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| Sponsors and Collaborators: |
University of Texas Southwestern Medical Center Novartis |
|---|---|
| Information provided by: | University of Texas Southwestern Medical Center |
| ClinicalTrials.gov Identifier: | NCT00745953 |
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 IV |
| Study Type: | Interventional |
| Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Uncontrolled, Parallel Assignment |
| Official Title: | Regression of Fatty Heart by Valsartan Therapy |
| 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 |
|---|---|
|
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.
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Drug: Valsartan
Valsartan 320mg PO daily for 8 months
|
|
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
Hydrochlorothiazide 25mg PO daily for 8 months
|
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 |
Inclusion Criteria:
Prediabetic individuals with impaired glucose tolerance (2 hr postprandial glucose > 140mg/dL) or having 3 of 5 Metabolic Syndrome criteria:
Exclusion Criteria:
Contacts and Locations| Contact: Angela L Price, MD | 214.648.0335 | Angela.Price@UTSouthwestern.edu |
| Contact: Lidia S Szczepaniak, PhD | 214.648.6886 | Lidia.Szczepaniak@UTSouthwestern.edu |
| United States, Texas | |
| University of Texas Southwestern Medical Center | Recruiting |
| Dallas, Texas, United States, 75390 | |
| 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
| Responsible Party: | University of Texas Southwestern Medical Center ( Dr. Ronald Victor, MD ) |
| Study ID Numbers: | IIRP Study US 73 |
| Study First Received: | August 29, 2008 |
| Last Updated: | September 2, 2008 |
| ClinicalTrials.gov Identifier: | NCT00745953 |
| Health Authority: | United States: Institutional Review Board |
|
Metabolic syndrome Lipotoxicity Insulin sensitivity |
Myocardial triglyceride levels Hepatic triglyceride levels Magnetic resonance spectroscopy |
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Hydrochlorothiazide Insulin Valsartan |
|
Disease Molecular Mechanisms of Pharmacological Action Diuretics Physiological Effects of Drugs Sodium Chloride Symporter Inhibitors Cardiovascular Agents Antihypertensive Agents |
Pharmacologic Actions Membrane Transport Modulators Pathologic Processes Natriuretic Agents Syndrome Therapeutic Uses |
