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Sitagliptin Effects on Arterial Vasculature and Inflammation in Obesity (SAVORO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02576288
Recruitment Status : Completed
First Posted : October 15, 2015
Last Update Posted : July 17, 2019
Sponsor:
Information provided by (Responsible Party):
Fred Sattler, MD, University of Southern California

Brief Summary:

Abdominal obesity is a major risk factor for heart attack, stroke, peripheral vascular disease, dementia, cancer and Type 2 diabetes. The central hypothesis for this proposal is that pro-atherogenic mediators emanate from inflammation in deep subcutaneous adipose tissue (dSAT) that are released into the systemic circulation and damage the arterial vasculature. The investigators postulate that inflammation of dSAT, when quantified by macrophage phenotyping/enumeration will be a) closely linked with systemic levels of pro-atherogenic mediators and b) tightly associated with endothelial dysfunction and loss of central arterial elasticity, which are highly predictive of future cardiovascular disease (CVD) complications. These relationships provide the basis for macrophage-targeted therapy to reduce obesity-related inflammation and impaired arterial vasoreactivity. The investigators will evaluate a novel approach using a dipeptidyl peptidase 4 inhibitor (DPP4i) sitagliptin, which blocks signal transduction for monocyte/macrophage activation. Thus, in abdominally obese, 18-40 years-old adults without clinical CVD, the show study is expected to show that sitagliptin versus placebo will:

  1. significantly improve early measures of arterial damage (brachial artery endothelial dysfunction and reduced carotid elasticity).
  2. significantly attenuate inflammation in dSAT and local production of pro-inflammatory mediators in adipose tissue, which will be associated with decreases in systemic pro-atherogenic mediators that contribute to atherogenesis.

Since many obese persons fail to sustain weight loss by lifestyle interventions including diet and exercise, an important public health goal is to identify relatively safe alternative strategies that can be used pre-emptively in "asymptomatic" obese persons when arterial dysfunction and damage is still reversible before atherosclerosis progresses to serious CVD events.


Condition or disease Intervention/treatment Phase
Atherosclerosis Inflammation Drug: Sitagliptin Drug: Placebo Phase 2

Detailed Description:

APPROACH:

Overview of Study Design: This is a double-masked, randomized, placebo-controlled pilot study of treatment sitagliptin (100mg/day) to suppress monocyte/macrophage activation in obese non-diabetic participants. 16 abdominally obese18-40 year-old largely minorities will be randomized 3:1 to receive sitagliptin (N=12) or matching placebo (N=4) daily for 28 days.

Eligibility Criteria for the Study Cohort: Based on prior studies conducted by the investigators, approximately 60-70% of participants enrolled will be Hispanics and African Americans. Both minorities have increased prevalence of insulin resistance (IR) at young ages. In their prior studies, insulin resistance (HOMA-IR* ≥3.0) had a predictive value of 88% for crown like structure in abdominal fat (a surrogate for fat inflammation); the inclusion criterion for IR will assure that most study subjects will have abdominal fat inflammation.

* homeostatic method of analysis-insulin resistance

Inclusion Criteria

  1. Age 18-40 years of age
  2. Stable weight (no change >3% in prior 6 months)
  3. Waist circumference ≥102cm for men; ≥88cm for women
  4. Fasting plasma glucose 100-125, HgbA1C 5.7-6.4% or HOMA-IR* ≥3.0

Exclusion Criteria:

  1. Regular use of a non-steroidal anti-inflammatory drug (NSAID); unwilling to stop NSAID drug
  2. On statin or other prescription anti-inflammatory drugs
  3. Diabetes or clinically evident cardiovascular disease
  4. Smoking daily or consuming >200g alcohol/day

Study participants will be adults 18-40 years of age to exclude older persons with irreversible atherosclerosis (e.g. calcified, stenotic plaque) or subclinical arterial thrombus which release inflammatory mediators. Persons with Type 2 diabetes (a myocardial infarction equivalent) and those receiving "statins" (also potent anti-inflammatory drugs) will be excluded, thereby further excluding participants with advanced atherosclerosis. The goal is to identify and study persons with abdominal obesity and inflammation at a younger age as a potential target population for pre-emptive anti-inflammatory therapy to prevent serious CVD events over ensuing years.

