1.73 m2 | Esaxerenone | Placebo | ACEi or ARB | ↓ UACR −38% for esaxerenone 1.25 mg; −50% for esaxerenone 2.5 mg; −56% for esaxerenone 5 mg; −7% for placebo (p < 0.001) Remission of albuminuria: 21% for esaxerenone groups 2.5 and 5.0 mg; 3% for placebo (p < 0.05 for both comparisons) HyperK leading to drug discontinuation: 3% for esaxerenone 1.25 and 2.5 mg; 10% esaxerenone 10 mg; 1% for placebo |
Ito et al., 2020 (ESAX-DN) [92] | Double-blind, parallel-group RCT | 52 weeks | 455 | T2DM, UACR 45–300 mg/g, eGFR ≥ 30 mL/min/1.73 m2 | Esaxerenone | Placebo | ACEi or ARB | ↓ UACR −58% for esaxerenone; +8% for placebo (p < 0.001); eGFR −11% for esaxerenone; −1% for placebo Remission of albuminuria: 22% in esaxerenone; 4% in placebo (p < 0.001) Time to 1st transition to overt proteinuria: HR 0.23; 95%CI 0.11–0.48 for esaxerenone HyperK episodes (>6.0 mmol/L or ≥5.5 mmol/L at two consecutive occasions): 9% esaxerenone; 2% placebo (p = 0.002) HyperK leading to drug discontinuation: 4% for esaxerenone; 1% for placebo |
Ito et al., 2021 [93] | Open-label, single-arm study | 28 weeks | 56 | T2DM, UACR ≥ 300 mg/g, eGFR ≥ 30 mL/min/1.73 m2 | Esaxerenone | - | ACEi or ARB | ↓ UACR −54.6% (p < 0.001); eGFR −8.3 mL/min /1.73 m2 for esaxerenone HyperK episodes (>6.0 mmol/L or ≥5.5 mmol/L at two consecutive occasions): 5.4% for esaxerenone |
Wada et al., 2021 [62] | Double-blind, parallel-group RCT with open-label extension | 24 weeks and 28 weeks | 293 | T2DM, UACR 50–300 mg/g | Apararenone | Placebo | ACEi or ARB | ↓ UACR at 23 weeks −62.9% apararenone 2.5 mg; −50.8% apararenone 5 mg; −46.5% apararenone 10 mg; +113.7% placebo (p < 0.001 vs. placebo for all comparisons) % change in eGFR at 52 weeks: −5.3% (−22.0, +10.5) apararenone 2.5 mg; −10.2% (−34.5, +14.6) apararenone 5 mg; −10.80% (−36.8, +19.1) apararenone 10 mg ↑ K at 52 weeks: +0.14 mmol/L (0.006–0.22) apararenone 2.5 mg; +0.18 mmol/L (0.1–0.26) apararenone 5 mg; +0.25 mmol/L (0.16–0.33) apararenone 10 mg |
3.2. Meta-Analyses of Randomized Clinical Studies with Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease
4. Future Directions and Perspectives
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Study | Study Design | Follow Up | Nr of Patients | Patient Characteristics | Comparator | Back- Ground Treatment | Main Results |
---|---|---|---|---|---|---|---|
Sato et al., 2003 [63] | Open-label, single-arm study | 24 weeks | 13 | T2DM, UACR 30–300 mg/g and creatinine clearance > 60 mL/min | - | Trandolapril | ↓ UAE and LVMI for spironolactone (p < 0.05 for both) Non-significant ↑ K (before 4.2 ± 0.3 mEq/L; after 4.3 ± 0.2 mEq/L) |
Rossing et al., 2005 [65] | Double-blind, cross-over RCT | 8 weeks | 21 | T2DM and UAE > 300 mg/24 h | Placebo | ACEi or ARB | ↓ UAE −33% (95%CI −41%, −25%); 24 h SBP −6 mmHg (95%CI −10, −2); 24 h DBP −4 mmHg (95%CI −6, −2); eGFR −3 mL/min/1.73 m2 (95%CI −0.3, +6.0) for spironolactone |
Schjoedt et al., 2005 [66] | Double-blind, cross-over RCT | 8 weeks | 20 | T1DM and UAE > 300 mg/24 h | Placebo | ACEi or ARB | ↓ UAE −30% (95%CI −41%, –17%); 24 h SBP −8 mmHg (95%CI −17, +1); 24 h DBP −3 mmHg (95%CI −7, +0.2); eGFR by −3.4 mL/min/ 1.73 m2 (−6.9, 0.1) for spironolactone 1 patient excluded due to hyperK in spironolactone |
Schjoedt et al., 2006 [67] | Double-blind, cross-over RCT | 8 weeks | 20 | T1DM or T2DM and UAE > 2500 mg/24 h | Placebo | ACEi or ARB | ↓ UAE −32% (95%CI −42%, −21%); 24 h SBP −6 mmHg (95%CI −10, −2); 24 h DBP −4 mmHg (95%CI −6, −2); eGFR −3 mL/min/1.73 m2 (−6.0, +1.0) ↑ K +0.2 mmol/L (95%CI −0.004, +0.5) |
van den Meiracker, 2006 [68] | Double-blind, parallel-group RCT | 1 year | 59 | T2DM and UAE > 300 mg/24 h or UACR > 20 mg/g | Placebo | ACEi or ARB | ↓ UAE −40.6% (95%CI −57.8%, −23.4%); 24 h SBP −7 mmHg (95%CI −12, −2); 24 h DBP −3 mmHg (95%CI −6, −1) eGFR −12.9 mL/min/1.73 m2 (−16.5, −9.5) for spironolactone; −4.9 mL/min/1.73 m2 (−8.9, −0.8) for placebo 5 patients excluded due to hyperK in spironolactone |
Saklayen et al., 2008 [69] | Double-blind, cross-over RCT | 7 weeks | 30 | T1DM or T2DM patients with any level of proteinuria | Placebo | ACEi or ARB | ↓ UPCR from 1.80 ± 1.78 to 0.79 ± 0.99 for spironolactone (p = 0.004); from 1.24 ± 1.13 to 1.57 ± 2.13 for placebo (p = 0.35); eGFR from 61.91 ± 23.4 to 53.94 ± 23.58 for spironolactone (p = 0.0001) |
Mehdi et al., 2009 [70] | Double-blind parallel-group RCT | 48 weeks | 81 | T1DM or T2DM patients and UACR > 300 mg/g | Placebo, Losartan 100 mg | Lisinopril 80 mg | ↓ UACR −34% (95%CI −51%, −11.2%) for spironolactone (p = 0.007 vs. placebo); −16.8% (95%CI −37.3%, +10.5%) for losartan (p = 0.2 vs. placebo); % change in creatinine clearance −13.1% (95%CI −21.3%, −3.9%) for spironolactone; −16.8% (95%CI −23.9%, −9.1%) for losartan; −16.0% (95% CI −23.3%, −7.9%) for placebo HyperK episodes (>6.0 mmol/L): 14 patients in spironolactone (p < 0.001 vs. placebo); 10 in losartan (p = 0.009 vs. placebo); 2 patients in placebo |
Nielsen et al., 2012 [71] | Double-blind, cross-over RCT | 60 days | 21 | T1D and UAE > 30 mg/day | Placebo | ACEi or ARB | ↓ UACR −60% (range −80% to −21%); eGFR from 78 ± 6 to 72 ± 6 mL/min/1.73 m2 (p = 0.003) HyperK episodes (>5.7 mmol/L): 2 patients in spironolactone group |
Ziaee et al., 2013 [72] | Parallel-group RCT | 12 weeks | 60 | T2DM and microalbuminuria | Placebo | Enalapril | ↓ UACR from 126 ± 69.3 to 59.3 ± 48.1 for spironolactone (p < 0.001); eGFR from 79.8 ± 18 to 75.6 ± 16.3 mL/min/1.73 m2 for spironolactone (p = 0.6) |
Esteghamati et al., 2013 [73] | Open-label, parallel-group RCT | 18 months | 136 | T2DM and UAE ≥ 30 mg/day | Enalapril | Losartan | ↓ UAE −60.5 mg (95%CI −148.8, −16.4) for spironolactone; +22.0 mg (95%CI −110.3, +108.9) for placebo (p = 0.017); SBP −8.89 mmHg (95%CI −15.88, −1.89) for spironolactone; −6.08 mmHg (−14.71, +2.57) for placebo (p < 0.001); DBP −4.44 mmHg (95%CI −8.10, −0.79) for spironolactone; −2.86 (−7.06, +1.34) for placebo (p = 0.001); eGFR −10.23 mL/min/1.73 m2 (95%CI −16.69, −3.76) for spironolactone; −9.08 mL/min/1.73 m2 (−16.06, −2.10) for placebo (p = 0.674) |
Oxlund et al., 2013 [13] | Double-blind, parallel-group RCT | 16 weeks | 119 | T2DM and resistant hypertension | Placebo | ACEi or ARB | ↓ UACR −7.3 mg/g (95%CI −1093, +12.2) for spironolactone; +0 mg/g (95% +7, +146.3) for placebo (p = 0.001); placebo-corrected 24 h SBP −8.9 mmHg (95%CI −13.2, −4.6); placebo-corrected 24 h DBP −3.9 mmHg (95%CI −6.2, −1.7) ↑ K +0.26 mmol/L (95%CI +0.1, +0.4) for spironolactone; +0.02 (95%CI +0.07, +0.10) for placebo (between-group p < 0.001) |
