Aldosterone, the Mineralocorticoid Receptor, and Cardiovascular Disease in Obesity

This study will evaluate whether the mineralocorticoid receptor antagonist eplerenone, when compared to chlorthalidone plus potassium chloride, can improve cardiac MRI-derived myocardial perfusion reserve and fibrosis, independent of blood pressure, and proportionately to the severity of autonomous aldosterone production.

Study Overview

• Status: Recruiting
• Conditions: Hypertension; Metabolic Syndrome; Overweight and Obesity
• Intervention / Treatment: Drug: Eplerenone; Drug: Chlorthalidone with potassium chloride

Detailed Description

Obesity is a dominant risk factor for the development of cardiovascular disease (CVD). The public health relevance of this relationship is underscored by the fact that 40% (93 million) of adult Americans are obese.

Activation of the mineralocorticoid receptor (MR) is a major mechanism implicated in the pathogenesis of obesity-associated CVD. MR activation causes vascular stiffness, inflammation, and fibrosis, and MR antagonists improve clinical outcomes in heart failure with reduced ejection fraction, especially in obesity. However, even in the absence of heart failure, multiple mechanisms of CVD in obesity are mediated by excessive activation of the MR. These mechanisms include: autonomous aldosterone production, increased cortisol action, high sympathetic nervous system activity, increased leptin, inflammation, and oxidative stress.

Autonomous aldosterone production is a highly prevalent and poorly recognized disorder that causes CVD independent of blood pressure (BP). Autonomous aldosterone production manifests across a wide severity spectrum, ranging from mild/subclinical (rarely recognized) to overt (primary aldosteronism). The investigators' work has characterized autonomous aldosterone production as a phenotype of non-physiologic, non-suppressible, and renin-independent aldosterone production that is highly prevalent in the general population of the U.S.A..

Autonomous aldosterone production and MR activation are especially enriched in obesity, particularly among obese/overweight individuals with hypertension and/or metabolic syndrome. Current treatment guidelines do not recommend the early use of MR antagonists in obesity or hypertension, thereby delaying or omitting a targeted therapy that may specifically mitigate the mechanism of CVD in this high-risk population.

The investigators have validated cardiac MRI methods to measure coronary microvascular function and myocardial fibrosis, both strong surrogates for CVD that correlate with aldosterone production and that improve with MR antagonist therapy.

Prospective studies to investigate the early mechanistic contribution of aldosterone-MR activation in the pathogenesis of CVD in obesity, and whether MR antagonists can prevent this, are lacking. Mechanistic studies, using innovative and robust intermediate phenotypes of clinical CVD outcomes in a cost-effective manner, could have a major public health impact by implicating a targeted medical therapy (MR antagonists) to prevent CVD in high-risk obesity (overweight/obese individuals with hypertension and/or metabolic syndrome).

HYPOTHESIS: MR antagonists in high-risk obesity improve cardiac MRI-derived myocardial perfusion reserve and fibrosis, independent of BP, and proportionately to the severity of autonomous aldosterone production.

STUDY DESIGN: This mechanistic study will investigate whether MR antagonist therapy in high-risk overweight or obese participants can be a targeted strategy to prevent CVD.

80 participants with overweight/obesity, untreated hypertension, and/or at least one other feature of the metabolic syndrome, will be enrolled. Participants will undergo a deep-phenotyping protocol to characterize aldosterone and cortisol physiology before randomization to eplerenone (25-100 mg/d) or chlorthalidone (6.25-25 mg/d + KCl 20 mEq/d) for one year. BP will be maintained in a target range to ensure outcomes are independent of BP control. Cardiac MRI-derived outcomes will be measured at baseline and after one year.

AIM 1: To investigate whether eplerenone therapy in high-risk obese/overweight participants, when compared to chlorthalidone + KCl, can improve coronary microvascular function independent of BP, as measured via stress cardiac MRI-derived myocardial perfusion reserve (a strong predictor for incident cardiovascular events and death that has been shown to improve with MR antagonist therapy).

