PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

Phase 2

Completed

Conditions: Healthy
Obese

Interventions: Drug: Placebo
Drug: Tadalafil

Registration Number: NCT02819440

Lead Sponsor: Vanderbilt University Medical Center

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 141

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	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).
Tadalafil	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).

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Dual Energy X-Ray Absorptiometry (DEXA) (g)	12 weeks	fat mass at 12 weeks.
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.
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).
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'.
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"