Sitagliptin Effects on Arterial Vasculature and Inflammation in Obesity
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 40 |
| Updated: | 4/21/2016 |
| Start Date: | January 2016 |
| End Date: | July 2017 |
| Contact: | Fred R Sattler, MD |
| Email: | fsattler@usc.edu |
| Phone: | 323-226-4635 |
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 events.
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.
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.
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.
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
We found this trial at
1
site
Click here to add this to my saved trials
