Antihypertensive Pharmacological Therapy With Mineralocorticoid Receptor Antagonists in Obese Hypertensive Patients

NCT03476616 | Completed Phase 4

• 1 other identifier: HEBRO
• Study Type: interventional
• Target: 198
• Locations: 1 country
• Sites: 1

Brief Summary

Obesity is a complex metabolic state at which many pathophysiological pathways seem to interfere, like imbalance of autonomic nervous system, as well as renin-angiotensin-aldosterone system (RAAS) activation. Latest studies have shown that the increase of peripheral fat in obese patients, alongside with the increase of P-450 aromatase leads to hyper-aldosteronism, which results to increased sodium intake and rise of blood pressure. The present study aims to investigate the potential superiority of an aldosterone antagonist based therapy (eplerenone) over the renin-angiotensin antagonists (ARBs) (valsartan) based therapy in hypertensive obese patients regarding reduction of blood pressure (office, home and ambulatory) over a 24-week period.

Conditions

Hypertension; Obesity

Keywords

Hypertension; Obesity; Ambulatory Blood Pressure; Eplerenone; Valsartan; Mineralocorticoid Receptor Antagonists; Angiotensin II Receptor Blockers

Outcome Measures

Primary Outcomes (1)

• Difference in change of ABPM from baseline, in the eplerenone arm versus the irbesartan arm as monotherapy at 8 weeks, as combined dual treatment with amlodipine at 16 weeks and as combined triple treatment with amlodipine and indapamide at 24 weeks.

  Ambulatory blood pressure measurements (metric unit: mmHg) at baseline and 8,16 and 24 weeks and evaluation of the difference of mean ambulatory systolic and diastolic blood pressure measurements between baseline and each time frame in all participants

  8, 16 and 24 weeks

Secondary Outcomes (1)

• Difference in change of office BP from baseline, in the eplerenone arm versus the valsartan arm as monotherapy at 8 weeks, as combined dual treatment with amlodipine at 16 weeks and as combined triple treatment with amlodipine and indapamide at 24 weeks.

  8, 16 and 24 weeks

Other Outcomes (1)

• Difference in frequency of controlled hypertension (mean ABPM < 130/80 mm Hg) between the study arms at 8, 16 and 24 weeks.

  8, 16 and 24 weeks

Study Arms (2)

Eplerenone (-based therapy) arm

ACTIVE COMPARATOR

Obese pts with hypertension, starting treatment with eplerenone 25mg twice daily (BD). ABPM wil be scheduled at wks 8, 16 and 24. At wk 8 if mean ABPM \< 130/80mm Hg will continue to monotherapy with eplerenone. If not controlled (mean ABPM \> 130/80mm Hg) at wk8, amlodipine 5mg OD will be added. At wk 16 if mean ABPM \< 130/80mm Hg will continue to monotherapy with eplerenone, or dual therapy with eplerenone and amlodipine. If not controlled (mean ABPM \> 130/80mm Hg) at wk16, indapamide 1,5mg OD will be added. All patients will be followed up for 24 weeks.

Drug: Eplerenone (-based therapy) arm

Irbesartan (-based therapy) arm

ACTIVE COMPARATOR

Obese pts with hypertension, starting treatment with irbesartan 150mg once daily (OD). ABPM wil be scheduled at wks 8, 16 and 24. At wk 8 if mean ABPM \< 130/80mm Hg will continue to monotherapy with irbesartan. If not controlled (mean ABPM \> 130/80mm Hg) at wk8, amlodipine 5mg OD will be added. At wk 16 if mean ABPM \< 130/80mm Hg will continue to monotherapy with irbesartan, or dual therapy with irbesartan and amlodipine. If not controlled (mean ABPM \> 130/80mm Hg) at wk16, indapamide 1,5mg OD will be added. All patients will be followed up for 24 weeks.

Drug: Valsartan (-based therapy) arm

Interventions

Eplerenone (-based therapy) arm DRUG

At randomization, pts meeting inclusion/exclusion criteria will be randomized (1:1) to either eplerenone (E) 25mg bd or valsartan (V) 160mg od for 8 wks. At 8, 16 and 24 wks, pts at both arms will be evaluated with ABPM primary, as well as home and office BP measurements. At wk 8, pts with controlled hypertension (mean ABPM \<130/80mmHg), will continue in monotherapy with eplerenone or valsartan and pts with uncontrolled hypertension (mean ABPM ≥130/80mmHg) will continue with the addition of amlodipine (C) 10mg od. At wk 16, pts achieving BP control will continue in either monotherapy (E), (V) or dual therapy (E+C), (V+C). However, in pts not achieving ABPM target, a third drug, will be added \[indapamide (D) 1.25 mg od\]. All groups at both arms will be evaluated at 24 wks by ABPM.

