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Original Article
Long-term effects of addition of mineralocorticoid receptor
antagonist to angiotensin II receptor blocker in patients with
diabetic nephropathy: a randomized clinical trial
1
Alireza Esteghamati1,
Sorour Jarrah ,
Mostafa Mousavizadeh ,
Seyed Hamid Khoee2
and Manouchehr Nakhjavani1
A B S T R AC T
Background. 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 efcacy of SPR/ARB
combination in comparison with the standard ACE/ARB
regimen in diabetic nephropathy.
Methods. 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 ltration rate (eGFR)
and serum potassium concentrations were determined.
Results. After 18 months, three patients in the SPR/ARB
group developed asymptomatic hyperkalemia. SPR/ARB signicantly reduced both systolic and diastolic BP (P < 0.001
INTRODUCTION
The burden of diabetic nephropathy is staggeringconsuming
a large proportion of health resources [1, 2]. A recent costof-illness study from Iran revealed that diabetic nephropathy
accounts for 23% of expenditures attributed to diabetes [3].
Hypertension and proteinuria are established risk factors for
progression to advanced stages of kidney disease in diabetic
populations [4]. Interruption of renin-angiotensin system
Sina Noshad1,
Assessment
Before study commencement, the patients were interviewed
using a pre-designed questionnaire. BP was measured using a
standard mercury sphygmomanometer (Riester, Big Ben
adults, Germany) with the patient in sitting position after ten
minutes of resting; The average of two readings ve minutes
apart was recorded.
Subject enrollment
At the diabetes clinic of Vali-Asr hospital (Tehran, Iran),
between April and December 2010, we screened 373 consecutive patients who were known cases of type 2 diabetes according to the American Diabetes Association criteria [16]. After
initial assessment, 136 patients meeting the inclusion criteria
were recruited. The inclusion criteria were as follows:
(i) urinary albumin excretion (UAE) 30 mg/24 h in at least
two out of three 24-h urine sample collections; (ii) taking a
combination of an ACE inhibitor (enalapril) and an ARB (losartan) with recommended doses for diabetic nephropathy for
at least the past year and (iii) willingness to participate in the
trial. Subjects were excluded if they had non-diabetic kidney
disease, known cardiovascular or liver disease, chronic kidney
disease stages 4 and baseline serum potassium concentrations 5.5 meq/L. No kidney biopsies were performed to
distinguish diabetic nephropathy from other causes of chronic
kidney disease. Before enrollment, all subjects gave written informed consent. All interventions involving human subjects
Laboratory evaluations
After an overnight 12-h fast, 10 mL of venous blood sample
was collected from each participant. At baseline and follow-up
visits, the patients were also instructed to collect 24-h urine
samples.
Fasting plasma glucose concentrations were measured
using the Glucose Oxidase Method. Fasting insulin concentrations were determined using radioimmunoassay techniques
(Immunotech, Prague, Czech Republic). High-performance
liquid chromatography (HPLC) was performed to assess glycated hemoglobin A1c (HbA1c). Total cholesterol was
2
A. Esteghamati et al.
ORIGINAL ARTICLE
R E S U LT S
One hundred and thirty-six patients met the inclusion criteria
and were allocated to either the SPR/ARB or the ACE inhibitor/ARB arm of the trial (Figure 1). All patients completed a
3-month follow-up. A total of 114 patients returned for the
12-month visit (16.2% were excluded or lost to follow-up).
Finally, 18 months after trial initiation, the 97 remaining
patients were evaluated.
A comparison of clinical and demographic variables of
patients who completed the trial and those lost to follow-up at
either the 12th or the 18th month can be found in Supplementary data, Table S1.
Baseline clinical and demographic data for each arm of the
trial are provided in Table 1. Fifty-ve percent of the patients
3
ORIGINAL ARTICLE
Statistical analysis
Continuous variables with normal distribution are expressed
as mean standard deviation (SD) and categorical variables as
proportions or ratios. Distribution of UAE values did not
comply with the assumption of normality and logarithmic
transformation was necessary to correct right-sided skewness.
In all analyses log-transformed values were used instead. UAE
values are presented as median (interquartile range). The baseline characteristics of the study participants were compared
using independent t-test or chi square, where appropriate. The
baseline characteristics of patients who completed the study and
those who were lost to follow-up were also compared to evaluate
whether loss to follow-up occurred at random. Within-group
changes of outcome variables after 12 and 18 months were assessed using paired t-test. Comparative efcacy of interventions
in short term (3 months), medium term (12 months) and long
term (18 months) was determined using mixed betweenwithin
analysis of variance (ANOVA) method. In each analysis, effect
size was calculated from partial eta squared (based on Cohens
recommendations: 1% small effect, 6% medium effect, 13.8%
large effect). Visit-to-visit changes in outcome variables were
examined by post hoc analysis using the Tukeys least signicant
difference (LSD) method. Additionally, mixed betweenwithin
ANOVA models, with mean SBP and DBP introduced as covariate, were constructed to assess whether the observed differences between two interventions with respect to parameters of
kidney function are confounded by changes in BP over the trial
period. All statistical analyses were performed using SPSS
version 19.0 (IBM Corporation, New York, United States).
