Using Salsalate to Target Adipocyte Macrophage Infiltration

NCT02130804 | Completed Phase 1

• 1 other identifier: HS-11-00017
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

Background: The prevalence of obesity has increased throughout the last three decades due to genetic, metabolic, behavioral, and environmental factors. Obesity and high-fat western diets activate inflammatory processes, which promote development of insulin resistance as well as other metabolic complications. Increasing obesity rates are a major public health concern in the Hispanic population due to the large number of Hispanics suffering from obesity. Based on preliminary data, we propose a double-blind randomized clinical trial of Salsalate therapy in obese Hispanic young adults. Salsalate treatment shows promise for decreasing inflammation under conditions of weight stability by reducing macrophage infiltration of adipocytes. Hispanics have the greatest amount of visceral adipose tissue (VAT), liver fat, and inflammation when compared to other ethnic groups, thereby increasing the potential for treatment effects in this high-risk population. Purpose: The purpose of this study is to demonstrate through a "proof-of-concept" trial that Salsalate induced reductions in adipose tissue inflammation are possible under conditions of weight stability. Methodology: We will recruit obese Hispanic young adults (18 - 35 years) from hospitals, clinics, and community centers. Study Endpoints: Primary outcomes will be macrophage infiltration as assessed by the presence of crown-like structures (CLS) in subcutaneous adipose tissue (SAT) biopsies, liver fat, insulin sensitivity, and fasting glucose. We will also assess plasma levels of monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, interleukin (IL)-1, C-reactive protein (CRP), and SAT gene expression of nuclear factor kB (NF-kB) and insulin signaling pathways. Intervention and Follow-up: Participants will be randomly assigned to four weeks of treatment with Salsalate (4 g/d) or placebo and will be studied under weight maintenance conditions. These measures will enable us to determine if Salsalate treatment is capable of reducing adipose tissue inflammation and related metabolic outcomes in the absence of weight loss.

Conditions

Diabetes Risk

Keywords

Obesity; Adipose tissue inflammation; Salsalate; Hispanics

Outcome Measures

Primary Outcomes (6)

• Change in plasma glucose levels over a 2-hour oral glucose tolerance test

  Glucose following 4 weeks of treatment with salsalate (4 g/day) or placebo. A 2-hour oral glucose tolerance test will be performed at baseline and 4 weeks to measure changes in plasma glucose levels.

  4 weeks

• Change in adipose tissue inflammation

  Adipose tissue inflammation following 4 weeks of treatment with salsalate (4 g/day) or placebo. Adipose tissue inflammation will be determined from abdominal subcutaneous adipose tissue biopsies performed at baseline and 4 weeks.

  4 weeks

• Change in systemic markers of inflammation

  Systemic markers of inflammation following treatment with salsalate (4 g/day) or placebo. Fasting blood samples will be taken at baseline and 4 weeks to measure systemic markers of inflammation.

  4 weeks

• Change in plasma insulin levels over a 2-hour oral glucose tolerance test

  Insulin following 4 weeks of treatment with salsalate (4 g/day) or placebo. A 2-hour oral glucose tolerance test will be performed at baseline and 4 weeks to measure changes in plasma insulin levels.

  4 weeks

• Change in plasma fasting free fatty acid levels

  Fasting free fatty acids (FFA) following 4 weeks of treatment with salsalate (4 g/day) or placebo. Fasting blood samples will be taken at baseline and 4 weeks to measure changes in plasma fasting FFA.

  4 weeks

• Change in plasma C-peptide levels over a 2-hour oral glucose tolerance test

  C-peptide following 4 weeks of treatment with salsalate (4 g/day) or placebo. A 2-hour oral glucose tolerance test will be performed at baseline and 4 weeks to measure changes in plasma C-peptide levels.