Kato et al., 2015 [74] | Open-label parallel-group RCT | 8 weeks | 52 | T2DM and UACR 100–2000 mg/g | Placebo | ACEi or ARB | ↓ UACR −33% (95%CI −54%, −22%); eGFR −3.2 ± 9.7 mL/min/1.73 m2 (p = 0.052) |
Chen et al., 2018 [75] | Open-label, parallel-group RCT | 72 weeks | 244 | T2DM and UAER 20–199 μg/min | Placebo | Irbesartan 150 mg or 300 mg | ↓ UAΕR −30 μg/min (95%CI −54, −15) for spironolactone/irbesartan 300 mg; −30 μg/min (95%CI −51, −12) for spironolactone/irbesartan 150 mg; −23 μg/min (95%CI −35, −12) for irbesartan 300 mg; −15 μg/min (95%CI −24, −11) for irbesartan 150 mg (between-group p < 0.001) |
Study | Study Design | Follow Up | Nr of Patients | Patient Characteristics | Comparator | Back- Ground Treatment | Main Results |
---|---|---|---|---|---|---|---|
Epstein et al., 2006 [77] | Double-blind, parallel-group RCT | 12 weeks | 268 | T2DM and UACR ≥ 50 mg/g | Placebo | Enalapril 20 mg | ↓ UACR −41% for eplerenone 50 mg; −48.4% for eplerenone 100 mg; −7.4% for placebo (p < 0.001 vs. placebo for both) Between-group differences in sustained hyperK (>5.5 mmol/L on two consecutive measurements) p = 0.29; severe hyperK (≥6.0 mmol/L at any timepoint) p = 0.38 |
Brandt-Jacobsen et al., 2020 (MIRAD trial) [79] | Double-blind, parallel-group RCT | 26 weeks | 140 | T2DM, median UACR 17 mg/g, 12% had eGFR < 60 mL/min/1.73 m2 | Placebo | Antihypertensive treatment | ↓ UACR by −34% for eplerenone vs. placebo (p = 0.005); eGFR −3.5 mL/min/1.73 m2 for eplerenone Between-group differences in episodes of hyperkalemia (≥5.5 mmol/L) p = 0.276 ↑ K by +0.26 mmol/L for eplerenone |
Mokadem et al., 2020 [78] | Single-blind, parallel-group RCT | 24 weeks | 75 | T2DM and UACR 30–300 mg/g and stage 1 hypertension | Treatment groups: Eplerenone/ramipril combination, ramipril monotherapy, eplerenone monotherapy | ↓ UACR −70% for eplerenone/ramipril; −37% for ramipril; −38% for eplerenone (p < 0.0001 for combination vs. both others) HyperK episodes (>5.5 mmol/L on 2 measurements): 8% for eplerenone/ramipril; 4% for ramipril; 4% for eplerenone (for eplerenone/ramipril vs. others p = 0.5, ramipril vs. eplerenone p = 0.6); for eGFR < 60 mL/min/1.73 m2: ↑ incidence of hyperK for eplerenone/ramipril vs. others (p < 0.05) |
Study | Study Design | Follow UP | Nr of Patients | Patient Characteristics | Comparator | Back- Ground Treatment | Main Results |
---|---|---|---|---|---|---|---|
Bakris et al., 2015 (ARTS-DN) [80] | Double-blind, parallel-group RCT | 90 days | 821 (4 different finerenone dose groups) | T2DM and UACR 30 to <300 mg/g or >300 mg/g (stratified randomization) | Placebo | ACEi or ARB | ↓ placebo-corrected mean ratio of UACR at day 90 relative to baseline: finerenone 7.5 mg 0.79 (p = 0.004); finerenone 10 mg 0.76 (p = 0.001); finerenone 15 mg 0.67 (p < 0.001); finerenone 20 mg 0.62 (p < 0.001) Significantly ↑ incidence of hyperK episodes leading to study discontinuation: finerenone 7.5 mg 2.1%, finerenone 15 mg 3.2% and finerenone 20 mg 1.7% No significant ↑ in the risk of hyperkalemia for placebo and finerenone 10 mg |
