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Regression of Fatty Heart by Valsartan Therapy

The recruitment status of this study is unknown because the information has not been verified recently.
Verified August 2009 by University of Texas Southwestern Medical Center.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by:
University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT00745953
First received: August 29, 2008
Last updated: August 17, 2009
Last verified: August 2009
History of Changes
  Purpose

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.


Condition Intervention Phase
Metabolic Syndrome
Lipotoxicity
 Drug: Valsartan
Drug: Hydrochlorothiazide
 Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Regression of Fatty Heart by Valsartan Therapy

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Myocardial triglyceride levels [ Time Frame: 8 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Hepatic triglyceride levels, insulin sensitivity, abdominal fat mass [ Time Frame: 8 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 28
Study Start Date: August 2007
Estimated Study Completion Date: August 2009
Estimated Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Valsartan
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
Valsartan 320mg PO daily for 8 months
Other Name: Diovan
Active Comparator: Hydrochlorothiazide
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
Hydrochlorothiazide 25mg PO daily for 8 months
Other Name: HCTZ

Detailed Description:

Basic science in animal models of genetic obesity have demonstrated that obese, insulin resistant animals have fatty hearts with reduced functional ability. More importantly, insulin sensitizing treatment of prediabetic rats delayed development of diabetes and improved heart function. A primary aim of our laboratory is to translate basic animal research, suggesting that excessive lipid accumulation in the myocardium is toxic, into the clinical setting using cardiac magnetic resonance imaging/spectroscopy technology. The results of this research may identify new biomarkers and drug targets to prevent cardiac disease in obese humans.

We used our novel in vivo magnetic resonance imaging and spectroscopy technique that enables quantification of triglyceride in human myocardium non-invasively, to demonstrate that obese humans like obese animals are characterized by elevated fat in myocardium. We hypothesize that in obese humans with elevated myocardial TG, blockade of the renin-angiotensin system will reduce myocardial fat with improvement of insulin sensitivity and heart function.

The aims of this study are to test if in obese people with impaired glucose tolerance (IGT):

Aim 1) Valsartan treatment will reduce myocardial fat and will improve heart geometry and function,

Aim 2) therapy with thiazide diuretic hydrochlorothiazide (HCTZ) treatment will elevate myocardial fat.

We are planning to test the action of Valsartan versus HCTZ as we expect that these drugs cause opposite metabolic effects. The landmark trial ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) has refocused attention to the thiazide-type diuretics as the first-line therapy for most patients with hypertension. Despite proven reduction in cardiovascular outcomes and low costs, there is on-going concern that one of the major side effect of the thiazides—glucose intolerance—may fuel the current U.S. epidemic of type 2 diabetes. Despite of efficacy and low cost thiazide diuretics are long known to cause insulin resistance, impaired glucose tolerance, and precipitation of overt diabetes.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Prediabetic individuals with impaired glucose tolerance (2 hr postprandial glucose > 140mg/dL) or having 3 of 5 Metabolic Syndrome criteria:

    1. Fasting glucose > 100mg/dL;
    2. Waist circumference: men > 102cm, women > 88cm (confirmed with abdominal MRI);
    3. HDL: men < 40mg/dL, women < 50mg/dL;
    4. Triglycerides > 150mg/dL;
    5. Blood pressure > 130/80mmHg;
  • Elevated hepatic triglycerides (>5.5%) and myocardial triglycerides (>0.6%)
  • Elevated blood triglycerides >150mg/dL
  • Age < 50 years

Exclusion Criteria:

  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00745953

Contacts
Contact: Angela L Price, MD 214.648.0335 Angela.Price@UTSouthwestern.edu
Contact: Lidia S Szczepaniak, PhD 214.648.6886 Lidia.Szczepaniak@UTSouthwestern.edu

Locations
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Novartis Pharmaceuticals
Investigators
Principal Investigator: Ronald G Victor, MD University of Texas Southwestern Medical Center
Study Director: Lidia S Szczepaniak, PhD University of Texas Southwestern Medical Center
  More Information

No publications provided

Responsible Party: Dr. Ildiko Lingvay, MD, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT00745953     History of Changes
Other Study ID Numbers: IIRP Study US 73
Study First Received: August 29, 2008
Last Updated: August 17, 2009
Health Authority: United States: Institutional Review Board

Keywords provided by University of Texas Southwestern Medical Center:
Metabolic syndrome
Lipotoxicity
Insulin sensitivity
 Myocardial triglyceride levels
Hepatic triglyceride levels
Magnetic resonance spectroscopy

Additional relevant MeSH terms:
Metabolic Syndrome X
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Hydrochlorothiazide
Valsartan
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
 Pharmacologic Actions
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on May 22, 2013