Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Addition of spironolactone (SPR) to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) might provide antiproteinuric effects beyond what is gained by either medication alone. This study was designed to assess the long-term efficacy of SPR/ARB combination in comparison with the standard ACE/ARB regimen in diabetic nephropathy.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>In an open-label, parallel-group, single-center, randomized clinical trial (NCT01667614), 136 patients with diabetes and proteinuria, already treated with enalapril and losartan, were included. In 74 patients, ACE inhibitors were discontinued. After a wash-out period of 2 weeks, 25 mg SPR daily was initiated. The remainder of the patients (n = 62) received ACE inhibitors and ARBs as before. Patients were followed every 3 months for 18 months. During each visit, systolic and diastolic blood pressure (BP), urinary albumin excretion (UAE), serum creatinine, estimated glomerular filtration rate (eGFR) and serum potassium concentrations were determined.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>After 18 months, three patients in the SPR/ARB group developed asymptomatic hyperkalemia. SPR/ARB significantly reduced both systolic and diastolic BP (P &amp;lt; 0.001 and 0.001, respectively). SPR/ARB decreased UAE by 46, 72 and 59% after 3, 12 and 18 months, respectively. Compared with the continuation regimen, SPR/ARB was superior in UAE reduction (P = 0.017 after 18 months), independent of BP change. In both groups, eGFR declined significantly over the trial course and the decline rate did not differ significantly between the two groups.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Addition of SPR to ARB provides added benefits with respect to BP control and proteinuria diminution. These antiproteinuric effects are not accompanied by prevention of eGFR loss compared with conventional therapy with ACE/ARB.</jats:p> </jats:sec>

Effects of Spironolactone in Combination with Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Patients with Proteinuria

“…A progressive decline in eGFR was observed in all groups, which is consistent with previous observations [17,18,19]. The proportion of patients that experienced a rise of 30% above baseline in serum creatinine after a median of 34 days was 39.1% [18].…”

“…The proportion of patients that experienced a rise of 30% above baseline in serum creatinine after a median of 34 days was 39.1% [18]. In another study of 136 patients, the eGFR showed a decline from 74.39 to 64.16 mL/min/1.73 m 2 after 12 months of treatment with spironolactone [19]. Our data revealed that the eGFR reduces by about 18 mL/min/1.73 m 2 in patients with 1≤UACR<3.5 g/g creatinine, which is higher than the finding of previous studies however, this reduction seems to be transient and could be restored.…”

Spironolactone Add-on for Preventing or Slowing the Progression of Diabetic Nephropathy: A Meta-analysis

“…From a total of 236 potentially eligible studies, 220 were excluded because they were not relevant to the study objectives; were reviews, meeting abstracts, case-only studies (ie, a control group [in which control medication or placebo was added to standard AD/RP/AHT treatment] was not included); or contained no detailed, usable data necessary for the meta-analysis. A total of 16 studies 23,28,34,35,[42][43][44][45][46][47][48][49][50][51][52][53] were included in the present metaanalysis and are described in the table (see also Supplemental Tables 1A-3B in the online version 28,34,43,45,47,49,52,53 ; and hyperkalemia, 12 studies (spironolactone, 319; control, 295). 28,34,35,[43][44][45][46]48,49,50,52,53 Effects of the Addition of Spironolactone on Urinary Protein/Albumin Excretion Compared with controls, the addition of spironolactone to standard AD/RP/AHT treatment significantly reduced end-of-treatment 24-hour urinary albumin/protein excretion (MD = -61.48; 95% CI, -96.74 to -26.23; P = 0.0006) (Figure 2A).…”

“…[30][31][32][33] There have also been reports that adding spironolactone to standard RP treatment provided added benefit in terms of proteinuria reduction and BP control. 34,35 However, large-scale, prospective clinical studies of the effects of adding spironolactone to standard RP treatment have not yet been conducted in patients with DN, mainly because of the reported hyperkalemia associated with spironolactone use. 36 There has been 1 meta-analysis of the effects of adding an aldosterone antagonist to ACEI/ARB treatment in patients with chronic kidney disease (CKD) 26 ; however, it was conducted in 2008 and thus did not include numerous later studies, and further it was not limited to DN and thus the effects of the addition of spironolactone in patients with DN was not specifically analyzed.…”

Polymorphisms in VEGFA gene affect the antihypertensive responses to enalapril

“…Patients were never treated (n=75) or underwent a washout period for at least 2 weeks (n=27). This washout period has been widely used [33][34][35][36] and described to be sufficient to eliminate the effects of previous antihypertensive treatments on physiological parameters [37]. Patients underwent a complete medical history, physical examination, and laboratory analysis to exclude subjects with evidence of severe or secondary hypertension; other concomitant cardiovascular diseases; or respiratory, hepatic, renal, or hematological dysfunction.…”