PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

Healthy Clinical Trial

Official title:

PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02819440
• Other study ID #: 160208
• Status: Completed
• Phase: Phase 2
• Start date: July 2016
• Est. completion date: June 2020

Study information

• Verified date: May 2022
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 141
• Est. completion date: June 2020
• Est. primary completion date: June 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy
• Obese
• Obesity

Intervention

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	12 weeks
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.	12 weeks
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.	12 weeks
Secondary	Dual Energy X-Ray Absorptiometry (DEXA) (g)	fat mass at 12 weeks.	12 weeks
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.	12 weeks
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).	12 weeks
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'.	12 weeks
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.	12 weeks
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"	12 weeks