Purpose

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

Eligibility

Eligible Ages
Between 18 Years and 65 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 Design

Phase
Phase 4
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Basic Science
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Treatment with liragultide or sitagliptin will be masked using matching placebo.

Arm Groups

ArmDescriptionAssigned Intervention
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: Sitagliptin
    oral sitagliptin 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
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.
  • Other: hypocaloric diet
    Reduced calorie intake to achieve weight loss.
  • 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.

Recruiting Locations

Vanderbilt University Medical Center
Nashville, Tennessee 37232
Contact:
Dustin Mayfield, RN
615-343-8701

More Details

NCT ID
NCT03101930
Status
Recruiting
Sponsor
Vanderbilt University Medical Center

Study Contact

Nancy J. Brown, M.D.
615-343-8701
nancy.j.brown@vanderbilt.edu

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.