Eplerenone (-based therapy) arm

Valsartan (-based therapy) arm DRUG

At randomization, pts meeting inclusion/exclusion criteria will be randomized (1:1) to either eplerenone (E) 25mg bd or valsartan (V) 160mg od for 8 wks. At 8, 16 and 24 wks, pts at both arms will be evaluated with ABPM primary, as well as home and office BP measurements. At wk 8, pts with controlled hypertension (mean ABPM \<130/80mmHg), will continue in monotherapy with eplerenone or valsartan and pts with uncontrolled hypertension (mean ABPM ≥130/80mmHg) will continue with the addition of amlodipine (C) 10mg od. At wk 16, pts achieving BP control will continue in either monotherapy (E), (V) or dual therapy (E+C), (V+C). However, in pts not achieving ABPM target, a third drug, will be added \[indapamide (D) 1.25 mg od\]. All groups at both arms will be evaluated at 24 wks by ABPM.

Irbesartan (-based therapy) arm

Eligibility Criteria

• Age: 30 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age
• Written consent
• Untreated or never-treated arterial hypertension with office systolic blood pressure of 140-180 mmHg and/or diastolic blood pressure of 90-120 mmHg, confirmed by 24-hour ambulatory blood pressure measurements of mean ambulatory systolic blood pressure over 130 mmHg and/or mean ambulatory diastolic blood pressure over 80 mmHg
• Obesity, confirmed estimated by Body Mass Index (BMI) of 30-40 kg/m2

You may not qualify if:

• Age \<30 or \>75
• Inability to give informed consent
• Participation in a clinical study involving an investigational drug or device within 4 weeks of screening
• Secondary hypertension
• Recent (\<6 months) cardiovascular event requiring hospitalization (eg. myocardial infarction or stroke)
• Type 1 diabetes
• Chronic kidney disease assessed by Estimated Glomerular Filtration Rate (eGFR) \<45 mL/min
• Bilateral renal arteries stenosis
• Addison's disease
• Hemodynamically significant valvular heart disease
• Plasma potassium outside of normal range on two successive measurements during screening
• Pregnancy, planning to conceive or women of childbearing potential, that is, not using effective contraception
• Scheduled surgery or cardiovascular surgery over the next 6 months
• Absolute contra-indication to study drugs (eg. asthma) or previous intolerance of trial therapy
• History of sustained atrial fibrillation

Sponsors & Collaborators

• Hippocration General Hospital: lead

Study Sites (1)

Hypertension Unit, First Cardiology Clinic, Hippocration General Hospital, University of Athens, Athens, Greece

Athens, Athens, 11527, Greece

Location

Related Publications (18)

• Tsioufis C, Tsiachris D, Dimitriadis K, Thomopoulos C, Syrseloudis D, Andrikou E, Chatzis D, Taxiarchou E, Selima M, Mazaraki A, Chararis G, Tolis P, Gennadi A, Andrikou I, Stefanadi E, Fragoulis V, Tzamou V, Panagiotakos D, Tousoulis D, Stefanadis C. Leontio Lyceum ALbuminuria (3L Study) epidemiological study: aims, design and preliminary findings. Hellenic J Cardiol. 2009 Nov-Dec;50(6):476-83.

  PMID: 19942561 BACKGROUND

• Schlaich MP, Grassi G, Lambert GW, Straznicky N, Esler MD, Dixon J, Lambert EA, Redon J, Narkiewicz K, Jordan J; European Society of Hypertension Working Group on Obesity; Australian and New Zealand Obesity Society. European Society of Hypertension Working Group on Obesity Obesity-induced hypertension and target organ damage: current knowledge and future directions. J Hypertens. 2009 Feb;27(2):207-11. doi: 10.1097/HJH.0b013e32831dafaf. No abstract available.

  PMID: 19155773 BACKGROUND

• Dimitriadis K, Tsioufis C, Mazaraki A, Liatakis I, Koutra E, Kordalis A, Kasiakogias A, Flessas D, Tentolouris N, Tousoulis D. Waist circumference compared with other obesity parameters as determinants of coronary artery disease in essential hypertension: a 6-year follow-up study. Hypertens Res. 2016 Jun;39(6):475-9. doi: 10.1038/hr.2016.8. Epub 2016 Feb 11.

  PMID: 26865004 BACKGROUND

• Tsioufis CP, Tsiachris DL, Selima MN, Dimitriadis KS, Thomopoulos CG, Tsiliggiris DC, Gennadi AS, Syrseloudis DC, Stefanadi ES, Toutouzas KP, Kallikazaros IE, Stefanadis CI. Impact of waist circumference on cardiac phenotype in hypertensives according to gender. Obesity (Silver Spring). 2009 Jan;17(1):177-82. doi: 10.1038/oby.2008.462. Epub 2008 Oct 23.

  PMID: 18948974 BACKGROUND

• Jordan J, Yumuk V, Schlaich M, Nilsson PM, Zahorska-Markiewicz B, Grassi G, Schmieder RE, Engeli S, Finer N. Joint statement of the European Association for the Study of Obesity and the European Society of Hypertension: obesity and difficult to treat arterial hypertension. J Hypertens. 2012 Jun;30(6):1047-55. doi: 10.1097/HJH.0b013e3283537347.