Katayama et al., 2017 [81] | Double-blind, parallel-group RCT | 90 days | 96 (4 different finerenone dose groups) | T2DM and UACR 30 to <300 mg/g or >300 mg/g (stratified randomization) | Placebo | ACEi or ARB | ↓ LS mean ratio of finerenone to baseline (0.712); LS mean ratio of finerenone to placebo (0.670) for finerenone 20 mg (p = 0.0240) ↑ K for finerenone (+0.025, +0.167 mmol/L) vs. placebo (−0.075 mmol/L) |
Bakris et al., 2020 (FIDELIO- DKD) [23] | Double-blind, parallel-group RCT | 2.6 years | 5734 | T2DM and: (a) UACR 300–5000 mg/g and eGFR 25–75 mL/min/1.73 m2 or (b) UACR 30–300 mg/g, eGFR 25–60 mL/min/1.73 m2, diabetic retinopathy | Placebo | ACEi or ARB | Primary composite endpoint of kidney failure (ESKD or eGFR < 15 mL/min/1.73 m2), eGFR decrease of ≥40%, renal death: HR 0.82; 95% CI 0.73–0.93 Secondary: kidney failure HR 0.87; 95% CI 0.72–1.05; eGFR decrease of ≥40% HR 0.81; 95% CI 0.72–0.92 Secondary composite endpoint of kidney failure (ESKD or eGFR <15 mL/min/1.73 m2), eGFR decrease of ≥57%, renal death: HR 0.76; 95% CI 0.65–0.90 Secondary composite endpoint of CV death, nonfatal MI/stroke, HHF: HR 0.86; 95% CI 0.75–0.99 Secondary: CV death HR 0.86; 95% 0.68–1.08; nonfatal MI HR 0.80; 95% CI 0.58–1.09; nonfatal stroke: HR 1.03; 95%CI 0.76–1.38; HHF HR 0.86; 95%CI 0.68–1.08HyperK leading to drug discontinuation: 2.3% for finerenone; 0.9% for placebo Pre-specified secondary analysis: new-onset AF HR 0.71, 95%CI 0.53–0.94; fatal/nonfatal stroke after new-onset AF: HR 7.13; 95%CI 4.01–12.70 |
Pitt et al., 2021 (FIGARO- DKD) [24] | Double-blind, parallel-group RCT | 3.4 years | 7437 | T2DM and: (a) UACR 30–300 mg/g, eGFR ≥ 25–90 mL/min/ 1.73 m2 or (b) UACR 300–5000 mg/g, eGFR ≥ 60 mL/min/1.73 m2 | Placebo | ACEi or ARB | Primary composite endpoint of CV death, nonfatal MI/stroke, HHF: HR 0.87; 95%CI 0.76–0.98 Secondary: HHF HR 0.71; 95%CI 0.56–0.90 Secondary composite endpoint of kidney failure (ESKD or eGFR <15 mL/min/1.73 m2), eGFR decrease of ≥40%, renal death: HR 0.87; 95%CI 0.76–1.01 Secondary: ESKD HR 0.64, 95%CI 0.41–0.995HyperK leading to drug discontinuation: 1.2% finerenone; 0.4% placebo |
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Alexandrou, M.-E.; Theodorakopoulou, M.P.; Sarafidis, P.A. Role of Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease. Kidney Dial. 2022, 2, 163-182. https://doi.org/10.3390/kidneydial2020019
Alexandrou M-E, Theodorakopoulou MP, Sarafidis PA. Role of Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease. Kidney and Dialysis. 2022; 2(2):163-182. https://doi.org/10.3390/kidneydial2020019
Chicago/Turabian StyleAlexandrou, Maria-Eleni, Marieta P. Theodorakopoulou, and Pantelis A. Sarafidis. 2022. "Role of Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease" Kidney and Dialysis 2, no. 2: 163-182. https://doi.org/10.3390/kidneydial2020019
APA StyleAlexandrou, M.-E., Theodorakopoulou, M. P., & Sarafidis, P. A. (2022). Role of Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease. Kidney and Dialysis, 2(2), 163-182. https://doi.org/10.3390/kidneydial2020019