Cardiovascular Effects of GLP-1 Receptor Activation
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 329
- 试验地点
- 1
- 主要终点
- Change in Flow-mediated Dilation
研究概览
简要总结
This project tests the principle hypothesis that stable glucagon like peptide-1 (GLP-1) analogues have specific GLP1R-dependent beneficial effects on vascular endothelial function, fibrinolysis and inflammation in obesity that exceed the benefits of weight loss, and that genetic or other individual factors that modulate GLP1R sensitivity can modify the effect of these analogues on cardiovascular risk.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Treatment with liraglutide or sitagliptin will be masked using matching placebo.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women,
- •Age 18 to 65 years, and
- •FPG (100-125 mg/dL) or, IGT (two-hour plasma glucose 140-199 mg/dL) or, HbA1C 5.7-6.4%
- •BMI≥30 kg/M2
- •The ability to provide informed consent before any trial-related activities.
排除标准
- •Diabetes type 1 or type 2, as defined by a FPG of 126 mg/dL or greater, a two-hour plasma glucose of 200 mg/dL or greater, or the use of anti-diabetic medication
- •Resistant hypertension, defined as hypertension requiring the administration of more than three anti-hypertensive agents including a diuretic to achieve control
- •Use of spironolactone
- •Known or suspected allergy to trial medications, excipients, or related products.
- •Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma
- •Personal history of non-familial medullary thyroid carcinoma
- •History of pancreatitis
- •Contraindications to study medications, worded specifically as stated in the product's prescribing information
- •Pregnancy or breast-feeding. Women of child-bearing potential will be required to have undergone tubal ligation or to be using an oral contraceptive or barrier methods of birth control
- •Subjects who have participated in a weight-reduction program during the last six month or whose weight has increased or decreased more than two kg over the preceding six months
- •Cardiovascular disease such as myocardial infarction within six months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (left ventricular hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
- •Treatment with anticoagulants
- •History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack
- •History or presence of immunological or hematological disorders
- •Diagnosis of asthma requiring regular inhaler use
- •Clinically significant gastrointestinal impairment that could interfere with drug absorption
- •Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3.0 x upper limit of normal range)
- •Individuals with an eGFR<30 mL/min/1.73 m2 or with a UACR >1000µg/mg, where eGFR is determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine is expressed in mg/dL and age in years: eGFR (mL/min/1.73m2)=186 • Scr-1.154 • age-0.203 • (1.212 if black) • (0.742 if female)
- •Hematocrit <35%
- •Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
- •Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
- •Treatment with lithium salts
- •History of alcohol or drug abuse
- •Treatment with any investigational drug in the one month preceding the study
- •Previous randomization in this trial
- •Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study
- •Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
研究组 & 干预措施
liraglutide
Subjects in the liraglutide group will receive subcutaneous liraglutide (0.6 mg/d for one week, 1.2 mg/d for one week, and then 1.8 mg/d for 12 weeks) and oral placebo.
干预措施: Liraglutide (Drug)
liraglutide
Subjects in the liraglutide group will receive subcutaneous liraglutide (0.6 mg/d for one week, 1.2 mg/d for one week, and then 1.8 mg/d for 12 weeks) and oral placebo.
干预措施: Placebos (Drug)
liraglutide
Subjects in the liraglutide group will receive subcutaneous liraglutide (0.6 mg/d for one week, 1.2 mg/d for one week, and then 1.8 mg/d for 12 weeks) and oral placebo.
干预措施: Exendin (9-39) (Drug)
sitagliptin
Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.
干预措施: Sitagliptin (Drug)
sitagliptin
Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.
干预措施: Placebos (Drug)
sitagliptin
Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.
干预措施: Exendin (9-39) (Drug)
hypocaloric diet
Subjects in the hypocaloric diet group will be given a caloric goal designed to achieve a weight loss similar to that expected in the liraglutide treatment arm based on his or her resting energy expenditure. Subjects will be provided counseling and written instructions on how to achieve their daily caloric goal, including use of their own mobile phone applications to monitor caloric intake. To assure compliance with the prescribed caloric goal, subjects will meet with the study dietitian every other week for problem solving and review of diet intake logs.
干预措施: hypocaloric diet (Other)
hypocaloric diet
Subjects in the hypocaloric diet group will be given a caloric goal designed to achieve a weight loss similar to that expected in the liraglutide treatment arm based on his or her resting energy expenditure. Subjects will be provided counseling and written instructions on how to achieve their daily caloric goal, including use of their own mobile phone applications to monitor caloric intake. To assure compliance with the prescribed caloric goal, subjects will meet with the study dietitian every other week for problem solving and review of diet intake logs.
干预措施: Placebos (Drug)
hypocaloric diet
Subjects in the hypocaloric diet group will be given a caloric goal designed to achieve a weight loss similar to that expected in the liraglutide treatment arm based on his or her resting energy expenditure. Subjects will be provided counseling and written instructions on how to achieve their daily caloric goal, including use of their own mobile phone applications to monitor caloric intake. To assure compliance with the prescribed caloric goal, subjects will meet with the study dietitian every other week for problem solving and review of diet intake logs.
干预措施: Exendin (9-39) (Drug)
结局指标
主要结局
Change in Flow-mediated Dilation
时间窗: Baseline to 2 and 14 weeks
Brachial artery diameter is measured under basal conditions and during reactive hyperemia (Flow Mediated Dilation as %)
Urine Albumin-to-creatinine Ratio
时间窗: Baseline to 13 weeks
Ratio of urine albumin to creatinine in a spot urine collected after overnight rest
Change in Plasminogen Activator Inhibitor-1
时间窗: Baseline to 2 and 14 weeks
Plasma plasminogen activator inhibitor-1 antigen
次要结局
- Blood Pressure(Baseline, and after 2 weeks and 14 weeks of treatment)
- Heart Rate(Baseline, and after 2 weeks and 14 weeks of treatment)
- Fasting Glucose(Baseline, and after 2 weeks and 14 weeks of treatment)
- Fasting Insulin(Baseline, and after 2 weeks and 14 weeks of treatment)
研究者
James Matt Luther
Associate Professor of Medicine and Pharmacology
Vanderbilt University Medical Center