  PMID: 22573071 BACKGROUND

• Badimon L, Bugiardini R, Cenko E, Cubedo J, Dorobantu M, Duncker DJ, Estruch R, Milicic D, Tousoulis D, Vasiljevic Z, Vilahur G, de Wit C, Koller A. Position paper of the European Society of Cardiology-working group of coronary pathophysiology and microcirculation: obesity and heart disease. Eur Heart J. 2017 Jul 1;38(25):1951-1958. doi: 10.1093/eurheartj/ehx181. No abstract available.

  PMID: 28873951 BACKGROUND

• Doll S, Paccaud F, Bovet P, Burnier M, Wietlisbach V. Body mass index, abdominal adiposity and blood pressure: consistency of their association across developing and developed countries. Int J Obes Relat Metab Disord. 2002 Jan;26(1):48-57. doi: 10.1038/sj.ijo.0801854.

  PMID: 11791146 BACKGROUND

• Mancia G, Bombelli M, Corrao G, Facchetti R, Madotto F, Giannattasio C, Trevano FQ, Grassi G, Zanchetti A, Sega R. Metabolic syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study: daily life blood pressure, cardiac damage, and prognosis. Hypertension. 2007 Jan;49(1):40-7. doi: 10.1161/01.HYP.0000251933.22091.24. Epub 2006 Nov 27.

  PMID: 17130308 BACKGROUND

• Tsioufis C, Tatsis I, Thomopoulos C, Wilcox C, Palm F, Kordalis A, Katsiki N, Papademetriou V, Stefanadis C. Effects of hypertension, diabetes mellitus, obesity and other factors on kidney haemodynamics. Curr Vasc Pharmacol. 2014 May;12(3):537-48. doi: 10.2174/157016111203140518173700.

  PMID: 23305375 BACKGROUND

• Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, Papademetriou V, Probstfield J, Wright JT Jr, Alderman MH, Weiss RJ, Piller L, Bettencourt J, Walsh SM; ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002 Nov-Dec;4(6):393-404. doi: 10.1111/j.1524-6175.2002.02045.x.

  PMID: 12461301 BACKGROUND

• Hall JE, Brands MW, Dixon WN, Smith MJ Jr. Obesity-induced hypertension. Renal function and systemic hemodynamics. Hypertension. 1993 Sep;22(3):292-9. doi: 10.1161/01.hyp.22.3.292.

  PMID: 8349321 BACKGROUND

• Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension. 2000 Jun;35(6):1270-7. doi: 10.1161/01.hyp.35.6.1270.

  PMID: 10856276 BACKGROUND

• de Paula RB, da Silva AA, Hall JE. Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension. 2004 Jan;43(1):41-7. doi: 10.1161/01.HYP.0000105624.68174.00. Epub 2003 Nov 24.

  PMID: 14638627 BACKGROUND

• Garg R, Kneen L, Williams GH, Adler GK. Effect of mineralocorticoid receptor antagonist on insulin resistance and endothelial function in obese subjects. Diabetes Obes Metab. 2014 Mar;16(3):268-72. doi: 10.1111/dom.12224. Epub 2013 Oct 31.

  PMID: 24125483 BACKGROUND

• de Souza F, Muxfeldt E, Fiszman R, Salles G. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension. 2010 Jan;55(1):147-52. doi: 10.1161/HYPERTENSIONAHA.109.140988. Epub 2009 Oct 26.

  PMID: 19858405 BACKGROUND

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  PMID: 25501057 BACKGROUND

• Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ; British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059-2068. doi: 10.1016/S0140-6736(15)00257-3. Epub 2015 Sep 20.

  PMID: 26414968 BACKGROUND

• Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013 Jul;31(7):1281-357. doi: 10.1097/01.hjh.0000431740.32696.cc. No abstract available.

  PMID: 23817082 BACKGROUND

Related Links

• PROTOCOL OF THE HYPERTENSION THERAPY WITH IRBESARTAN VERSUS EPLERENONE FOR OBESE HYPERTENSIVE PATIENTS (HEBRO)
• EPLERENONE VS IRBESARTAN AS FIRST LINE THERAPY IN OBESE HYPERTENSIVE PATIENTS: BASELINE CHARACTERISTICS

MeSH Terms

Conditions

Hypertension; Obesity

Interventions

Eplerenone; Valsartan

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Study Officials

• Konstantinos P Tsioufis, Ass. Prof.

  Hypertension Unit, First Cardiology Clinic, Hippocration General Hospital, University of Athens, Greece

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator. Prof. Konstantinos P.Tsioufis, MD, PhD, FESC, FACC, Associate Professor of Cardiology, Head of Hypertension Unit, ESH Excellesh center

Study Record Dates

• First Submitted: March 19, 2018
• First Posted: March 26, 2018
• Study Start: September 1, 2018
• Primary Completion: June 30, 2025
• Study Completion: June 30, 2025
• Last Updated: July 31, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

GR (1)