Effect of Liraglutide (Victoza) on Inflammation in Human Adipose Tissue and Blood

Phase 1

Completed

• Conditions: Diabetes Mellitus, Type II; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Type 2; Inflammation
• Interventions: Drug: Victoza (liraglutide) with dietician monitoring; Other: Placebo with dietician monitoring

• Registration Number: NCT02650206
• Lead Sponsor: Stanford University

Brief Summary

The objective of this study is to test the hypothesis that liraglutide (commonly known as Victoza) can promote an anti-inflammatory macrophage phenotype in human adipose tissue and blood, thereby reducing localized and systemic inflammation which are risk factors for cardiovascular disease and may contribute to hyperglycemia. This will be done after 4 weeks of treatment during which weight will remain stable, and again after 12 weeks, during which liraglutide-related weight loss occurs.

Detailed Description

It has now been established that the high risk of cardiovascular disease that is associated with obesity and type 2 diabetes is related to the systemic inflammation that underlies these conditions. Previous studies have shown that there are numerous types of immune cells in human adipose tissue, some of these are the macrophages. These cells can exist in two states: M2, which can inhibit classical inflammatory response, and M1 which secrete proinflammatory cytokines. The investigators have data to suggest that the role of inflammatory cells in adipose tissue is a strong contributor to systemic inflammation. A recent study showed that a GLP-1 analog (liraglutide, also known as Victoza) may help decrease inflammation via promoting M2 differentiation of macrophages. The purpose of this study is to quantify macrophage phenotype (M1 vs M2) in subcutaneous adipose tissue in moderately-obese diet controlled diabetics at baseline, after four weeks of weight-maintenance using liraglutide, and after 12 weeks of liraglutide treatment as compared to placebo.

Aim 1: Quantify M1 and M2 (surface and intracellular markers) polarization via flow cytometry in subcutaneous abdominal adipose tissue and peripheral blood mononuclear cells at baseline and after 4 weeks administration of liraglutide versus placebo to weight-stable, obese, type 2 diabetic patients. Weight loss will be prevented in order to ascertain the effect of liraglutide alone.

Aim 2: Quantify M1 and M2 (surface and intracellular markers) polarization via flow cytometry in subcutaneous adipose tissue and peripheral blood mononuclear cells after 12 weeks of liraglutide treatment, during which dietary restrictions are lifted and spontaneous weight loss, as would occur in the clinical setting, is allowed. To eliminate confounding by weight loss, a placebo-treated group will undergo matched dietary weight loss for comparison to the liraglutide group to ascertain whether changes in macrophage polarization at 12 weeks are greater in the liraglutide group.

Aim 3: Quantify macrophage-mediated localized and systemic inflammation by measuring M1/M2-related inflammatory cytokines in adipose tissue and peripheral blood after 4 and 12 weeks administration of liraglutide versus placebo to obese, type 2 diabetic patients.

Study Timeline

• Study Start: 2015-01
• Study First Submitted: 2015-06-05
• Study First Submitted QC: 2016-01-07
• Study First Posted: 2016-01-08
• Primary Completion: 2019-09-27
• Study Completion: 2019-09-27
• Status Verified: 2020-06
• Last Update Submitted: 2020-06-06
• Last Update Posted: 2020-06-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 56

Inclusion Criteria

• BMI between 25 and 42 kg/m2
• Diet-controlled diabetics, or diabetics on Metformin that have permission from Primacy Care Physician to wash-out of the drug for 6 weeks prior to the study and for the duration of the study
• HbA1C between 6.0 - 7.9 (those on Metformin must have a HbA1c level below 7.5 prior to wash-out period)
• Fasting Blood Glucose < 150 mg/dl
• Women must be post-menopausal or surgically sterile within age range
• Subjects must live in vicinity of Stanford University

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Exclusion Criteria

• Prior Bariatric surgery
• Personal or family history of medullary thyroid cancer
• MEN2 Syndrome
• Thyroid Nodules (not evaluated by PCP)
• Pancreatitis (acute or chronic)
• Gallstones
• Fasting plasma triglycerides > 400 mg/dl
• Cardiovascular disease
• Major organ disease
• Unstable hypertension (BP >160/100 mm Hg)
• Heavy alcohol use
• Self-reported weight change of >2kg over past 6 weeks
• Medication known to affect blood glucose, insulin sensitivity, or inflammation
• NSAIDs (must cease use 4 weeks prior to study enrollment)
• Previous use of liraglutide, Januvia, Byetta, or Lira.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Liraglutide group	Victoza (liraglutide) with dietician monitoring	Drug with diet control intervention: Subjects assigned to this group receive blinded pens containing liraglutide (commonly known as Victoza), manufactured by Novo Nordisk. Subjects will inject 0.6 mg daily into abdomen during the first week of the study, and if tolerated, will increase dose to 1.2 mg the second week of the study, and then up to 1.8 mg daily from the third week until the end of the 12-week study. Any adverse symptoms as well as fasting blood glucose will be monitored weekly for safety. Subjects, with the guidance of the study's dietitian, will remain weight-stable for the first four weeks of the study, and then will be allowed to lose weight for the remaining eight weeks of the study.
Placebo group	Placebo with dietician monitoring	Diet control-only intervention: Subjects assigned to this group receive blinded pens containing placebo (normal saline) instead of liraglutide (commonly known as Victoza). Subjects will inject 0.6 mg of placebo daily during the first week of the study, will increase to 1.2 mg the second week of the study, and then up to 1.8 mg daily from the third week until the end of the 12-week study. Any adverse symptoms as well as fasting blood glucose will be monitored weekly for safety. Subjects, with the guidance of the study's dietitian, will remain weight-stable for the first four weeks of the study, and then will be allowed to lose weight for the remaining eight weeks of the study.

Primary Outcome Measures

Name	Time	Method
Macrophage polarization: % M2 macrophages in adipose tissue and peripheral blood according to positivity for cell surface markers (measured by flow cytometry).	30 months

Secondary Outcome Measures

Name	Time	Method
Inflammation, localized: Pro- and anti-inflammatory cytokines will be measured (IL6, IL-8, TNF-α, MCP-1, cell surface markers, and adiponectin) by rtPCR in adipose tissue and blood macrophages	30 months
Inflammation, systemic: Plasma pro/anti-inflammatory cytokines: IL-6, hsCRP, cell surface markers, and adiponectin will be measured in plasma.	30 months
Macrophage polarization: M1 to M2 ratio in adipose tissue and peripheral blood according to cell surface markers (measured by flow cytometry)	30 months

Trial Locations

Locations (1)

Freidenrich Center for Translational Research (FCTR); 🇺🇸 Stanford, California, United States