Cardiovascular Effects of GLP-1 Receptor Activation

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.

Study Overview

• Status: Completed
• Conditions: Obesity; PreDiabetes
• Intervention / Treatment: Drug: Liraglutide; Drug: Placebos; Drug: Exendin (9-39); Drug: Sitagliptin; Other: hypocaloric diet

• Study Type: Interventional
• Enrollment (Actual): 329
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men and women,
2. Age 18 to 65 years, and
3. FPG (100-125 mg/dL) or, IGT (two-hour plasma glucose 140-199 mg/dL) or, HbA1C 5.7-6.4%
4. BMI≥30 kg/M2
5. The ability to provide informed consent before any trial-related activities.

Exclusion Criteria:

1. 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
2. Resistant hypertension, defined as hypertension requiring the administration of more than three anti-hypertensive agents including a diuretic to achieve control
3. Use of spironolactone
4. Known or suspected allergy to trial medications, excipients, or related products.
5. Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma
6. Personal history of non-familial medullary thyroid carcinoma
7. History of pancreatitis
8. Contraindications to study medications, worded specifically as stated in the product's prescribing information
9. 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
10. 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
11. 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
12. Treatment with anticoagulants
13. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack
14. History or presence of immunological or hematological disorders
15. Diagnosis of asthma requiring regular inhaler use
16. Clinically significant gastrointestinal impairment that could interfere with drug absorption
17. Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3.0 x upper limit of normal range)
18. 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)
19. Hematocrit <35%
20. 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
21. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
22. Treatment with lithium salts
23. History of alcohol or drug abuse
24. Treatment with any investigational drug in the one month preceding the study
25. Previous randomization in this trial
26. Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study
27. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Liraglutide; subcutaneous liraglutide daily; Drug: Placebos; 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.; Drug: Exendin (9-39); 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.
Active Comparator: sitagliptin; Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.	Drug: Placebos; 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.; Drug: Exendin (9-39); 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.; Drug: Sitagliptin; oral sitagliptin daily
Active Comparator: 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.	Drug: Placebos; 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.; Drug: Exendin (9-39); 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.; Other: hypocaloric diet; Reduced calorie intake to achieve weight loss.

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Weight	Weight measured in light clothing without shoes	Change from baseline to 14 weeks

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: American Heart Association
• Investigators: Principal Investigator: James M. Luther, M.D., Vanderbilt University Medical Center

Publications and helpful links

Helpful Links

• Study Pre-print on medRxiv

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2017
• Primary Completion (Actual): June 24, 2021
• Study Completion (Actual): June 24, 2021

Study Registration Dates

• First Submitted: March 27, 2017
• First Submitted That Met QC Criteria: March 30, 2017
• First Posted (Actual): April 5, 2017

Study Record Updates

• Last Update Posted (Actual): October 18, 2022
• Last Update Submitted That Met QC Criteria: September 25, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Prediabetic State; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Liraglutide; Sitagliptin Phosphate
• Other Study ID Numbers: IRB# 170213

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available to researchers who provide a methodologically sound proposal that has been approved by the Vanderbilt Institutional Review Board and the study executive committee.
• IPD Sharing Time Frame: The data will become available 3 months following publication of outcomes and will remain available for at least 5 years.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes