Regression of Fatty Heart by Valsartan Therapy

NCT00745953 | Withdrawn Phase 4 DMC

• 1 other identifier: IIRP Study US 73
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Traditionally, obesity is considered an indirect cause of heart disease. Obese individuals typically present with a number of traditional Framingham risk factors (hypertension, dyslipidemia, and type 2 diabetes), predisposing them to heart attacks and subsequent heart failure. However, an emerging body of basic research revisits a hypothesis that fat is a direct cardiotoxin. Under healthy conditions, most triglyceride is stored in fatty tissue (adipocytes) while the amount of triglyceride stored in non-adipocyte tissues (such as the pancreas, the liver, skeletal muscle, and heart) is minimal and very tightly regulated. When this regulation is disrupted, intracellular triglyceride accumulates excessively in these organs ("steatosis") and has been implicated in activating adverse pathways which culminate in irreversible cell death ("lipotoxicity"), leading to several well-recognized clinical syndromes. These include non-alcoholic steatohepatitis (NASH), pancreatic beta-cell failure in type 2 diabetes, and dilated cardiomyopathy. It has been recently observed that angiotensin II receptor blockers (ARBs) in addition to lowering blood pressure improve insulin sensitivity and decrease the risk for type 2 diabetes. This study will test the above theory in two study groups: Valsartan vs. Hydrochlorothiazide. We hypothesize that in obese humans with elevated myocardial triglycerides, blockade of the renin-angiotensin system (Valsartan group) will reduce myocardial fat with improvement of insulin sensitivity and heart function.

Conditions

Metabolic Syndrome; Lipotoxicity

Keywords

Metabolic syndrome; Lipotoxicity; Insulin sensitivity; Myocardial triglyceride levels; Hepatic triglyceride levels; Magnetic resonance spectroscopy

Outcome Measures

Primary Outcomes (1)

• Myocardial triglyceride levels

  8 months

Secondary Outcomes (1)

• Hepatic triglyceride levels, insulin sensitivity, abdominal fat mass

  8 months

Study Arms (2)

Valsartan

ACTIVE COMPARATOR

This arm will determine if blockade of the renin-angiotensin system reduces myocardial fat levels and improves insulin sensitivity. It consists of 6 visits: visit1 (baseline); visit2 (2 weeks); visit3 (1 month); visit4 (3 month); visit5 (6 month); visit6 (8 month). Visits 1 \& 6 will consist of blood tests, glucose tolerance test by FSivGTT, MRS, \& 24 hr ambulatory blood pressure monitoring. During visit 1, patients receive automatic blood pressure monitor, OMRON, to record blood pressure between visits. Visits 2 \& 3 are needed for the adjustment of medication to the final dose level. During visits 4 \& 5, Dr. Price will check subject's status as they continue the medication. In case of uncontrolled blood pressure, Dr. Price will prescribe amlodipine for the additional BP control.

Drug: Valsartan

Hydrochlorothiazide

ACTIVE COMPARATOR

This arm will determine if thiazide diuretics elevate myocardial triglyceride levels. It consists of 6 visits: visit1 (baseline); visit2 (2 weeks); visit3 (1 month); visit4 (3 month); visit5 (6 month); visit6 (8 month). Visits 1 \& 6 will consist of blood tests, glucose tolerance test by FSivGTT, MRS, \& 24 hr ambulatory blood pressure monitoring. During visit 1, patients receive automatic blood pressure monitor, OMRON, to record blood pressure between visits. Visits 2 \& 3 are needed for the adjustment of medication to the final dose level. During visits 4 \& 5, Dr. Price will check subject's status as they continue the medication. In case of uncontrolled blood pressure, Dr. Price will prescribe amlodipine for the additional BP control.

Drug: Hydrochlorothiazide

Interventions

Valsartan DRUG

Valsartan 320mg PO daily for 8 months

Also known as: Diovan

Valsartan

Hydrochlorothiazide DRUG

Hydrochlorothiazide 25mg PO daily for 8 months

Also known as: HCTZ

Hydrochlorothiazide

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Prediabetic individuals with impaired glucose tolerance (2 hr postprandial glucose \> 140mg/dL) or having 3 of 5 Metabolic Syndrome criteria:
• Fasting glucose \> 100mg/dL;
• Waist circumference: men \> 102cm, women \> 88cm (confirmed with abdominal MRI);
• HDL: men \< 40mg/dL, women \< 50mg/dL;
• Triglycerides \> 150mg/dL;
• Blood pressure \> 130/80mmHg;
• Elevated hepatic triglycerides (\>5.5%) and myocardial triglycerides (\>0.6%)
• Elevated blood triglycerides \>150mg/dL
• Age \< 50 years

You may not qualify if:

• Type 2 Diabetes mellitus
• Prior exposure to renin system blockers or HCTZ
• BP \> 160/100mmHg
• Claustrophobia
• Metallic implants in body
• Pregnant or planning to become pregnant
• Prior exposure to statin medications

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Metabolic Syndrome; Insulin Resistance

Interventions

Valsartan; Hydrochlorothiazide

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Chlorothiazide; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Ronald G Victor, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

• Lidia S Szczepaniak, PhD

  University of Texas Southwestern Medical Center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: August 29, 2008
• First Posted: September 3, 2008
• Study Start: August 1, 2007
• Primary Completion: August 1, 2009
• Study Completion: August 1, 2009
• Last Updated: January 17, 2019

Record last verified: 2019-01

Locations

US (1)