A P-value of <0.05 was considered statistically signicant.
ORIGINAL ARTICLE
F I G U R E 1 : Recruitment, randomization and follow-up of patients. Between April and December 2010, 373 type 2 diabetes patients were
screened. One hundred and thirty-six patients were eligible and were randomly allocated to trial arms. Patients were followed up regularly every
3 months for up to 18 months and the trial was completed in May 2012. Intervention in three patients in the SPR/ARB group was discontinued
due to laboratory abnormalities in serum potassium. Another patient was asked to stop taking SPR due to bothersome gynecomastia. Main
reasons for discontinued intervention as stated by patients included (i) personal issues; (ii) nancial restraints keeping them from frequent travel
to Tehran in those not residing in the capital and (iii) Preferring receiving care from the private sector rather than a teaching hospital.
Abbreviations: SPR, spironolactone; ARB, angiotensin II receptor blocker; ACE inhibitor, angiotensin-converting enzyme inhibitor.
controlling for the effect of mean SBP and DBP (data not
shown). Post hoc analysis of eGFR revealed a signicant
decline of 3.5 mL/min/1.73 m2 3 months after trial initiation
(P = 0.015 for baseline to third month). After that, patients
in the SPR/ARB group experienced an indolent but progressive decline in eGFR. Similar analyses for ACE inhibitor/ARB
group revealed no signicant difference in visit-to-visit
decline of eGFR (P > 0.05 for all tests). Overall, the monthly
decline rate of eGFR was 0.441 and 0.410 mL/min/1.73 m2 in
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A. Esteghamati et al.
ACE inhibitor/ARB
P-value
74
62
Age (years)
57.80 8.91
58.33 9.33
0.729
Sex (female/male)
23/51
22/40
0.587
Anti-diabetes medication
0.419
Metformin
34 (46%)
28 (45%)
Glibenclamide
4 (6%)
6 (10%)
Metformin + glibenclamide
35 (47%)
26 (42%)
Insulin
1 (1%)
2 (3%)
11.59 7.80
12.41 8.49
0.548
Hypertension (%)
45 (55%)
39 (62%)
0.497
Anti-hypertension medication
0.363
25 (30%)
21 (33%)
6 (7%)
7 (11%)
Anti-hyperlipidemia medication
0.749
33 (44.6%)
33 (53.2%)
Fibrates
8 (10.8%)
7 (11.3%)
Statins + brates
6 (8.1%)
4 (6.5%)
FPG (mmol/L)
9.86 3.71
9.75 3.43
0.852
73.96 54.80
89.73 42.64
0.442
HbA1c (mmol/mol)
64.63 12.33
63.19 11.71
0.604
Sodium (mmol/L)
139.95 2.46
139.87 2.61
0.855
Potassium (mmol/L)
4.40 0.43
4.32 0.44
0.304
4.54 0.086
4.44 1.16
0.554
Triglycerides (mmol/L)
1.97 1.03
1.92 1.03
0.776
SBP (mmHg)
134.27 18.12
140.08 18.67
0.061
DBP (mmHg)
82.26 8.54
83.17 10.29
0.558
UAE (mg/24 h)
0.727
Target variables
Albuminria
0.796
Microalbuminuria
54 (73.0%)
44 (71.0%)
Marcoalbuminria
20 (27.0%)
18 (29.0%)
92.82 23.87
99.01 24.75
0.152
73.75 16.78
69.13 19.69
0.131
eGFR (mL/min/1.73 m )
Abbreviations: SPR/ARB, spironolactone + angiotensin II receptor blocker; ACE inhibitor/ARB, angiotensin converting enzyme
inhibitor + angiotensin II receptor blocker; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin A1c; SBP, systolic blood pressure;
DBP, diastolic blood pressure; UAE, urinary albumin excretion; eGFR, estimated glomerular ltration rate.
a
Microalbuminuria was dened as 30 mg/24 h UAE < 300 mg/24 h, and macroalbuminuria as UAE 300 mg/24 h.
ORIGINAL ARTICLE
Statins
Beta blockers
12 months
P-value
SBP (mmHg)
133.57 17.20
126.71 12.59
0.001
DBP (mmHg)
82.64 8.54
79.14 5.31
0.002
UAE (mg/24 h)
<0.001
91.94 22.10
103.43 43.32
0.013
73.98 15.79
66.88 18.77
0.001
Baseline
18 months
SBP (mmHg)
134.17 16.45
125.28 17.15
0.014
DBP (mmHg)
83.05 9.80
78.61 7.98
0.019
UAE (mg/24 h)
<0.001
92.82 15.91
141.44 222.77
0.202
74.39 15.47
64.16 20.73
0.003
Baseline
12 months
SBP (mmHg)
141.27 18.73
137.45 21.43
0.230
DBP (mmHg)
83.40 10.42
81.20 7.73
0.207
UAE (mg/24 h)
74.0 (45.0330.0)
63.0 (23.0205.0)
0.120
98.12 23.87
106.08 38.90
0.110
68.36 19.45
63.19 20.50
0.056
Baseline
18 months
SBP (mmHg)
144.11 21.65
138.03 22.70
0.161
DBP (mmHg)
86.07 11.00
83.21 6.12
0.207
UAE (mg/24 h)
0.809
94.59 20.33
106.08 38.90
0.059
69.35 19.49
60.27 20.47
0.013
SPR/ARB
eGFR (mL/min/1.73 m )
P-value
ORIGINAL ARTICLE
ACE inhibitor/ARB
eGFR (mL/min/1.73 m )
P-value
Abbreviations: SPR/ARB, spironolactone + angiotensin II receptor blocker; ACE inhibitor/ARB, angiotensin-converting enzyme
inhibitor + angiotensin II receptor blocker; SBP, systolic blood pressure; DBP, diastolic blood pressure; UAE, urinary albumin excretion;
eGFR, estimated glomerular ltration rate.
