Overweight and Obesity, Insulin Resistance
Conditions
Brief summary
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.
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.
Interventions
DRUGPlacebo - Cap
6 months of 1 pill a day
DRUGAmiloride Pill
Max dose of 5 mg a day for 6 months
Sponsors
University of Missouri-Columbia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Carotid Femoral Pulse Wave Velocity | baseline, 3 and 6 mo | cfPWV is the gold standard of arterial stiffness. It was assessd during experimental visits, under the same conditions in a blinded manner |
Other
| Measure | Time frame | Description |
|---|---|---|
| Systolic Blood Pressure | 3 and 6 mo | Systolic blood pressure obtained during experimental visits at the different time points |
| Brachial Artery Flow Mediated Dilation (FMD) | Baseline, 3 months (interim) and 6 months (final) | Brachial artery flow-mediated dilation will be assessed at baseline, 12, and 24 weeks. FMD is a measurement of conduit artery endothelial function. |
| Popliteal Artery Flow Mediated Dilation (FMD) | Baseline, 3 months (interim) and 6 months (final) | Popliteal artery flow-mediated dilation will be assessed at baseline, 12, and 24 weeks. FMD is a measurement of conduit artery endothelial function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo 6 months of daily placebo
Placebo - Cap: 6 months of 1 pill a day | 47 |
| Amiloride 6 months of amiloride (max dose 5 mg) treatment
Amiloride Pill: Max dose of 5 mg a day for 6 months | 90 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Placebo | Amiloride | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 4 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 86 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 87 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 6 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 40 Participants | 80 Participants | 120 Participants |
| Region of Enrollment United States | 47 participants | 90 participants | 137 participants |
| Sex: Female, Male Female | 28 Participants | 59 Participants | 87 Participants |
| Sex: Female, Male Male | 19 Participants | 31 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 90 |
| other Total, other adverse events | 5 / 47 | 9 / 90 |
| serious Total, serious adverse events | 0 / 47 | 0 / 90 |
Outcome results
Primary
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
Time frame: baseline, 3 and 6 mo
Population: Number of participants that finished clinical trial
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Carotid Femoral Pulse Wave Velocity | 3 months | 7.25 m/s |
| Placebo | Carotid Femoral Pulse Wave Velocity | 6 months | 7.12 m/s |
| Amiloride | Carotid Femoral Pulse Wave Velocity | 3 months | 6.80 m/s |
| Amiloride | Carotid Femoral Pulse Wave Velocity | 6 months | 6.81 m/s |
Other Pre-specified
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.
Time frame: Baseline, 3 months (interim) and 6 months (final)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Brachial Artery Flow Mediated Dilation (FMD) | 3 months (interim) | 6.03 Percentage | 95% Confidence Interval 0.62 |
| Placebo | Brachial Artery Flow Mediated Dilation (FMD) | Delta 6 months (final) | 5.59 Percentage | 95% Confidence Interval 0.56 |
| Amiloride | Brachial Artery Flow Mediated Dilation (FMD) | 3 months (interim) | 6.25 Percentage | 95% Confidence Interval 0.42 |
| Amiloride | Brachial Artery Flow Mediated Dilation (FMD) | Delta 6 months (final) | 6.16 Percentage | 95% Confidence Interval 0.44 |
Other Pre-specified
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.
Time frame: Baseline, 3 months (interim) and 6 months (final)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Popliteal Artery Flow Mediated Dilation (FMD) | 3 months (interim) | 1.71 Percentage | 95% Confidence Interval 0.3 |
| Placebo | Popliteal Artery Flow Mediated Dilation (FMD) | 6 months (final) | 1.80 Percentage | 95% Confidence Interval 0.31 |
| Amiloride | Popliteal Artery Flow Mediated Dilation (FMD) | 3 months (interim) | 2.22 Percentage | 95% Confidence Interval 0.29 |
| Amiloride | Popliteal Artery Flow Mediated Dilation (FMD) | 6 months (final) | 2.55 Percentage | 95% Confidence Interval 0.34 |
Other Pre-specified
Systolic Blood Pressure
Systolic blood pressure obtained during experimental visits at the different time points
Time frame: 3 and 6 mo
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Systolic Blood Pressure | 3 mo | 127.53 mmHg |
| Placebo | Systolic Blood Pressure | 6 mo | 125.51 mmHg |
| Amiloride | Systolic Blood Pressure | 3 mo | 122.90 mmHg |
| Amiloride | Systolic Blood Pressure | 6 mo | 120.27 mmHg |