Sitagliptin Effects on Arterial Vasculature and Inflammation in Obesity
Status:
Completed
Trial end date:
2017-12-31
Target enrollment:
Participant gender:
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.