Metabolic Syndrome
Conditions
Brief summary
This study will measure the effect of the agent tadalafil on glucose and insulin homeostasis in people with metabolic syndrome in the presence and absence of an ACE inhibitor.
Interventions
DRUGRamipril
Ramipril 10 mg per day for three weeks
DRUGTadalafil
tadalafil 10 mg every other day for three weeks
DRUGplacebo
placebo matching ramipril
Sponsors
National Institutes of Health (NIH)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Ambulatory subjects, 18 to 70 years of age, inclusive 2. For female subjects, the following conditions must be met: * Postmenopausal status for at least 1 year, * Status-post surgical sterilization, or * If of childbearing potential, utilization of adequate birth control, and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day 3. Metabolic syndrome as defined by 3 or more of the following: * Fasting plasma glucose of at least 100 mg/dL (5.5 mmol/L), * Serum triglycerides of at least 150 mg/dL (1.7 mmol/L), * Serum HDL cholesterol less than 40 mg/dL (1.04 mmol/L) in males and less than 50mg/dl (1.30mmol/L) in females, * Blood pressure of at least 130/85 mmHg, or * Waist girth of more than 102 cm in men or 88 cm in women
Exclusion criteria
Subjects presenting with any of the following will not be included in the study: 1. Diabetes type 1 or type 2, as defined by a fasting glucose of 126 mg/dL or greater or the use of anti-diabetic medication 2. Use of hormone replacement therapy 3. Statin therapy 4. In hypertensive subjects, a seated systolic blood pressure greater than 179 mmHg or a seated diastolic blood pressure greater than 110 mmHg 5. Pregnancy 6. Breast-feeding 7. 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 8. Treatment with anticoagulants 9. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack 10. History or presence of immunological or hematological disorders 11. Diagnosis of asthma 12. Clinically significant gastrointestinal impairment that could interfere with drug absorption 13. Impaired hepatic function (aspartate amino transaminase \[AST\] and/or alanine amino transaminase \[ALT\] \> 1.5 x upper limit of normal range) 14. Impaired renal function (serum creatinine \> 1.5 mg/dl) 15. Hematocrit \< 35% 16. 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 17. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month) 18. Treatment with lithium salts 19. History of alcohol or drug abuse 20. Treatment with any investigational drug in the 1 month preceding the study 21. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study 22. Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Beta Cell Function | 3 hours | Beta cell function as measured during a frequently sampled IV glucose tolerance test |
| Insulin Sensitivity | three weeks | As assessed using IV glucose tolerance test and calculated using Min Mod units mU/mm |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Completed Subjects Subjects who completed all four treatment arms. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Treatment | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| First Treatment | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Second Treatment | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Second Treatment | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Third Treatment | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Completed Subjects |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 23 | 3 / 24 | 0 / 23 | 5 / 25 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 | 0 / 23 | 0 / 25 |
Outcome results
Primary
Beta Cell Function
Beta cell function as measured during a frequently sampled IV glucose tolerance test
Time frame: 3 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placeb Treatment | Beta Cell Function | 241.2 microU/mM | Standard Error 45.2 |
| Ramipril Treatment | Beta Cell Function | 232.3 microU/mM | Standard Error 38.1 |
| Tadalafil Treatment | Beta Cell Function | 292.1 microU/mM | Standard Error 38.9 |
| Combination Treatment | Beta Cell Function | 287.6 microU/mM | Standard Error 54.3 |
Primary
Insulin Sensitivity
As assessed using IV glucose tolerance test and calculated using Min Mod units mU/mm
Time frame: three weeks
Population: Those who completed protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placeb Treatment | Insulin Sensitivity | 2.21 (mU/L)-1x(min)-1xL | Standard Error 0.35 |
| Ramipril Treatment | Insulin Sensitivity | 1.76 (mU/L)-1x(min)-1xL | Standard Error 0.34 |
| Tadalafil Treatment | Insulin Sensitivity | 1.88 (mU/L)-1x(min)-1xL | Standard Error 0.25 |
| Combination Treatment | Insulin Sensitivity | 1.76 (mU/L)-1x(min)-1xL | Standard Error 0.29 |