ENAC Blockade and Arterial Stiffness

Estrogen Receptor Alpha Signaling in Endothelial Cells Exacerbates Arterial Stiffening Via Upregulation of ENaC in Insulin Resistant Females

To determine whether treatment with the ENaC inhibitor, amiloride, improves endothelial function and arterial stiffness in obese insulin resistant subjects in a randomized placebo-controlled trial examining pre and postmenopausal women and age-matched men.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance; Overweight and Obesity
• Intervention / Treatment: Drug: Placebo - Cap; Drug: Amiloride Pill

Detailed Description

Overweight/obese males, pre- and post-menopausal females with insulin resistance, 30-70 years of age will be recruited. Following screening, eligible men and women will be randomly assigned to either amiloride (max dose 5mg) or placebo in a double-blinded design manner.

After randomization, subjects will be scheduled for an outpatient visit to the undergo baseline assessment of arterial stiffness (carotid femoral pulse wave velocity - cfPWV) and endothelial function (brachial popliteal artery flow mediated dilation). Subject assessment will be repeated at 12 weeks and at 24 weeks.

• Study Type: Interventional
• Enrollment (Actual): 137
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Columbia, Missouri, United States, 65201
      • University of Missouri Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 30 to 70 years of age at randomization
• Body mass index (BMI) 25.1-50 kg/m2 or waist circumference > 88 cm (> 35 in) in women and >102 cm (>40 in) in men. 3, 4
• One other characteristic of metabolic syndrome (elevated triglycerides ≥150 mg/dl; HDL cholesterol <40 mg/dl in men and <50 mg/dl in women; blood pressure ≥130/85 mm Hg or treatment for hypertension; impaired fasting glucose (≥100 mg/dl)) or fasting insulin level >10 mU/L (correlates with insulin resistance).

Exclusion Criteria:

1. History of type 1 or type 2 diabetes
2. Known cardiovascular events within the last 12 months (stroke, acute coronary event, revascularization, heart failure hospitalization).
3. History of uncontrolled thyroid disease, chronic liver disease (cirrhosis) or GFR <50 ml/min.
4. Use of potassium sparing medications (angiotensin II receptor blockers, angiotensin converting enzymes inhibitors or mineralocorticoid receptor blockers) or use of potassium supplements.
5. Active cancer (This criterion does not apply to those subjects with basal cell carcinoma or stage 1 squamous cell carcinoma of the skin)
6. Excessive alcohol consumption (>14 drinks/week for men, >7 drinks/week for women)
7. Current tobacco use
8. Non controlled hypertension
9. Participation in regular exercise > 3 days/wk per week at a moderate or vigorous intensity
10. Pregnancy or lactation in women (or women not using contraceptives)
11. Women who plan to become pregnant during the duration of the trial
12. Chronic use of NSAIDs
13. Potassium level > 5.0 mqE/L at time of screening
14. Blood pressure at screening <110/70

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 6 months of daily placebo	Drug: Placebo - Cap; 6 months of 1 pill a day
Experimental: Amiloride; 6 months of amiloride (max dose 5 mg) treatment	Drug: Amiloride Pill; Max dose of 5 mg a day for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Carotid Femoral Pulse Wave Velocity	cfPWV is the gold standard of arterial stiffness. It was assessd during experimental visits, under the same conditions in a blinded manner	baseline, 3 and 6 mo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brachial artery flow mediated dilation (FMD)	The goal is to assess changes from baseline when compared to interim and final time point. ] Brachial artery FMD will be assessed at baseline and at 12-wk. FMD is a measurement of conduit artery endothelial function. FMD is assessed immediately after each PWV measurement. Shear rate AUC until peak diameter is calculated as stimulus for FMD and used in covariate analysis as described. All measurements will be performed, under co-I supervision by the same blinded technician.	Baseline, 3 months (interim) and 6 months (final)
Popliteal artery flow mediated dilation (FMD)	The goal is to assess changes from baseline when compared to interim and final time point. ] Popliteal artery FMD will be assessed at baseline and at 12-wk. FMD is a measurement of conduit artery endothelial function. FMD is assessed immediately after each PWV measurement. Shear rate AUC until peak diameter is calculated as stimulus for FMD and used in covariate analysis as described. All measurements will be performed, under co-I supervision by the same blinded technician.	Baseline, 3 months (interim) and 6 months (final)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic Blood Pressure	Systolic blood pressure obtained during experimental visits at the different time points	3 and 6 mo
Brachial Artery Flow Mediated Dilation (FMD)	Brachial artery flow-mediated dilation will be assessed at baseline, 12, and 24 weeks. FMD is a measurement of conduit artery endothelial function.	Baseline, 3 months (interim) and 6 months (final)
Popliteal Artery Flow Mediated Dilation (FMD)	Popliteal artery flow-mediated dilation will be assessed at baseline, 12, and 24 weeks. FMD is a measurement of conduit artery endothelial function.	Baseline, 3 months (interim) and 6 months (final)

Collaborators and Investigators

• Sponsor: University of Missouri-Columbia
• Investigators: Principal Investigator: Camila Manrique Acevedo, MD, University of Missouri-Columbia

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2019
• Primary Completion (Actual): October 5, 2024
• Study Completion (Actual): April 30, 2025

Study Registration Dates

• First Submitted: February 8, 2019
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (Actual): February 12, 2019

Study Record Updates

• Last Update Posted (Estimated): December 30, 2025
• Last Update Submitted That Met QC Criteria: December 21, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Hyperinsulinism; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity; Insulin Resistance; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Amiloride
• Other Study ID Numbers: 2012990

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