Healthy, Obese
Conditions
Brief summary
Obesity and its adverse cardiometabolic consequences are major public health problems. Several features of obesity contribute to the associated cardiovascular risk and are potential targets for intervention. These include insulin resistance and beta cell dysfunction, reduced metabolic rate, and impaired aerobic capacity.The purpose of this study is to examine if the phosphodiesterase type 5A inhibitor tadalafil improves cardiometabolic health in individuals who are obese and insulin resistant.
Detailed description
Obesity is a risk factor for nearly all cardiovascular (CV) disease including coronary artery disease, hypertension, and heart failure. Increased CV risk in obese individuals appears to depend largely on the degree of metabolic dysregulation and metabolic risk factors (glucose intolerance, dyslipidemia, etc.). Notably, interventions that improve insulin sensitivity and cardiorespiratory fitness can reduce CV risk in obese individuals, even in the absence of weight loss. The cyclic guanylate monophosphate pathway (cGMP) is involved in energy homeostasis and systemic metabolism. Multiple lines of evidence suggest that increasing cGMP activity is beneficial from a metabolic standpoint. Tadalafil is a clinically-available drug that inhibits the enzyme that breaks down cGMP. The study investigators hypothesize that chronic PDE5 inhibition in obese, insulin-resistant adults will improve cardiometabolic health. Aim 1: To examine the effect of PDE5 inhibition on energy expenditure. Aim 2: To examine the effect of PDE5 inhibition on insulin sensitivity and secretion. Aim 3: To examine the effect of PDE5 inhibition on cGMP tone and circulating mediators of cardiometabolic risk.
Interventions
DRUGTadalafil
Tadalafil is an FDA approved, clinically-available drug that inhibits the enzyme phosphodiesterase type 5A (PDE5). Subjects who are randomized to this arm will be provided with 20mg of Tadalafil to take every day for 12 weeks, beginning at their baseline visit.
DRUGPlacebo
100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit.
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Adults (ages 21-50) * Obesity (BMI ≥ 30 kg/m2) * Prediabetes on oral glucose tolerance test.
Exclusion criteria
* Age \<21 or \> 50 * BMI \< 30 kg/m2 * Systolic blood pressure (SBP) \< 100, \> 150 mmHg * Current anti-hypertensive medication use, including diuretics * Current use of organic nitrates * Current use of PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) * History of reaction to PDE-5 inhibitors * Known HIV infection * Use of medications that strongly alter CYP3A4 activity * History of myocardial infarction, angina, uncontrolled cardiac arrhythmia, stroke, transient ischemic attack, or seizure * Known non-arteritic ischemic optic retinopathy (NAIOR) * History of hearing loss * Estimated glomerular filtration rate (eGFR) \< 60 ml/min/1.73 m2 by the modified diet in renal disease (MDRD) equation * Hepatic transaminase (AST and ALT) levels greater than three times the upper limit of normal * Known pregnancy or breastfeeding or those unwilling to avoid pregnancy during the course of the study * History of priapism * Use in excess of four alcoholic drinks daily * History of diabetes mellitus or use of anti-diabetic medications * Known anemia (men, Hct \< 38% and women, Hct \<36%) * Menopause * Inability to exercise on a bicycle * Weight \> 300 pounds
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day) | 12 weeks | Subjects will undergo a metabolic chamber protocol to measure resting exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement. |
| Insulin Sensitivity After 12 Weeks of Drug Therapy | 12 weeks | Subjects will undergo an insulin modified fasting intravenous glucose tolerance test (FS-IVGTT) protocol at 12 weeks adjusted statistically for the baseline measurement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score | 12 weeks | Quality of life will be assessed using the Medical Outcomes Study Short-Form Health Survey (SF-36). The SF-36 is a 36 question survey with a total score range from 0-100; higher scores indicate better quality of life. |
| Change in cGMP/NP Ratio After 12 Weeks of Drug Therapy | 12 weeks | Subjects will undergo a fasting blood draw at baseline and 12 weeks to measure the change in ratio of plasma cyclic guanylate monophosphate pathway (cGMP) to plasma natriuretic peptides (NP) in response to the drug intervention (placebo or tadalafil). |
| Physical Activity-induced Energy Expenditure (kcal/Day) | 12 weeks | During the metabolic chamber protocol, conducted at baseline and at 12 weeks, the cardiopulmonary exercise test protocol will be conducted. The Energy Expenditure (EE) related to physical activity will be calculated as peak EE above the resting level while performing the exercise test. |
| Sexual Function | 12 weeks | The Female Sexual Function Index will be used to measure sexual function in women with a range from 2-36 with higher scores indicating better sexual function. |
| Maximal Exercise Energy Expenditure (kcal/Day) | 12 weeks | Subjects will undergo a metabolic chamber protocol to measure maximal exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement. Maximal Exercise Energy Expenditure will be measured as kcal/day |
| Maximal Oxygen Consumption | 12 weeks | Subjects will undergo a symptom-limited cardiopulmonary exercise test to measure peak oxygen consumption (VO2 max). Maximal oxygen consumption will be measured as 'mL/min'. |
| Dual Energy X-Ray Absorptiometry (DEXA) (g) | 12 weeks | fat mass at 12 weeks. |
Countries
United States
Participant flow
Pre-assignment details
141 participants passed our screening procedures and were enrolled however only 125 were randomized due to dropouts and scheduling conflicts. We allowed up to 30 days between the screening process and the baseline visit. Participants were assigned to a group after the baseline visit.
Participants by arm
| Arm | Count |
|---|---|
| Tadalafil Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the Tadalafil arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of Tadalafil (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the active comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days).
Tadalafil: Tadalafil is an FDA approved, clinically-available drug that inhibits the enzyme phosphodiesterase type 5A (PDE5). Subjects who are randomized to this arm will be provided with 20mg of Tadalafil to take every day for 12 weeks, beginning at their baseline visit. | 61 |
| Placebo Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the placebo arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of a placebo pill (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the placebo comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days).
Placebo: 100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit. | 64 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Withdrawal by Subject | 9 | 8 |
Baseline characteristics
| Characteristic | Total | Tadalafil | Placebo |
|---|---|---|---|
| Age, Continuous | 36.2 Years STANDARD_DEVIATION 7.9 | 36.5 Years STANDARD_DEVIATION 7.8 | 36.0 Years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 115 Participants | 58 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 12 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 88 Participants | 46 Participants | 42 Participants |
| Region of Enrollment United States | 125 participants | 61 participants | 64 participants |
| Sex: Female, Male Female | 87 Participants | 43 Participants | 44 Participants |
| Sex: Female, Male Male | 38 Participants | 18 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 64 |
| other Total, other adverse events | 36 / 61 | 19 / 64 |
| serious Total, serious adverse events | 0 / 61 | 0 / 64 |
Outcome results
Primary
Insulin Sensitivity After 12 Weeks of Drug Therapy
Subjects will undergo an insulin modified fasting intravenous glucose tolerance test (FS-IVGTT) protocol at 12 weeks adjusted statistically for the baseline measurement.
Time frame: 12 weeks
Population: Missing data from 2 participants in the Tadalafil arm, 5 participants in the placebo arm caused by inability to obtain intravenous access, which is necessary to make measurements for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tadalafil | Insulin Sensitivity After 12 Weeks of Drug Therapy | 1.4 ml/kg/min/μIU ml |
| Placebo | Insulin Sensitivity After 12 Weeks of Drug Therapy | 1.5 ml/kg/min/μIU ml |
Primary
Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day)
Subjects will undergo a metabolic chamber protocol to measure resting exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil | Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day) | 1267 kcal/day | Standard Deviation 133 |
| Placebo | Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day) | 1268 kcal/day | Standard Deviation 164 |
Secondary
Change in cGMP/NP Ratio After 12 Weeks of Drug Therapy
Subjects will undergo a fasting blood draw at baseline and 12 weeks to measure the change in ratio of plasma cyclic guanylate monophosphate pathway (cGMP) to plasma natriuretic peptides (NP) in response to the drug intervention (placebo or tadalafil).
Time frame: 12 weeks
Population: Due to lack of funding, the assays required to measure the participant samples were not performed and there is no data to report.
Secondary
Dual Energy X-Ray Absorptiometry (DEXA) (g)
fat mass at 12 weeks.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil | Dual Energy X-Ray Absorptiometry (DEXA) (g) | 47 grams | Standard Deviation 12 |
| Placebo | Dual Energy X-Ray Absorptiometry (DEXA) (g) | 50 grams | Standard Deviation 12 |
Secondary
Maximal Exercise Energy Expenditure (kcal/Day)
Subjects will undergo a metabolic chamber protocol to measure maximal exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement. Maximal Exercise Energy Expenditure will be measured as kcal/day
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil | Maximal Exercise Energy Expenditure (kcal/Day) | 4535 kcal/day | Standard Deviation 760 |
| Placebo | Maximal Exercise Energy Expenditure (kcal/Day) | 4588 kcal/day | Standard Deviation 976 |
Secondary
Maximal Oxygen Consumption
Subjects will undergo a symptom-limited cardiopulmonary exercise test to measure peak oxygen consumption (VO2 max). Maximal oxygen consumption will be measured as 'mL/min'.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil | Maximal Oxygen Consumption | 883 mL/min | Standard Deviation 142 |
| Placebo | Maximal Oxygen Consumption | 893 mL/min | Standard Deviation 186 |
Secondary
Physical Activity-induced Energy Expenditure (kcal/Day)
During the metabolic chamber protocol, conducted at baseline and at 12 weeks, the cardiopulmonary exercise test protocol will be conducted. The Energy Expenditure (EE) related to physical activity will be calculated as peak EE above the resting level while performing the exercise test.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil | Physical Activity-induced Energy Expenditure (kcal/Day) | 3320 kcal/day | Standard Deviation 866 |
| Placebo | Physical Activity-induced Energy Expenditure (kcal/Day) | 3269 kcal/day | Standard Deviation 714 |
Secondary
Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score
Quality of life will be assessed using the Medical Outcomes Study Short-Form Health Survey (SF-36). The SF-36 is a 36 question survey with a total score range from 0-100; higher scores indicate better quality of life.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil | Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score | 52.7 score on a scale | Standard Deviation 5.6 |
| Placebo | Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score | 51.0 score on a scale | Standard Deviation 6.9 |
Secondary
Sexual Function
The Female Sexual Function Index will be used to measure sexual function in women with a range from 2-36 with higher scores indicating better sexual function.
Time frame: 12 weeks
Population: Test only performed in women as designed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil | Sexual Function | 23.9 score on a scale | Standard Deviation 6.9 |
| Placebo | Sexual Function | 19.8 score on a scale | Standard Deviation 8.9 |