Insulin Resistance, Obesity
Conditions
Keywords
Obesity, Insulin resistance, Mineralocorticoid receptor
Brief summary
The purpose of this study is to find out if spironolactone, a drug that blocks the action of aldosterone, can make the blood vessels work better in people with obesity. The investigators also want to find out whether spironolactone causes changes in levels of insulin and markers of inflammation.
Interventions
DRUGSpironolactone
50 mg once daily for 6 weeks.
DRUGPlacebo
Placebo-matching spironolactone once daily for 6 weeks.
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-70 years 2. Good health as evidenced by history and physical exam 3. Body Mass Index (BMI): \>30 kg/m2 and \<45 kg/m2
Exclusion criteria
1. Medical illnesses other than treated hypothyroidism 2. Blood Pressure (BP) \>135/85 or systolic BP \<90 mm Hg 3. Hepatic disease (transaminase \> 3 times normal) 4. Renal impairment (Creatinine clearance \<60 ml/min) 5. Baseline serum Potassium (K) \>5.0 mmol/L 6. History of drug or alcohol abuse 7. Allergies to spironolactone 8. Participation in any other concurrent clinical trial 9. Women using oral contraceptives within the last 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Post-ischemic Dilatation | Baseline and Week 6 | Ultrasonography of the brachial artery was performed to evaluate endothelial function by flow mediated dilatation (FMD) studies. A blood pressure cuff was placed on the participant's upper arm and was compressed for 5 minutes. After release of compression, brachial artery diameter and blood flow velocity were measured. FMD was expressed as the percentage change in brachial artery diameter. A positive change from Baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Sensitivity Index (ISI) | Baseline and Week 6 (Prior to ingesting glucose and every 30 minutes for 120 minutes) | Insulin sensitivity was measured using the 75 gram (G) glucose tolerance test. Participants ingested 75 grams of glucose in 300-400 milliliters (mL) of water over 5 minutes. Blood samples were taken before ingesting glucose and then every 30 minutes for 120 minutes. Insulin sensitivity index was calculated by Matsuda and Defronzo's formula using the values obtained. A positive change from Baseline (increase in insulin sensitivity) indicates improvement. |
| Change From Baseline in Para-aminohippurate (PAH) Clearance | Baseline and Week 6 (Prior to PAH infusion and at 50 and 60 minutes post PAH infusion) | Renal plasma blood flow was determined by clearance of para-aminohippurate (PAH). A loading dose of PAH (8 mg/kg) was given intravenously followed by a 1 hour constant infusion of PAH at a rate of 12 mg/minute (min). Plasma samples were obtained at Baseline and at 50 and 60 minutes. PAH clearance was calculated from the plasma levels and infusion rates and reported in millimeters (mL)/minute (min). A positive change from Baseline indicates improvement. |
| Change From Baseline in Markers of Inflammation | Baseline and Week 6 | Blood was to be collected and tested for Tumor Necrosis Factor Alpha (TNF-α) and Monocyte Chemotactic Protein-1 (MCP-1), markers of inflammation; However, due to lack of funding, blood samples were not analyzed and data for levels of inflammation markers were not collected. |
| Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Baseline and Week 6 (Prior to ingesting glucose and every 30 minutes for 120 minutes) | Insulin resistance was measured using the 75 G glucose tolerance test. Participants ingested 75 grams of glucose in 300-400 mL of water over 5 minutes. Blood samples were taken before ingesting glucose and then every 30 minutes for 120 minutes. HOMA-IR was calculated using the Insulin and glucose levels obtained. A negative change (decrease in insulin resistance) indicates improvement. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Spironolactone Spironolactone 50 mg once daily for 6 weeks. | 16 |
| Placebo Placebo-matching spironolactone once daily for 6 weeks. | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Spironolactone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 11.6 | 40 years STANDARD_DEVIATION 12.3 | 43.4 years STANDARD_DEVIATION 12.3 |
| Body Mass Index (BMI) | 38 kg/m^2 STANDARD_DEVIATION 6.6 | 36 kg/m^2 STANDARD_DEVIATION 4.6 | 36.8 kg/m^2 STANDARD_DEVIATION 5.8 |
| Sex: Female, Male Female | 10 Participants | 12 Participants | 22 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 0 / 19 | 0 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 |
Outcome results
Primary
Change From Baseline in Post-ischemic Dilatation
Ultrasonography of the brachial artery was performed to evaluate endothelial function by flow mediated dilatation (FMD) studies. A blood pressure cuff was placed on the participant's upper arm and was compressed for 5 minutes. After release of compression, brachial artery diameter and blood flow velocity were measured. FMD was expressed as the percentage change in brachial artery diameter. A positive change from Baseline indicates improvement.
