GLP-1 Therapy: The Role of IL-6 Signaling and Adipose Tissue Remodeling in Metabolic Response

NCT04387201 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: HSC-MS-19-0787R21DK122234
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

This project investigates the anti-obesity mechanisms of glucagon-like peptide-1 (GLP-1) analogs, which are used in the treatment of human obesity and diabetes mellitus. The investigators will test if GLP-1 induces secretion of interleukin-6 (IL-6), a cytokine that may collaborate with GLP-1 analogs to induce the formation of brown fat, which has anti-diabetic properties. The results will guide future obesity and diabetes mellitus therapies.

Conditions

Glucose Intolerance; Overweight and Obesity; Drug Effect; Adiposity

Keywords

GLP-1; prediabetes; brown fat; adipose tissue; IL-6

Outcome Measures

Primary Outcomes (3)

• Cytokine Interleukin-6 (IL-6) Messenger Ribonucleic Acid (mRNA) Level (From Adipose Tissue)

  natural log transformed data is reported

  6 weeks after start of each intervention

• Uncoupling Protein 1 (UCP1) Messenger Ribonucleic Acid (mRNA) Level (From Adipose Tissue)

  Uncoupling protein 1 (UCP1) is a marker of beige/brown fat. natural log transformed data is reported

  6 weeks after start of each intervention

• Signal Transducer and Activator of Transcription 3 (STAT3) Band Intensity/Western Blot (From Adipose Tissue)

  signaling intermediary with interleukin-6

  6 weeks after start of each intervention

Secondary Outcomes (22)

• PR Domain Containing 16 (PRDM16) Messenger Ribonucleic Acid (mRNA) Level ((From Adipose Tissue)

  6 weeks after start of each intervention

• Nicotinamide Adenine Dinucleotide Dehydrogenase (Ubiquinone) Iron-sulfur protein3 (NDUFS3) (From Adipose Tissue)

  6 weeks after start of each intervention

• Beta1-adrenoceptor (ADRB1) (From Adipose Tissue)

  6 weeks after start of each intervention

• Beta2-adrenoceptor (ADRB2) (From Adipose Tissue)

  6 weeks after start of each intervention

• Beta3-adrenoceptor (ADRB3) (From Adipose Tissue)

  6 weeks after start of each intervention

Study Arms (2)

Cyanocobalamin, then Dulaglutide

EXPERIMENTAL

Participants first received Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks. After a washout period of 3 weeks, they then received Dulaglutide 0.75 mg subcutaneous weekly for 2 weeks, followed by 1.5 mg subcutaneous weekly for 4 weeks

Drug: Cyanocobalamin; Drug: Dulaglutide

Dulaglutide, then Cyanocobalamin

EXPERIMENTAL

Participants first received Dulaglutide 0.75 mg subcutaneous weekly for 2 weeks, followed by 1.5 mg subcutaneous weekly for 4 weeks. After a washout period of of 3 weeks, they then Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks.

Drug: Cyanocobalamin; Drug: Dulaglutide

Interventions

Cyanocobalamin DRUG

Cyanocobalamin (vitamin B12) 1000 mcg subcutaneous weekly for 6 weeks.

Also known as: Vitamin B12

Cyanocobalamin, then Dulaglutide; Dulaglutide, then Cyanocobalamin

Dulaglutide DRUG

Dulaglutide 0.75 mg subcutaneous weekly for 2 weeks, followed by 1.5 mg subcutaneous weekly for 4 weeks

Also known as: Trulicity

Cyanocobalamin, then Dulaglutide; Dulaglutide, then Cyanocobalamin

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Men and women, ages 18-50 years
• Diagnosis of Prediabetes - defined as either impaired fasting glucose (fasting glucose of 100-125 mg/dL), impaired glucose tolerance (2-hour postprandial blood glucose of 140-199 mg/dL after 75-gram oral glucose challenge), and/or a hemoglobin A1C ranging from 5.5% to 6.4%.
• BMI ≤ 35 kg/m2
• Women of childbearing age must agree to use an acceptable method of pregnancy prevention (barrier methods, abstinence, oral contraception, vaginal rings, long-acting reversible contraceptives, or surgical sterilization) for the duration of the study
• Patients must have the following laboratory values: Hematocrit ≥ 33 vol%, estimated glomerular filtration rate ≥ 60 mL/min per 1.73 m2, AST (SGOT) \< 2.5 times ULN, ALT (SGPT) \< 2.5 times ULN, alkaline phosphatase \< 2.5 times ULN
• If patients are receiving antihypertensive medications (other than beta blockers) and/or lipid-lowering medications, they must remain on stable doses for the duration of the study.
• If patients are receiving NSAIDs or antioxidant vitamins, these must be discontinued one week prior to study initiation and cannot be restarted during the study.
• If patient takes thyroid medications, these must be dosed to control hypo- or hyperthyroidism.

You may not qualify if:

• History of Type 1 or Type 2 diabetes mellitus
• Pregnant or breastfeeding women
• Medications: Beta blockers, corticosteroids, monoamine oxidase inhibitors, diabetes medications (including incretin mimetics and thiazolidinediones), and/or immunosuppressive therapy over the last 2 months.
• Uncontrolled hypo- or hyperthyroidism
• Current tobacco use
• Active malignancy
• History of clinically significant cardiac, hepatic, or renal disease.
• History of any serious hypersensitivity reaction to study medications, any other incretin mimetic, any other formulation of supplemental vitamin B12, and/or cobalt
• Personal or family history of Leber hereditary optic nerve atrophy
• Prisoners or subjects who are involuntarily incarcerated
• Compulsorily detention for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Prior history of pancreatitis, medullary thyroid cancer, or multiple endocrine neoplasia type 2 (MEN 2)
• Serum vitamin B12 level above the upper limit of assay detection

Sponsors & Collaborators

• The University of Texas Health Science Center, Houston: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

The University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Glucose Intolerance; Overweight; Obesity; Prediabetic State

Interventions

Vitamin B 12; dulaglutide

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Corrinoids; Tetrapyrroles; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Absalon D Gutierrez, MD
• Organization: The University of Texas Health Science Center at Houston

absalon.d.gutierrez@uth.tmc.edu

713-500-6641

Study Officials

• Absalon D Gutierrez, MD

  The University of Texas Health Science Center at Houston, Dept. of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: Crossover clinical trial

Study Record Dates

• First Submitted: May 6, 2020
• First Posted: May 13, 2020
• Study Start: May 15, 2020
• Primary Completion: October 6, 2023
• Study Completion: October 6, 2023
• Last Updated: December 5, 2024
• Results First Posted: December 5, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data will become available one year after the primary completion date of the clinical trial, or 6 months post-publication, or 18 months after award end date - whichever comes first. Data will then be available indefinitely.
• Access Criteria: Anyone can access the data via clinicaltrials.gov. If applicable, data will also be shared via the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Information Network.

Locations

US (1)