a
A positive sign indicates increase, whereas negative signs denote decrease in outcome variables.
DISCUSSION
In the present study, replacement of enalapril with SPR proved
to be signicantly more effective than continuation of dual
RAS blockade in reduction of both SBP and DBP over a
follow-up period of 18 months (9 mmHg in SBP and 5 mmHg
in DBP). Rossing and colleagues (2005) found a signicant
reduction of about 10 mmHg in SBP and 5 mmHg in DBP
after addition of SPR 25 mg daily in 21 type 2 diabetes patients
[15]. Contrary to these observations, some have reported that
SPR at the doses used for proteinuria reduction does not affect
BP [18, 19]. Differences in the patients recruited with respect
6
A. Esteghamati et al.
P-value
Table 3. Comparison of medication efcacy on improvement of blood pressure, microalbuminuria and renal function
Baseline
3 months
P-value
Effect size
SPR/ARB
ACE inhibitor/ARB
SPR/ARB
ACE inhibitor/ARB
SBP (mmHg)
134.27 18.12
140.08 18.67
130.00 14.74
137.38 17.74
7.04
0.009
4.7%
DBP (mmHg)
82.26 8.54
83.17 10.29
80.37 7.10
83.25 9.72
2.33
0.129
1.6%
UAE (mg/24 h)
1.53
0.218
1.1%
92.82 23.87
99.01 24.75
98.12 22.98
97.24 22.10
0.34
0.559
0.2%
73.75 16.78
69.13 19.69
70.82 17.91
70.78 19.43
0.77
0.382
0.5%
12.70
0.001
9.6%
eGFR (mL/min/1.73 m )
Baseline
12 months
SPR/ARB
ACE/ARB
SPR/ARB
ACE/ARB
SBP (mmHg)
133.57 17.20
141.27 18.73
126.71 12.59
137.45 21.43
DBP (mmHg)
82.64 8.54
83.40 10.42
79.14 5.31
81.20 7.73
4.07
0.046
3.3%
UAE (mg/24 h)
74.0 (45.0330.0)
63.0 (23.0205.0)
4.13
0.044
3.4%
91.94 22.10
98.12 23.87
105.20 41.55
105.20 28.29
0.02
0.900
<0.1%
73.72 15.59
68.71 19.35
66.96 17.57
65.48 19.94
0.20
0.652
0.2%
eGFR (mL/min/1.73 m )
Baseline
18 months
ACE/ARB
SPR/ARB
ACE/ARB
SBP (mmHg)
134.17 16.45
144.11 21.65
125.28 17.15
138.04 22.70
13.88
<0.001
18.3%
DBP (mmHg)
83.06 9.80
86.07 11.00
78.61 7.98
83.21 6.12
12.14
0.001
16.4%
UAE (mg/24 h)
5.70
0.020
8.4%
92.82 15.91
94.59 20.22
105.20 24.75
110.50 32.71
0.06
0.802
0.1%
73.97 15.83
69.17 19.29
66.03 17.29
61.79 20.58
0.18
0.674
0.3%
eGFR (mL/min/1.73 m )
Abbreviations: SPR/ARB, spironolactone + angiotensin II receptor blocker; ACE inhibitor/ARB, angiotensin-converting enzyme inhibitor + angiotensin II receptor blocker; UAE, urinary
albumin excretion; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular ltration rate.
ORIGINAL ARTICLE
SPR/ARB
ORIGINAL ARTICLE
F I G U R E 2 : Mean changes in outcome variables over the trial course (18 months, seven visits). Variables are presented as mean standard
error. For UAE, log-transformed values are presented. P-values for between-group comparisons: systolic blood pressure (P < 0.001); diastolic
blood pressure (P = 0.001); urinary albumin excretion (P = 0.017); serum creatinine (P = 0.802); estimated glomerular ltration rate (P = 0.674).
Abbreviations: SPR, spironolactone; ARB, angiotensin II receptor blocker; ACE inhibitor, angiotensin-converting enzyme inhibitor.
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A. Esteghamati et al.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
None declared.
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Spironolactone and proteinuria
ORIGINAL ARTICLE
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Spironolactone and proteinuria