Time frame: Baseline and Week 6
Population: All randomized participants who completed the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Spironolactone | Change From Baseline in Post-ischemic Dilatation | Baseline | 9.6 percent dilalation | Standard Deviation 7.8 |
| Spironolactone | Change From Baseline in Post-ischemic Dilatation | Change from Baseline at Week 6 | -1.2 percent dilalation | Standard Deviation 6.1 |
| Placebo | Change From Baseline in Post-ischemic Dilatation | Baseline | 10.2 percent dilalation | Standard Deviation 6.9 |
| Placebo | Change From Baseline in Post-ischemic Dilatation | Change from Baseline at Week 6 | -2.0 percent dilalation | Standard Deviation 4.7 |
Secondary
Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Insulin resistance was measured using the 75 G glucose tolerance test. Participants ingested 75 grams of glucose in 300-400 mL of water over 5 minutes. Blood samples were taken before ingesting glucose and then every 30 minutes for 120 minutes. HOMA-IR was calculated using the Insulin and glucose levels obtained. A negative change (decrease in insulin resistance) indicates improvement.
Time frame: Baseline and Week 6 (Prior to ingesting glucose and every 30 minutes for 120 minutes)
Population: All randomized participants who completed the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Spironolactone | Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Baseline | 2.7 IR index | Standard Deviation 1.2 |
| Spironolactone | Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Change from Baseline at Week 6 | 0.1 IR index | Standard Deviation 1.1 |
| Placebo | Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Baseline | 3.4 IR index | Standard Deviation 3.2 |
| Placebo | Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Change from Baseline at Week 6 | 0.1 IR index | Standard Deviation 4.4 |
Secondary
Change From Baseline in Insulin Sensitivity Index (ISI)
Insulin sensitivity was measured using the 75 gram (G) glucose tolerance test. Participants ingested 75 grams of glucose in 300-400 milliliters (mL) of water over 5 minutes. Blood samples were taken before ingesting glucose and then every 30 minutes for 120 minutes. Insulin sensitivity index was calculated by Matsuda and Defronzo's formula using the values obtained. A positive change from Baseline (increase in insulin sensitivity) indicates improvement.
Time frame: Baseline and Week 6 (Prior to ingesting glucose and every 30 minutes for 120 minutes)
Population: All randomized participants who completed the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Spironolactone | Change From Baseline in Insulin Sensitivity Index (ISI) | Baseline | 3.7 IS index | Standard Deviation 1.4 |
| Spironolactone | Change From Baseline in Insulin Sensitivity Index (ISI) | Change from Baseline at Week 6 | -0.1 IS index | Standard Deviation 0.8 |
| Placebo | Change From Baseline in Insulin Sensitivity Index (ISI) | Baseline | 4.6 IS index | Standard Deviation 3.7 |
| Placebo | Change From Baseline in Insulin Sensitivity Index (ISI) | Change from Baseline at Week 6 | -1.1 IS index | Standard Deviation 2.7 |
Secondary
Change From Baseline in Markers of Inflammation
Blood was to be collected and tested for Tumor Necrosis Factor Alpha (TNF-α) and Monocyte Chemotactic Protein-1 (MCP-1), markers of inflammation; However, due to lack of funding, blood samples were not analyzed and data for levels of inflammation markers were not collected.
Time frame: Baseline and Week 6
Population: Analysis was not performed.
Secondary
Change From Baseline in Para-aminohippurate (PAH) Clearance
Renal plasma blood flow was determined by clearance of para-aminohippurate (PAH). A loading dose of PAH (8 mg/kg) was given intravenously followed by a 1 hour constant infusion of PAH at a rate of 12 mg/minute (min). Plasma samples were obtained at Baseline and at 50 and 60 minutes. PAH clearance was calculated from the plasma levels and infusion rates and reported in millimeters (mL)/minute (min). A positive change from Baseline indicates improvement.
Time frame: Baseline and Week 6 (Prior to PAH infusion and at 50 and 60 minutes post PAH infusion)
Population: All randomized participants who completed the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Spironolactone | Change From Baseline in Para-aminohippurate (PAH) Clearance | Baseline | 488 mL/min | Standard Deviation 80 |
| Spironolactone | Change From Baseline in Para-aminohippurate (PAH) Clearance | Change from Baseline at Week 6 | -2.3 mL/min | Standard Deviation 28.7 |
| Placebo | Change From Baseline in Para-aminohippurate (PAH) Clearance | Baseline | 521 mL/min | Standard Deviation 116 |
| Placebo | Change From Baseline in Para-aminohippurate (PAH) Clearance | Change from Baseline at Week 6 | -5.2 mL/min | Standard Deviation 25.3 |