Clinical Trial Details
— Status: Suspended
Administrative data
| NCT number |
NCT04329806 |
| Other study ID # |
190479 |
| Secondary ID |
R01HL149386 |
| Status |
Suspended |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
February 23, 2021 |
| Est. completion date |
April 2026 |
Study information
| Verified date |
November 2023 |
| Source |
Vanderbilt University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The purpose of this study is to study the role of sympathetic mechanisms involved in chronic
regulation of cardiovascular and metabolic abnormalities seen in obesity. The investigators
will study the effects chronic sympathetic inhibition on insulin sensitivity, inflammation
and endothelial function in obese hypertensive human subjects.
Description:
Continuing Review (CR, 2021/08/04) Update: Removal of the angiotensin receptor blockade arm
of the study
The presence of obesity increases the risk for hypertension and diabetes, in part due to the
development of insulin resistance. Obesity is also associated with sympathetic activation and
the overarching hypothesis is that sympathetic activation contributes to insulin resistance
with impairment of its vascular and metabolic actions. Preliminary studies suggest that 1)
Blood pressure can be normalized by autonomic blockade in obese hypertensives, 2) Sympathetic
activation provides no metabolic benefit because the increase in resting energy expenditure
associated with obesity is due to an increase in fat free mass rather than sympathetic
activation. On the contrary, autonomic blockade: 3) Improves insulin sensitivity in obese
hypertensives, 4) Reverses their impaired NO-mediated dilation, and 5) Reduces plasma
isoprostanes, a measure of oxidative stress. Furthermore, these abnormalities are
interrelated in negative feedback loops, whereby inflammation/oxidative stress impairs nitric
oxide mechanisms, which in turn reduces insulin-mediated vasodilation important for substrate
delivery, thus contributing to insulin resistance; insulin resistance leads to compensatory
increases in insulin levels, which contributes to further sympathetic activation. Current
treatment guidelines do not specifically address the treatment of obesity hypertension, and
do not target sympathetic activation as a first line approach. It is important, therefore, to
determine whether or not targeting sympathetic activation offers unique advantages in the
treatment of obesity hypertension over current approaches. The investigators propose a
proof-of-concept mechanistic study comparing the metabolic, vascular, and anti-inflammatory
effects of sympathetic inhibition, calcium channel blockade and angiotensin receptor blockade
in obesity hypertension. The investigators will test the hypotheses that sympathetic
activation contributes to 1) metabolic insulin resistance, which impairs the suppression of
endogenous glucose production and the stimulation of glucose uptake normally provided by
insulin, 2) vascular insulin resistance, which impairs insulin-mediated vasodilation and
microvascular recruitment that normally promote glucose uptake, and 3) inflammation and
oxidative stress, which contribute to insulin resistance and hypertension. The proposed
studies will gauge the contribution of sympathetic activation to the cardiovascular and
metabolic complications of obesity and provide the mechanistic insight to determine whether
or not it should foster the efforts currently under way to develop novel therapies targeting
sympathetic activation for hypertension.
