Aldosterone Antagonism and Microvascular Function

NCT01887119 | Terminated Phase 4

• 1 other identifier: 133031
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Abdominal Obesity Metabolic Syndrome; Insulin Resistance; Hypertension

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Eplerenone

ACTIVE COMPARATOR

Eplerenone 50 mg 1dd during four weeks

Drug: Eplerenone

Placebo

PLACEBO COMPARATOR

Eplerenone-matched placebo

Other: Placebo

Interventions

Eplerenone DRUG

Eplerenone

Placebo OTHER

Eplerenone-matched placebo

Placebo

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Maastricht University Medical Center: lead

Study Sites (1)

Maastricht University

Maastricht, Limburg, 6229 ER, Netherlands

Location

MeSH Terms

Conditions

Abdominal obesity metabolic syndrome; Insulin Resistance; Hypertension

Interventions

Eplerenone

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• prof. C.D.A. Stehouwer, MD, PhD

  Maastricht University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: June 19, 2013
• First Posted: June 26, 2013
• Study Start: October 1, 2013
• Primary Completion: November 1, 2018
• Study Completion: November 1, 2018
• Last Updated: November 5, 2018

Record last verified: 2018-11

Locations

NL (1)