AIM 2: To investigate whether eplerenone therapy in high-risk obese/overweight participants, when compared to chlorthalidone + KCl, can decrease myocardial fibrosis independent of BP, as measured via extracellular volume fraction on T1 mapping cardiac MRI (an established surrogate for myocardial fibrosis and inflammation that is also strongly associated with autonomous aldosterone production and mortality).

Exploratory Aims: To investigate whether the severity of autonomous aldosterone production is associated with cardiac MRI-derived outcomes and predicts the response to eplerenone therapy; and, to investigate whether eplerenone therapy can improve measures of cardiac fat content, arterial stiffness (via pulse-wave velocity), and inflammation (via inflammatory markers and adipocytokines), when compared to chlorthalidone + KCl.

IMPACT: Obesity/overweight status is enriched with autonomous aldosterone production and MR activation, mechanisms known to cause CVD. This study will investigate targeted mechanisms for the prevention of MR-mediated CVD in high-risk obesity using innovative physiologic phenotyping and surrogate imaging outcomes. This study will establish a mechanistic foundation for future outcome studies in obesity with incident CVD events.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anand Vaidya, MD; Phone Number: 6175258285; Email: anandvaidya@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Anand Vaidya, MD; Phone Number: 617-525-8285; Email: anandvaidya@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. BMI ≥ 30 with at least one of the following, or BMI ≥ 25 with at least two of the following:

   1. Untreated Hypertension: Stage I (BP 120-139/80-89 mmHg) or stage II (BP 140-159/90-99 mmHg).
   2. Treated Hypertension: On one anti-hypertensive medication with BP<140/90 mmHg and willing to undergo a 2-week washout of the medication before initiating eplerenone or chlorthalidone + KCl
   3. Dysglycemia: Impaired fasting plasma glucose (100-125 mg/dL) or glycated A1c 5.7-6.4%
   4. Dyslipidemia: Fasting triglyceride level > 150 mg/dL and HDL< 40 mg/dL in men or <50 mg/dL in women.
2. Age between 18 and 70 years old

Exclusion Criteria:

• Estimated glomerular filtration rate < 60 mL/min/1.73m2)
• Serum potassium > 5.2 mEq/L
• Known diagnosis or treatment for type 1 or type 2 diabetes
• Known history of CVD (myocardial infarction, heart failure, atrial fibrillation, or stroke)
• EKG with ischemic ST-segment or T-wave changes or Q waves in more than one territorial lead or a left bundle branch block
• Pregnancy (verified with a pregnancy test) or breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eplerenone; Participants will receive eplerenone, ranging from 25-100mg daily for one year.	Drug: Eplerenone; mineralocorticoid receptor antagonist and potassium-sparing diuretic; Other Names: Inspra
Active Comparator: Chlorthalidone with potassium chloride; Participants will receive chlorthalidone (6.25-25mg daily for one year) along with potassium chloride (up to 20 mEq daily for one year)	Drug: Chlorthalidone with potassium chloride; potassium-wasting diuretic with potassium chloride; Other Names: hygroton

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in stress myocardial perfusion reserve on cardiac MRI	Change in myocardial perfusion	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in extracellular volume fraction on cardiac MRI	change in myocardial fibrosis	one year

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Anand Vaidya, MD, Brigham and Women's Hospital, Harvard Medical School

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Estimated): November 30, 2025
• Study Completion (Estimated): November 30, 2025

Study Registration Dates

• First Submitted: August 17, 2020
• First Submitted That Met QC Criteria: August 18, 2020
• First Posted (Actual): August 19, 2020

Study Record Updates

• Last Update Posted (Actual): November 14, 2023
• Last Update Submitted That Met QC Criteria: November 13, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: aldosterone; mineralocorticoid receptor antagonist
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Overnutrition; Nutrition Disorders; Body Weight; Insulin Resistance; Hyperinsulinism; Cardiovascular Diseases; Obesity; Metabolic Syndrome; Overweight; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Chloride Symporter Inhibitors; Chlorthalidone; Eplerenone
• Other Study ID Numbers: 2020P002311

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes