Cardiovascular Effects of GLP-1 Receptor Activation

Phase 4

Completed

Conditions: Obesity
PreDiabetes

Interventions: Other: hypocaloric diet
Drug: Liraglutide
Drug: Sitagliptin
Drug: Placebos
Drug: Exendin (9-39)

Registration Number: NCT03101930

Lead Sponsor: Vanderbilt University Medical Center

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 329

Inclusion Criteria

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.

Exclusion Criteria

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
liraglutide	Placebos	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.
sitagliptin	Placebos	Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.
hypocaloric diet	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.
hypocaloric diet	Placebos	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.
liraglutide	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.
sitagliptin	Sitagliptin	Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.
liraglutide	Exendin (9-39)	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.
sitagliptin	Exendin (9-39)	Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.
hypocaloric diet	Exendin (9-39)	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.

Primary Outcome Measures

Name	Time	Method
Change in Flow-mediated Dilation	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	Baseline to 13 weeks	Ratio of urine albumin to creatinine in a spot urine collected after overnight rest
Change in Plasminogen Activator Inhibitor-1	Baseline to 2 and 14 weeks	Plasma plasminogen activator inhibitor-1 antigen

Secondary Outcome Measures

Name	Time	Method
Blood Pressure	Baseline, and after 2 weeks and 14 weeks of treatment	The mean of three systolic blood pressure measurements one minute apart using a oscillometric recording device with patient in supine position
Heart Rate	Baseline, and after 2 weeks and 14 weeks of treatment	The mean of three measurements with the patient in the supine position
Fasting Glucose	Baseline, and after 2 weeks and 14 weeks of treatment	Blood glucose collected after overnight fast
Fasting Insulin	Baseline, and after 2 weeks and 14 weeks of treatment	Plasma insulin collected after overnight fast