Aldosterone Antagonism and Microvascular Function

Effects of Aldosterone Antagonism on Insulin-mediated Microvascular Function in Subjects With the Metabolic Syndrome

The prevalence of obesity and obesity-related complications is currently taking epidemic proportions. These complications increase the risk of type 2 diabetes and cardiovascular disease, which are important causes of morbidity and mortality worldwide.

It is important to gain insight in the mechanisms underlying obesity-related complications, because this may lead to the development of directed therapeutic strategies.

Currently, there is significant evidence that the cause of both insulin resistance and hypertension must be sought at the level of the microcirculation.

Over activity of the renin-angiotensin-aldosterone system is a potential cause of microvascular dysfunction. Angiotensin II was indeed found to be implicated in the pathogenesis of obesity-associated hypertension and insulin resistance, possibly through interference with the vascular effects of insulin.

Increased aldosterone levels have also been associated with resistant hypertension and insulin resistance, which is illustrated in patients with primary aldosteronism. Furthermore, aldosterone is known to exert several detrimental effects on the vasculature, some of which are offset by mineralocorticoid receptor antagonists.

In obese individuals, plasma aldosterone concentrations are increased as well. We hypothesize that increased aldosterone levels in adipose persons induce microvascular dysfunction, which contributes to the development of insulin resistance and hypertension, and mineralocorticoid receptor antagonism results in improved insulin sensitivity and decreased blood pressure by counteracting the adverse effects of aldosterone on the microvasculature.

Study Overview

• Status: Terminated
• Conditions: Hypertension; Insulin Resistance; Abdominal Obesity Metabolic Syndrome
• Intervention / Treatment: Drug: Eplerenone; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 ER
      • Maastricht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 40-65 years
• Caucasian
• Waist circumference > 102 cm (men)/> 88 cm (women)
• Triglycerides > 1.7 mmol/L
• High-normal blood pressure (office blood pressure: 130/85 - 139/89 mm Hg) or stage I hypertension (office blood pressure: 140/90 mm Hg - 159/99 mm Hg; 24h ABPM: 125/80 - 149/89 mm Hg)

Exclusion Criteria:

• Cardiovascular disease (stroke, coronary artery disease, peripheral vascular disease, congestive heart failure, cardiac shunts, cardiac surgery, pulmonary hypertension, cardiac arrhythmias, family history of cardiac arrhythmias or sudden cardiac death)
• Diabetes mellitus/impaired glucose metabolism (fasting glucose values > 5.6 mmol/L)
• Grade 2 or 3 hypertension (office blood pressure: > 160/100 mm Hg; ABPM > 150/90 mm Hg)
• Unstable or severe pulmonary disease
• Unstable or severe thyroid disorders
• Inflammatory diseases
• Alcohol use > 2 U/day (women)/> 3 U/day (men)
• Use of antihypertensive, lipid-lowering or glucose-lowering medications,
• Use of corticosteroids, medication known to inhibit or induce CYP3A4, lithium, and tricyclic antidepressants or antipsychotic medication, and regular use (weekly or several times a week) of NSAIDs
• Plasma potassium levels < 3.2 mmol/L or > 5 mmol/L
• eGFR < 60 mL/min
• Impairment of hepatic function
• Pregnancy or lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Eplerenone; Eplerenone 50 mg 1dd during four weeks	Drug: Eplerenone
Placebo Comparator: Placebo; Eplerenone-matched placebo	Other: Placebo; Eplerenone-matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in capillary recruitment (insulin-induced increase in microvascular blood volume in skeletal muscle) from baseline after 4 weeks of Eplerenone treatment or placebo	The difference in microvascular blood volume in skeletal muscle of the forearm, which is assessed with contrast enhanced ultrasound, before and during a hyperinsulinemic, euglycemic clamp (performed to determine insulin sensitivity)	Change from baseline after 4 weeks of treatment with either Eplerenone or placebo

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: prof. C.D.A. Stehouwer, MD, PhD, Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2013
• Primary Completion (Actual): November 1, 2018
• Study Completion (Actual): November 1, 2018

Study Registration Dates

• First Submitted: June 19, 2013
• First Submitted That Met QC Criteria: June 22, 2013
• First Posted (Estimate): June 26, 2013

Study Record Updates

• Last Update Posted (Actual): November 5, 2018
• Last Update Submitted That Met QC Criteria: November 1, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Overnutrition; Nutrition Disorders; Hyperinsulinism; Obesity; Syndrome; Metabolic Syndrome; Insulin Resistance; Obesity, Abdominal; Physiological Effects of Drugs; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Eplerenone
• Other Study ID Numbers: 133031