Regression of Fatty Heart by Valsartan Therapy

NCT ID: NCT00745953

Last Updated: 2019-01-17

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-08-31
• Study Completion Date: 2009-08-31

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.

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.

Conditions

Metabolic Syndrome; Lipotoxicity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Valsartan

Intervention Type: DRUG

Valsartan 320mg PO daily for 8 months

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.

Group Type: ACTIVE_COMPARATOR

Hydrochlorothiazide

Intervention Type: DRUG

Hydrochlorothiazide 25mg PO daily for 8 months

Interventions

Valsartan

Valsartan 320mg PO daily for 8 months

Intervention Type: DRUG

Hydrochlorothiazide

Hydrochlorothiazide 25mg PO daily for 8 months

Intervention Type: DRUG

Other Intervention Names

Diovan; HCTZ

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

University of Texas Southwestern Medical Center

OTHER

Sponsor Role: lead

Responsible Party

University of Texas Southwestern Medical Center

Principal Investigators

Ronald G Victor, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas Southwestern Medical Center

Lidia S Szczepaniak, PhD

Role: STUDY_DIRECTOR

University of Texas Southwestern Medical Center

Locations

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Countries

United States

Other Identifiers

IIRP Study US 73

Identifier Type: -

Identifier Source: org_study_id