PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

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.

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