Cardiovascular Effects of GLP-1 Receptor Activation

NCT03101930 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: IRB# 170213
• Study Type: interventional
• Target: 329
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity; PreDiabetes

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (4)

• 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

Other Outcomes (1)

• Change in Weight

  Change from baseline to 14 weeks

Study Arms (3)

liraglutide

EXPERIMENTAL

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; Drug: Placebos; Drug: Exendin (9-39)

sitagliptin

ACTIVE COMPARATOR

Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.

Drug: Sitagliptin; Drug: Placebos; Drug: Exendin (9-39)

hypocaloric diet

ACTIVE COMPARATOR

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; Drug: Placebos; Drug: Exendin (9-39)

Interventions

Liraglutide DRUG

subcutaneous liraglutide daily

liraglutide

Sitagliptin DRUG

oral sitagliptin daily

sitagliptin

hypocaloric diet OTHER

Reduced calorie intake to achieve weight loss.

hypocaloric diet

Placebos DRUG

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.

hypocaloric diet; liraglutide; sitagliptin

Exendin (9-39) DRUG

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.

hypocaloric diet; liraglutide; sitagliptin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead
• American Heart Association: collaborator

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Links

• Study Pre-print on medRxiv

MeSH Terms

Conditions

Obesity; Prediabetic State

Interventions

Liraglutide; Sitagliptin Phosphate; exendin (9-39)

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines

Limitations and Caveats

Study enrollment and conduct interrupted due to COVID-19 pandemic. Exendin not available for all study participants.

Results Point of Contact

• Title: Dr. James M. Luther, MD MSCI (Principal Investigator)
• Organization: Vanderbilt University Medical Center

james.luther@vumc.org

(615) 936-3420

Study Officials

• James M. Luther, M.D.

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Treatment with liraglutide or sitagliptin will be masked using matching placebo.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine and Pharmacology

Study Record Dates

• First Submitted: March 27, 2017
• First Posted: April 5, 2017
• Study Start: May 1, 2017
• Primary Completion: June 24, 2021
• Study Completion: June 24, 2021
• Last Updated: October 18, 2022
• Results First Posted: August 16, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: The data will become available 3 months following publication of outcomes and will remain available for at least 5 years.

Locations

US (1)