Metabolic Syndrome, Obesity
Conditions
Keywords
African American, Women, Metabolic Syndrome, Endothelial function, Sildenafil citrate
Brief summary
Obesity has a greater detrimental impact on the health of African American women than on any other racial or gender group. Nearly 80% of African American women are overweight or obese in the United States. Hypertension and insulin resistance are more prevalent among African American women as compared to men and Caucasians. These conditions put them at increased risk for the development of diabetes mellitus and cardiovascular disease. Recent studies have reported that a substance named Nitric Oxide (NO)may have some beneficial effect on how the body handles blood sugar and blood pressure. Of interest,some studies have shown that African Americans have decreased function of NO in their blood vessels. In this study proposal the investigators will test if increasing NO function with a PDE-5 inhibitor (sildenafil citrate) will improve pre-diabetes and the health of the inner layer of the blood vessels in obese African American women.
Interventions
DRUGSildenafil
20 mg three times a day.
DRUGPlacebo
No active drug
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Pfizer
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Race will be self-defined, but only subjects who report both parents of the same race will be included. * Age 18-60 years old. * The investigators will recruit subjects with wide range of BMI 30-45 kg/m2. * Subjects who have metabolic syndrome or who have a fasting insulin \>13. The diagnosis include 3 of the following: Fasting blood glucose of greater than 100 Triglyceride levels of greater than 150 HDL cholesterol of less than 50 in women Blood pressure of at least 130/85, or on blood pressure medicine Waist girth of more than 35 inches in women. Subjects of childbearing potential will be required to have a negative serum/urine pregnancy test. In addition, they will be asked to use a reliable contraceptive method prior to enrollment as determined by the PI (Dr. Cyndya Shibao).
Exclusion criteria
* Previous allergic reactions to any of the study medication (sildenafil) or inability to take study medications as prescribed during the course of the study. * Type 1 or 2 diabetes mellitus as defined by a fasting glucose of 126 mg/dl or greater. * Use of antidiabetic medication (insulin, metformin, sulfonylurea, troglitazone) * Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy. * Current smokers. * Significant weight change \>5% from baseline in the past three months. * Pregnancy or breast-feeding. * History of serious neurological disease such as cerebral hemorrhage stroke, transient ischemic attack. * History or presence of immunological or hematological disorders. * Clinical significant gastrointestinal impairment that could interfere with drug absorption. * Impaired hepatic function (aspartate amino transaminase \[AST\] and/or alanine amino transaminase \[ALT\] \>1.5X upper limit of normal range). * Impaired renal function (estimated glomerular filtration rate (eGFR) of \<60mL/min). * Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult. * History of alcohol or drug abuse. * Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study. * Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study. * Patients must not be taking nitratest in any form (e.g., nitroglycerin, isosorbide dinitrate, nitroprusside, and others) during this study * Patients on alpha-blocking drugs (doxazosin, terazosin , or prazosin) will be excluded * Patients on protease inhibitors (ritonavir and others) will be excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | Insulin sensitivity measured at baseline and 4 weeks after the intervention | insulin sensitivity as measured by frequently sampled intravenous glucose tolerance test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Function | Difference between FMD at baseline and 4 weeks | Endothelial function was measured with flow mediated dilation, percent change |
Countries
United States
Participant flow
Recruitment details
The recruitment started on 03/16/2011 and the first subject was screened on 03/17/2011. Participants were enrolled at Vanderbilt University Medical Center.
Pre-assignment details
We screened 132 participants. Eighty six participants were excluded because of the following reasons: * 80 did not meet inclusion criteria * 5 declined to participate after the screening visit * 1 excluded because of difficult intravenous access.
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Sildenafil 20 mg three times a day for 4 weeks | 23 |
| Placebo Placebo three times a day for 4 weeks | 23 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
Baseline characteristics
| Characteristic | Sildenafil | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 23 Participants | 46 Participants |
| Age, Continuous | 42 years STANDARD_DEVIATION 9.5 | 43 years STANDARD_DEVIATION 10.4 | 42.4 years STANDARD_DEVIATION 9.9 |
| Body mass index | 39 kg/m^2 STANDARD_DEVIATION 5.3 | 39 kg/m^2 STANDARD_DEVIATION 5.7 | 39 kg/m^2 STANDARD_DEVIATION 5.4 |
| glucose | 90 mg/dL STANDARD_DEVIATION 10.6 | 97 mg/dL STANDARD_DEVIATION 11.4 | 93.5 mg/dL STANDARD_DEVIATION 11.4 |
| HDL | 44.0 mg/dL STANDARD_DEVIATION 9.9 | 45 mg/dL STANDARD_DEVIATION 11.1 | 44 mg/dL STANDARD_DEVIATION 10.4 |
| Height | 164 cm STANDARD_DEVIATION 5.2 | 162 cm STANDARD_DEVIATION 4.8 | 163 cm STANDARD_DEVIATION 5 |
| insulin | 15 uU/ml STANDARD_DEVIATION 7.7 | 14 uU/ml STANDARD_DEVIATION 9.9 | 14.6 uU/ml STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 23 Participants | 23 Participants | 46 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| triglycerides | 94.0 mg/dL STANDARD_DEVIATION 52.9 | 85 mg/dL STANDARD_DEVIATION 48.5 | 89 mg/dL STANDARD_DEVIATION 50.5 |
| Waist circumference | 112 cm STANDARD_DEVIATION 10.1 | 108 cm STANDARD_DEVIATION 11.4 | 110 cm STANDARD_DEVIATION 11 |
| Weight | 104.5 kG STANDARD_DEVIATION 16.7 | 102 kG STANDARD_DEVIATION 16.4 | 103.3 kG STANDARD_DEVIATION 16.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 23 | 14 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 |
Outcome results
Primary
Insulin Sensitivity
insulin sensitivity as measured by frequently sampled intravenous glucose tolerance test
Time frame: Insulin sensitivity measured at baseline and 4 weeks after the intervention
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Insulin Sensitivity | Baseline | 3.4 min-1/pmol/mlx10-5 | Standard Deviation 2.53 |
| Sildenafil | Insulin Sensitivity | 4-week during intervention | 3.2 min-1/pmol/mlx10-5 | Standard Deviation 3.02 |
| Placebo | Insulin Sensitivity | Baseline | 2.7 min-1/pmol/mlx10-5 | Standard Deviation 1.83 |
| Placebo | Insulin Sensitivity | 4-week during intervention | 3.0 min-1/pmol/mlx10-5 | Standard Deviation 2.12 |
Comparison: H0= 4-week treatment with sildenafil citrate does not improve insulin sensitivity in obese African American women.p-value: 0.5595% CI: [-0.33, 0.58]Regression, Linear
Secondary
Endothelial Function
Endothelial function was measured with flow mediated dilation, percent change
Time frame: Difference between FMD at baseline and 4 weeks
Population: We detected problems with the ultrasound images obtained to measure flow mediated dilation and therefore only data in 14 subjects in the sildenafil group and in 16 subjects in the placebo were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Endothelial Function | 4.7 percentage of brachial artery diameter | Standard Deviation 2.9 |
| Placebo | Endothelial Function | 5.3 percentage of brachial artery diameter | Standard Deviation 3.1 |
p-value: 0.64995% CI: [-1.58, 2.49]Regression, Linear