Cardiovascular Effects of GLP-1 Receptor Activation

Study Overview
=================
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.

Official Title
-----------------
Cardiovascular Effects of GLP-1 Receptor Activation

Conditions
-----------------
Obesity, PreDiabetes

Intervention / Treatment
-----------------
* Drug: Liraglutide
* Drug: Sitagliptin
* Other: hypocaloric diet
* Drug: Placebos
* Drug: Exendin (9-39)


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: liraglutide<br>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. | Drug: Liraglutide<br>* subcutaneous liraglutide daily<br>Drug: Placebos<br>* Subjects in the liraglutide arm will receive a placebo for sitagliptin. Those in the sitagliptin arm will receive a placebo for liraglutide. All subjects will receive a placebo for Exendin 9-39.<br>Drug: Exendin (9-39)<br>* All subjects will receive Exendin (9-39) or matching placebo in crossover fashion during study days on the first and third days of the second week after randomization and again on the 5th and 7th days of the 14th week of treatment.<br>|
| Active Comparator: sitagliptin<br>Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks. | Drug: Sitagliptin<br>* oral sitagliptin daily<br>Drug: Placebos<br>* Subjects in the liraglutide arm will receive a placebo for sitagliptin. Those in the sitagliptin arm will receive a placebo for liraglutide. All subjects will receive a placebo for Exendin 9-39.<br>Drug: Exendin (9-39)<br>* All subjects will receive Exendin (9-39) or matching placebo in crossover fashion during study days on the first and third days of the second week after randomization and again on the 5th and 7th days of the 14th week of treatment.<br>|
| Active Comparator: hypocaloric diet<br>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. | Other: hypocaloric diet<br>* Reduced calorie intake to achieve weight loss.<br>Drug: Placebos<br>* Subjects in the liraglutide arm will receive a placebo for sitagliptin. Those in the sitagliptin arm will receive a placebo for liraglutide. All subjects will receive a placebo for Exendin 9-39.<br>Drug: Exendin (9-39)<br>* All subjects will receive Exendin (9-39) or matching placebo in crossover fashion during study days on the first and third days of the second week after randomization and again on the 5th and 7th days of the 14th week of treatment.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Flow-mediated Dilation | Brachial artery diameter is measured under basal conditions and during reactive hyperemia (Flow Mediated Dilation as %) | Baseline to 2 and 14 weeks | 
| Urine Albumin-to-creatinine Ratio | Ratio of urine albumin to creatinine in a spot urine collected after overnight rest | Baseline to 13 weeks | 
| Change in Plasminogen Activator Inhibitor-1 | Plasma plasminogen activator inhibitor-1 antigen | Baseline to 2 and 14 weeks | 

Secondary Outcome Measures

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