Cardiorenal Med

© 2020 S. Karger AG, Basel www.karger.com/crm

DOI: 10.1159/000508670 Received: April 8, 2020 Accepted: May 7, 2020 Published online: September 30, 2020

Research Article

A Prospective Single-Blind Randomized Trial of Ramipril, Eplerenone and Their Combination in Type 2 Diabetic Nephropathy Mostafa El Mokadem a  

Yasser Abd El Hady a  

Ashraf Aziz b  

a Department b

 

of Cardiology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt; Department of Cardiology, Sohag General Hospital, Sohag, Egypt

Keywords Diabetic nephropathy · Microalbuminuria · Eplerenone · Ramipril · Hyperkalemia Abstract Introduction: Angiotensin-converting enzyme inhibitors (ACEI) combined with mineralocorticoid receptor antagonists were found to have a beneficial effect on patients with chronic kidney disease. Objective: The aim of our clinical trial was to compare the antialbuminuric effect of ramipril monotherapy, eplerenone monotherapy and eplerenone/ramipril combination therapy in patients with stage 1 hypertension and type 2 diabetes mellitus. Methods: In a single-blind, randomized clinical trial, 75 hypertensive patients (stage 1 hypertension) with type 2 diabetes mellitus and microalbuminuria were randomized in a 1: 1: 1 ratio to 1 of 3 groups: ramipril 10 mg monotherapy (25 patients), eplerenone 50 mg monotherapy (25 patients) and combination therapy of eplerenone/ramipril 50/10 mg (25 patients) through a randomized clinical trial. Blood pressure, urinary albumin/creatinine ratio (UACR), serum creatinine, estimated glomerular filtration rate (eGFR) and serum K level were measured before randomization and after 24 weeks. Results: Ramipril and eplerenone monotherapy showed a significant lowering of UACR compared with baseline levels (p ≤ 0.0001). The eplerenone/ramipril combination group showed a more significant reduction of UACR compared with the ramipril and eplerenone monotherapy groups (p = 0.0001). There was a more significant lowering of systolic blood pressure in the combination group (p < 0.0001). A nonsignificant change of serum potassium level, serum creatinine and eGFR was found among the 3 groups. Conclusion: Addition of eplerenone to ACEI shows an added antialbuminuric effect without significant change of the serum K level compared with eplerenone or ACEI. © 2020 S. Karger AG, Basel

Mostafa El Mokadem Department of Cardiology Faculty of Medicine, Beni-Suef University Mohamed Hasen Street, Beni-Suef 62511(Egypt) mostafa.elmokadem9 @ gmail.com

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ClinicalTrials.gov (NCT04143412). Registered October 29, 2019 – retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04143412.

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Cardiorenal Med DOI: 10.1159/000508670

© 2020 S. Karger AG, Basel www.karger.com/crm

El Mokadem et al.: Ramipril, Eplerenone and Their Combination in Type 2 Diabetic Nephropathy

Introduction

Diabetic nephropathy (DN) was found to be the main cause of end-stage renal disease in different countries [1]. It was associated in the early stage by microalbuminuria [2]. Different pathological factors like hyperglycemia, increased activity of the renin-angiotensin-aldosterone-system (RAAS), uncontrolled high systemic and glomerular pressure were involved in the pathophysiology of diabetic nephropathy [3]. The main lines of management include tight glycemic and blood pressure (BP) control [4]. Use of angiotensin-converting enzyme inhibitors (ACEIs) was found to reduce microalbuminuria both in normotensive and hypertensive patients with diabetic nephropathy [5]. The beneficial effect of control of high systemic blood pressure can be explained by reducing the filtration pressure. Use of angiotensin receptor blockers (ARBs) in patients with type 2 diabetes mellitus can be protective to reduce microalbuminuria [6]. Inadequate inhibition of aldosterone may lead to suboptimal antialbuminuric effects. In addition, different studies have found that renin-angiotensin-aldosterone system blockade with an ACEI/ARB alone sometimes does not achieve ideal antialbuminuric effects [7, 8]. Mineralocorticoid receptor antagonists (MRAs) in combination with ACEI or angiotensin II receptor blocker therapy was found to control proteinuria in diabetic nephropathy patients and can delay progression of chronic kidney disease [9]. The aim of our clinical trial was to compare the antialbuminuric effect of ramipril monotherapy, eplerenone monotherapy and eplerenone/ramipril combination therapy in patients with stage 1 hypertension and type 2 diabetes mellitus. Methods

Study Design The study included a 1-week screening period during which patients were subjected to (1) careful history taking including type of antidiabetic medications, (2) manual office arterial blood pressure measurement, (3) 12-lead surface ECG and (4) laboratory investigations including: (a) HbA1c, (b) serum potassium level, (c) renal function tests including serum creatinine and eGFR (GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation) and (d) UACR measured by first morning void urine sample. Eligible patients were randomized through a parallel single-blind randomized clinical trial in a 1:1:1 ratio according to a computer-generated randomization schedule to 1 of 3 treatment arms. The 1st arm (25 patients) included ramipril 10 mg/day; the 2nd arm (25 patients) included eplerenone 50 mg/day while the 3rd arm (25 patients) included combined ramipril 10 mg and eplerenone 50 mg daily regimen. Full doses were reached by forced titration after 4 weeks. All patients who completed the study were kept in the treatment phase for

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Seventy-five patients were randomly selected from outpatient cardiology clinics of Beni-Suef University Hospital and Sohag General Hospital using the following inclusion criteria: adult male and nonpregnant female patients with type 2 diabetes mellitus minimally 5 years ago with glycosylated hemoglobin (HbA1c) ≤8.5%, stage 1 hypertension (systolic BP 140–159 mm Hg and/or diastolic BP 90–99 mm Hg) and microalbuminuria diagnosed by measuring the urinary albumin/creatinine ratio (UACR). Microalbuminuria was diagnosed at a level between 30 and 300 mg/g [10]. Patients included in our study had never received ACEIs, ARBs or aldosterone antagonists. The baseline serum potassium level was ≥3.5 and ≤5.0 mmol/L with an estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2. Exclusion criteria included patients with type 1 diabetes mellitus, patients with either uncontrolled BP ≥160/100 mm Hg or secondary hypertension, nondiabetic nephropathy, bilateral renal artery stenosis or renal artery stenosis of a solitary functioning kidney, decompensated heart failure patients (New York Heart Association functional classes III and IV), patients with rapidly progressive chronic kidney disease, pregnant and breastfeeding women. The study conforms to the principles outlined in the Declaration of Helsinki and adherent to CONSORT guidelines, it was approved by the local Ethics Committee. All eligible patients provided written informed consent to participate in the study. Our study was registered at ClinicalTrials.gov (NCT04143412).

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Cardiorenal Med DOI: 10.1159/000508670

© 2020 S. Karger AG, Basel www.karger.com/crm

El Mokadem et al.: Ramipril, Eplerenone and Their Combination in Type 2 Diabetic Nephropathy

Table 1. Baseline demographic, clinical and laboratory features

Baseline features

Age (mean ± SD), years Gender, n (%) Female Male Systolic BP (mean ± SD), mm Hg Diastolic BP (mean ± SD), mm Hg Serum creatinine (mean ± SD), mg/dL eGFR (mean ± SD), mL/min/1.73 m² K (mean ± SD), mmol/L UACR (mean ± SD), mg/g Hemoglobin A1c (mean ± SD), %

Ramipril group (n = 25)

Eplerenone group (n = 25)

Eplerenone/ramipril combination group (n = 25)

p value

12 (48.00) 13 (52.00) 145.2±5.30 90.6±3.63 1.06±0.10 71.8±8.46 3.98±0.30 155.36±66.21 7.41±0.45

10 (40.00) 15 (60.00) 143.6±5.68 90.6±3.90 1.07±0.11 72.28±8.85 3.97±0.27 159.68±70.96 7.40±0.51

10 (40.00) 15 (60.00) 145.4±6.11 90.8±4.0 1.09±0.13 72.84±11.93 3.92±0.36 162.4±69.09 7.40±0.46

0.48 0.98 0.77 0.93 0.80 0.93 0.99

50.4±6.70

50.4±6.63

48.48±6.12

BP, blood pressure; UACR, urinary albumin/creatinine ratio; eGFR, estimated glomerular filtration rate.

0.49 0.80

24 weeks. Patients were instructed to take study medications at the same time each day before breakfast. All patients were followed up monthly with measurement of blood pressure, serum creatinine, eGFR and serum K level. Other add-on antihypertensive agents were not allowed. Patients were excluded from the study when: (a) symptomatic hypotension occurred at any time during the study, (b) uncontrolled hypertension, i.e. SBP was ≥140 mm Hg and/or DBP was ≥90 mm Hg at 2 consecutive visits 1–3 days apart after the 4th week, (c) sustained hyperkalemia, i.e. elevated serum potassium >5.5 mmol/L on 2 consecutive occasions 1–3 days apart at any time of the study or (d) change in type of antidiabetic medications to exclude their independent antiproteinuric effect; patients were followed finally after 24 weeks with measurement of blood pressure, serum K level, renal function tests including eGFR measurement and UACR.

Study End Points The primary study end point was the percentage change in UACR at the 24th week compared with the baseline value; the secondary end points were changes in BP, eGFR and serum potassium level at the 24th week.

Statistical Analysis Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS) computer software (version 22), IBM software, USA. Numerical variables were expressed as means ± SD. Qualitative data were presented as number and percentage and compared using the χ2 test. Analysis of numerical variables was done using the unpaired one-way ANOVA test for normally distributed data followed by Bonferroni post hoc analysis for comparison of the means of 3 groups. The Kruskal-Wallis test was used when the data were not normally distributed followed by the Mann-Whitney test to compare every 2 groups separately. For baseline and followup results of the same group, the paired t test was used if data were normally distributed, and the Wilcoxon test was used if data were not normally distributed. Linear regression analysis was used to identify independent predictors affecting percent change in UACR. A p value