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Effects of Sitagliptin on Arterial Vasoreactivity and Proatherogenic Mediators in Obesity
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
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
* homeostatic method of analysis-insulin resistance
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
1. Regular use of a non-steroidal anti-inflammatory drug (NSAID); unwilling to stop NSAID
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.
1. Change in arterial vasoreactivity measured and quantified by ultrasound assessment of
brachial artery flow mediated dilation and carotid stiffness (elasticity and
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.
Phase 4 - refines the treatment to become part of standard care.
Inclusion and Exclusion 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
- 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
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