Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity

• ClinicalTrials.gov Identifier: NCT04329806
• Recruitment Status: Recruiting
• First Posted: April 1, 2020
• Last Update Posted: August 23, 2022
• Sponsor: Italo Biaggioni
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Italo Biaggioni, Vanderbilt University Medical Center

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Obesity-Associated Insulin Resistance	Drug: Moxonidine 0.2 MG; Drug: Amlodipine 5 MG	Phase 1

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity
• Actual Study Start Date: February 23, 2021
• Estimated Primary Completion Date: April 2024
• Estimated Study Completion Date: April 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Moxonidine; Moxonidine to be administered at a dose to produce a decrease in BP of at least 20% of baseline for 9 weeks	Drug: Moxonidine 0.2 MG; Moxonidine 0.2 MG twice daily
Active Comparator: Amlodipine; Amlodipine to be administered at a dose to produce a decrease in BP of at least 20% of baseline for 9 weeks	Drug: Amlodipine 5 MG; Amlodipine 5 MG twice daily

Outcome Measures

Primary Outcome Measures :

1. Insulin Sensitivity [ Time Frame: 6 hours ]
   Dose response curve to insulin ( measure as glucose infusion rate In mg/kg/min)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Males and females of all races between 18 and 60 years of age
• Hypertension defined by two or more properly measured seated blood pressure readings >130/85 mmHg or currently on antihypertensive medication.
• Obesity will be defined as having a body mass index (BMI) ≥ 30 kg/m2.
• Able and willing to provide informed consent.

Exclusion Criteria:

• Pregnancy or breast feeding
• Current smokers or history of heavy smoking (>2 packs/day)
• History of alcohol or drug abuse
• Previous allergic reaction to study medications
• Evidence of type I diabetes
• Cardiovascular disease other than hypertension
• History of serious cerebrovascular disease
• History or presence of immunological or hematological disorders
• Impaired renal function
• Treatment with any investigational drug in the 1 month preceding the study
• Inability to give, or withdraw, informed consent
• Other factors which in the investigator's opinion would prevent the subject from completing the protocol

Contacts and Locations

Contacts

Contact: Cynthia D Laws, MS,RHIA,CCRP; 615-421-1994; autonomicgroup@vumc.org

Contact: Alfredo Gamboa; 615-875-1003; alfredo.gamboa@vumc.org

Locations

United States, Tennessee

Vanderbilt University; Recruiting

Nashville, Tennessee, United States, 37232

Contact: Cynthia D Laws, MS, RHIA,ASQ-CQIA, CCRP 615-421-1994 autonomicgroup@vumc.org

Contact: Emily C Smith, RN 615.875.1516 autonomics@vumc.org

Principal Investigator: Italo Biaggioni, MD

Sub-Investigator: Alfredo Gamboa, MD

Sub-Investigator: Luis E Okamoto, MD

Sub-Investigator: Cyndya A Shibao, MD

Sub-Investigator: Andre Diedrich, MD/PhD

Sub-Investigator: Emily C Smith

Sponsors and Collaborators

Italo Biaggioni

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Italo Biaggioni, MD; Vanderbilt University Medical Center

More Information

• Responsible Party: Italo Biaggioni, Professor, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT04329806
• Other Study ID Numbers: 190479; R01HL149386 ( U.S. NIH Grant/Contract )
• First Posted: April 1, 2020
• Last Update Posted: August 23, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Obesity; Insulin Resistance; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Amlodipine; Moxonidine; Antihypertensive Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents