PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

Study Overview
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Brief Summary
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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
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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.

Official Title
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PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

Conditions
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Healthy, Obese

Intervention / Treatment
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* Drug: Tadalafil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tadalafil<br>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). | Drug: Tadalafil<br>* 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.<br>* Other names: CIALIS;|
| Placebo Comparator: Placebo<br>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). | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 12 weeks | 
| 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. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 12 weeks | 
| Dual Energy X-Ray Absorptiometry (DEXA) (g) | fat mass at 12 weeks. | 12 weeks | 
| 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. | 12 weeks | 
| 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). | 12 weeks | 
| 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'. | 12 weeks | 
| 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. | 12 weeks | 
| 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 | 12 weeks |