A Trial of Tadalafil and Glycemic Traits

Phase 3

Completed

Conditions: Cardiovascular Disease
Obesity
Insulin Resistance
Glucose Intolerance

Interventions: Drug: Tadalafil
Drug: Placebo

Registration Number: NCT01444651

Lead Sponsor: Thomas J. Wang, MD

Brief Summary: The purpose of this study is to find out if tadalafil can help overweight and obese people metabolize blood sugar more efficiently. The investigators also want to find out if 20 mg/day of tadalafil for 3 months is safe to take without causing too many side effects. The investigators are plan to enroll 100 subjects at Massachusetts General Hospital (MGH).

Detailed Description: This study is examining changes in insulin resistance and glucose tolerance following 3 months of treatment with oral, once daily tadalafil.

The investigators primary hypotheses are that measurable decreases in insulin resistance (as measured by HOMA-IR) and increases in insulin sensitivity (as measured by the Matsuda index) will occur following 3 months of treatment with oral tadalafil 20 mg daily compared to placebo.

The investigators secondary hypotheses are that improvements in average glycemia (as measured by hemoglobin A1C), pancreatic beta cell function (as measured by the oral disposition index), and body composition (including weight, waist circumference, body mass index, and waist-hip ratio) will occur as a result of tadalafil-mediated changes in the cGMP pathway.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 73

Inclusion Criteria

Age > 18 years and < 50 years
BMI > 30 kg/m2
Fasting insulin > 10 uU/mL

Exclusion Criteria

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 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%)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tadalafil	Tadalafil	20 mg Tadalafil tablet taken by mouth once a day for 3 months
Placebo	Placebo	Placebo tablet taken by mouth once a day for 3 months

Primary Outcome Measures

Name	Time	Method
Change in Insulin Resistance From Baseline to 3 Months, as Measured by HOMA-IR	Baseline and 3 months	The primary endpoint is defined as the treatment group difference in the change in insulin resistance (baseline HOMA-IR minus 3-month HOMA-IR). HOMA-IR = \[fasting glucose \* fasting insulin\]/405

Secondary Outcome Measures

Name	Time	Method
Baseline to 3-month Change in Insulin Sensitivity, as Measured by the Matsuda Index	Baseline and 3 months	The secondary endpoint is defined as the treatment group difference in the change in Matsuda Index (baseline minus 3-month). This index is a measure of insulin resistance derived from a frequently sampled oral glucose tolerance test, obtaining glucose and insulin levels in the fasting state, as well as 30, 60, 90, and 120 min after administration of oral glucose load. Matsuda index = 10,000/SQRT \[fasting glucose\fasting insulin\ (mean glucose from time 30, 60, 90, 120 min) \* (mean insulin at time 30, 60, 90, and 120 min)\]
Baseline to 3-month Change in Endothelial Function Measured by EndoPAT	Baseline and 3 months	Endothelial function was measured using the reactive hyperemia index, acquired using EndoPAT device. Peripheral arterial tonometry probes were placed on both index fingers. After a 5 min equilibration period, a blood pressure cuff was inflated to 200 mmHg and kept inflated for 5 min. The cuff was then rapidly deflated and the reactive hyperemic response pulse volume recorded, where RHI = ratio of hyperemic finger pulse volume (post-cuff inflation / pre-cuff inflation) to control finger pulse volume (post-cuff inflation / pre-cuff inflation)
Insulinogenic Index	Baseline and 3 months	The secondary endpoint is defined as the treatment group difference in the change in insulinogenic index (baseline minus 3-month). This index is thought to reflect insulin secretion, and is derived from fasting and 30 min-post oral glucose tolerance testing glucose and insulin values. Insulinogenic index = \[fasting insulin - insulin at time 30 min\] / \[fasting glucose - glucose at time 30 min\]
Baseline to 3 Month Change in Composite of Insulin Resistance and Sensitivity, as Measured by the Oral Disposition Index	Baseline and 3 months	The secondary endpoint is defined as the treatment group difference in the change in oral disposition index (baseline minus 3-month). This is thought to reflect a composite of both insulin resistance and secretion. Oral disposition index = insulinogenic index / fasting insulin
Baseline to 3-month Change in Matsuda Disposition Index	Baseline and 3 months	Change in disposition index from baseline to 3 months. This index is a composite measure thought to reflect insulin resistance and secretion. Matsuda disposition index = \[Matsuda sensitivity index \* insulinogenic index\]