Clinical trial NCT02819440: PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction
Official title: PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Healthy
Obese
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2016-06-30
Enrollment: 141
Sex: ALL
Minimum age (years): 21
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day)
timeFrame: 12 weeks
measure: Insulin Sensitivity After 12 Weeks of Drug Therapy
timeFrame: 12 weeks
Secondary outcomes:
measure: Physical Activity-induced Energy Expenditure (kcal/Day)
timeFrame: 12 weeks
measure: Dual Energy X-Ray Absorptiometry (DEXA) (g)
timeFrame: 12 weeks
measure: Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score
timeFrame: 12 weeks
measure: Change in cGMP/NP Ratio After 12 Weeks of Drug Therapy
timeFrame: 12 weeks
measure: Maximal Oxygen Consumption
timeFrame: 12 weeks
measure: Sexual Function
timeFrame: 12 weeks
measure: Maximal Exercise Energy Expenditure (kcal/Day)
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt Cardiovascular Medicine
name: Evan L Brittain, MD, MSCI
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt Cardiovascular Medicine
name: Thomas J Wang, MD
role: PRINCIPAL_INVESTIGATOR
References: