Sitagliptin Effects on Arterial Vasculature and Inflammation in Obesity
Condition: Atherosclerosis; Inflammation
MeSH terms: Atherosclerosis; Inflammation
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): Sitagliptin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): anti-inflammatory properties; No anti-inflammatory properties
Other intervention name(s): Januvia; Dummy pill
Intervention MeSH terms: Sitagliptin Phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Sitagliptin; Brachial artery flow mediated dilation; Carotid stiffness; Pro-inflammatory; Pro-atherogenic; M1 macrophages