Cardiovascular Effects of GLP-1 Receptor Activation

NCT ID: NCT03101930

Last Updated: 2022-10-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 329 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-01
• Study Completion Date: 2021-06-24

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Liraglutide

Intervention Type: DRUG

subcutaneous liraglutide daily

Placebos

Intervention Type: 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.

Exendin (9-39)

Intervention Type: 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.

sitagliptin

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

Group Type: ACTIVE_COMPARATOR

Sitagliptin

Intervention Type: DRUG

oral sitagliptin daily

Placebos

Intervention Type: 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.

Exendin (9-39)

Intervention Type: 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

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.

Group Type: ACTIVE_COMPARATOR

hypocaloric diet

Intervention Type: OTHER

Reduced calorie intake to achieve weight loss.

Placebos

Intervention Type: 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.

Exendin (9-39)

Intervention Type: 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.

Interventions

Liraglutide

subcutaneous liraglutide daily

Intervention Type: DRUG

Sitagliptin

oral sitagliptin daily

Intervention Type: DRUG

hypocaloric diet

Reduced calorie intake to achieve weight loss.

Intervention Type: OTHER

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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

American Heart Association

OTHER

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

James Matt Luther

Associate Professor of Medicine and Pharmacology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

James M. Luther, M.D.

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.medrxiv.org/content/10.1101/2022.02.23.22271434v1

Study Pre-print on medRxiv

Other Identifiers

IRB# 170213

Identifier Type: -

Identifier Source: org_study_id