Clinical trial NCT02130804: Using Salsalate to Target Adipocyte Macrophage Infiltration
Official title: Using Salsalate to Target Adipocyte Macrophage Infiltration and Reverse Metabolic Disease Risk in Obese Hispanic Young Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes Risk
Keywords: Obesity
Adipose tissue inflammation
Salsalate
Hispanics
Lead sponsor: University of Southern California
Sponsor class: OTHER
First posted: 2014-05-05
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

* 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
* Has smoked greater than 100 cigarettes in their lifetime and now smokes everyday or some days
* Drinks greater than 200 g/day of alcohol
* Those with a waist circumference (or widest part of body measurement) greater than or equal to 185 cm due to MRI size restrictions

Primary outcomes:
measure: Change in plasma glucose levels over a 2-hour oral glucose tolerance test
timeFrame: 4 weeks
measure: Change in adipose tissue inflammation
timeFrame: 4 weeks
measure: Change in systemic markers of inflammation
timeFrame: 4 weeks
measure: Change in plasma insulin levels over a 2-hour oral glucose tolerance test
timeFrame: 4 weeks
measure: Change in plasma fasting free fatty acid levels
timeFrame: 4 weeks
measure: Change in plasma C-peptide levels over a 2-hour oral glucose tolerance test
timeFrame: 4 weeks
Secondary outcomes:
measure: Change in body composition
timeFrame: 4 weeks
measure: Change in ectopic fat
timeFrame: 4 weeks
measure: Change in diet
timeFrame: 4 weeks
measure: Change in physical activity
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California Diabetes Obesity Research Institute (DORI)
state: California
city: Los Angeles
country: United States
facility: University of Southern California, Clinical Trials Unit (CTU)
state: California
Study officials:
affiliation: University of Southern California
name: Michael I Goran, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Southern California
name: Tanya L Alderete
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.