  4 weeks

Secondary Outcomes (4)

• Change in body composition

  4 weeks

• Change in ectopic fat

  4 weeks

• Change in diet

  4 weeks

• Change in physical activity

  4 weeks

Study Arms (2)

Salsalate

EXPERIMENTAL

Salsalate (4 g/day)

Drug: Salsalate (4 g/day)

Placebo

PLACEBO COMPARATOR

Placebo (4 g/day)

Drug: Placebo (4 g/day)

Interventions

Salsalate (4 g/day) DRUG

Given orally twice daily

Also known as: Salicylate

Salsalate

Placebo (4 g/day) DRUG

Given orally twice daily

Also known as: Inactive control

Placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Obese (body mass index \>30 kg/m\^2)
• Hispanic males and females age 18-35 years

You may not qualify if:

• Women with hemoglobin \<11.5 g/dL or men with hemoglobin \<12.5 g/dL will be excluded
• AST / ALT \>2 times the upper limit of normal
• Evidence of any liver disease other than non-alcoholic steatosis
• Diabetes
• Diagnosis of any disease that is known to influence insulin action and secretion
• Current or past involvement in any weight loss, exercise, or sports program in the six months prior to participation
• Use of medication known to influence body composition or fat distribution (e.g. Cushing syndrome)
• History of renal disease
• Use of non-steroidal anti-inflammatory drugs (NSAIDs)
• Chicken pox, flu, or influenza infection
• Those taking high doses of vitamin C, antacids (containing Ca2+ or Mg+2), or taking Warfarin
• Hypertension
• Allergies to Salsalate, aspirin or other NSAIDs
• History of peptic ulcer or upper GI bleeding
• A positive pregnancy test or current lactation

Sponsors & Collaborators

• University of Southern California: lead

Study Sites (2)

University of Southern California Diabetes Obesity Research Institute (DORI)

Los Angeles, California, 90089, United States

Location

University of Southern California, Clinical Trials Unit (CTU)

Los Angeles, California, 90089, United States

Location

Related Publications (7)

• Goldfine AB, Conlin PR, Halperin F, Koska J, Permana P, Schwenke D, Shoelson SE, Reaven PD. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia. 2013 Apr;56(4):714-23. doi: 10.1007/s00125-012-2819-3. Epub 2013 Jan 31.

  PMID: 23370525 BACKGROUND

• Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE; TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2010 Mar 16;152(6):346-57. doi: 10.7326/0003-4819-152-6-201003160-00004.

  PMID: 20231565 BACKGROUND

• Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J, Shoelson SE. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci. 2008 May;1(1):36-43. doi: 10.1111/j.1752-8062.2008.00026.x.

  PMID: 19337387 BACKGROUND

• Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care. 2008 Feb;31(2):289-94. doi: 10.2337/dc07-1338. Epub 2007 Oct 24.

  PMID: 17959861 BACKGROUND

• Koska J, Ortega E, Bunt JC, Gasser A, Impson J, Hanson RL, Forbes J, de Courten B, Krakoff J. The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study. Diabetologia. 2009 Mar;52(3):385-93. doi: 10.1007/s00125-008-1239-x. Epub 2008 Dec 23.

  PMID: 19104769 BACKGROUND

• Faghihimani E, Aminorroaya A, Rezvanian H, Adibi P, Ismail-Beigi F, Amini M. Reduction of insulin resistance and plasma glucose level by salsalate treatment in persons with prediabetes. Endocr Pract. 2012 Nov-Dec;18(6):826-33. doi: 10.4158/EP12064.OR.

  PMID: 22784842 BACKGROUND

• Faghihimani E, Aminorroaya A, Rezvanian H, Adibi P, Ismail-Beigi F, Amini M. Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes. Acta Diabetol. 2013 Aug;50(4):537-43. doi: 10.1007/s00592-011-0329-2. Epub 2011 Sep 22.

  PMID: 21938543 BACKGROUND

MeSH Terms

Conditions

Obesity

Interventions

salicylsalicylic acid; Salicylates

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Hydroxybenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols

Study Officials

• Michael I Goran, PhD

  University of Southern California

  PRINCIPAL INVESTIGATOR

• Tanya L Alderete

  University of Southern California

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor in the Departments of Preventive Medicine, Physiology & Biophysics and Pediatrics in the Keck School of Medicine, Director of the Childhood Obesity Research Center

Study Record Dates

• First Submitted: April 29, 2014
• First Posted: May 5, 2014
• Study Start: July 1, 2011
• Primary Completion: October 1, 2013
• Study Completion: October 1, 2013
• Last Updated: May 5, 2014

Record last verified: 2014-05

Locations

US (2)