PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 141
- 试验地点
- 1
- 主要终点
- Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 21 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Adults (ages 21-50)
- •Obesity (BMI ≥ 30 kg/m2)
- •Prediabetes on oral glucose tolerance test.
排除标准
- •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
研究组 & 干预措施
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).
干预措施: Tadalafil (Drug)
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).
干预措施: Placebo (Drug)
结局指标
主要结局
Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day)
时间窗: 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
时间窗: 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.
次要结局
- Dual Energy X-Ray Absorptiometry (DEXA) (g)(12 weeks)
- Physical Activity-induced Energy Expenditure (kcal/Day)(12 weeks)
- Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score(12 weeks)
- Change in cGMP/NP Ratio After 12 Weeks of Drug Therapy(12 weeks)
- Maximal Oxygen Consumption(12 weeks)
- Sexual Function(12 weeks)
- Maximal Exercise Energy Expenditure (kcal/Day)(12 weeks)
研究者
Evan Brittain
Principal Investigator
Vanderbilt University Medical Center