Outcome Measures:

  1. Change in arterial vasoreactivity measured and quantified by ultrasound assessment of brachial artery flow mediated dilation and carotid stiffness (elasticity and distensibility).
  2. Change in measures of inflammation in intra-abdominal adipose tissue:

    1. M1 pro-inflammatory macrophages and M2 anti-inflammatory macrophages by fluorescent activated cell sorting.
    2. Ex vivo secretion of inflammatory mediators from macrophages fractions.
  3. Change in systemic pro-inflammatory/pro-atherogenic markers and insulin resistance.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Sitagliptin on Arterial Vasoreactivity and Proatherogenic Mediators in Obesity
Actual Study Start Date : January 2016
Actual Primary Completion Date : December 31, 2017
Actual Study Completion Date : December 31, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Atherosclerosis

Arm Intervention/treatment
Experimental: Sitagliptin
100mg will be administered by mouth daily for 28days
Drug: Sitagliptin
anti-inflammatory properties
Other Name: Januvia

Placebo Comparator: Matching Placebo
One placebo will be administered by mouth daily for 28days
Drug: Placebo
No anti-inflammatory properties
Other Name: Dummy pill




Primary Outcome Measures :
  1. Ultrasound quantification of change in brachial artery flow mediated dilation and carotid stiffness (elasticity and distensibility) [ Time Frame: Immediately before and after 28 days of study thearpy ]
    To ascertain effects of sitagliptin vs placebo on endothelial function (brachial artery flow) and structural measure of atherosclerosis (carotid stiffness)


Secondary Outcome Measures :
  1. Deep subcutaneous adipose tissue inflammation [ Time Frame: Immediately before and after 28 days of study thearpy ]
    quantify M1 and M2 macrophages by fluorescence activated cell sorting and ex vivo secretion of pro-inflammatory mediators


Other Outcome Measures:
  1. Systemic markers of inflammation/atherogenic mediators and insulin resistance [ Time Frame: Immediately before and after 28 days of study thearpy ]
    To ascertain if sitagliptin vs placebo will decrease C-reactive protein, Tumor Necrosis Factor alpha, interleukin 6, soluble CD40 ligand, interferon like protein 10, IP-10, homeostatic method of assessment for insulin resistance.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • abdominal obesity (≥102cm for men and ≥88cm for women)
  • impaired glucose tolerance with fasting plasma glucose 100-125 or HgbA1C 5.7-6.4%
  • insulin resistance with HOMA-IR ≥3.0
  • stable weight with no change >3% in prior 6 months

Exclusion Criteria:

  • regular use of non-steroidal anti-inflammatory drug and unwilling to stop
  • on statin or other anti-inflammatory medication or herbal remedy
  • diabetes or clinically evident cardiovascular disease
  • smoking daily or consuming >200g of alcohol daily
  • active renal, hepatic, rheumatological or infectious disorder within 28 days

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02576288


Locations
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United States, California
University of Southern California Health Sciences Campus
Los Angeles, California, United States, 90033
Sponsors and Collaborators
University of Southern California
Investigators
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Principal Investigator: Fred Sattler, MD University of Southern California
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Responsible Party: Fred Sattler, MD, Professor of Medicine, University of Southern California
ClinicalTrials.gov Identifier: NCT02576288    
Other Study ID Numbers: HS-13-00345
First Posted: October 15, 2015    Key Record Dates
Last Update Posted: July 17, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fred Sattler, MD, University of Southern California:
Sitagliptin
Brachial artery flow mediated dilation
Carotid stiffness
Pro-inflammatory
Pro-atherogenic
M1 macrophages
Additional relevant MeSH terms:
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Atherosclerosis
Inflammation
Pathologic Processes
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action