Official Title: “Neural Mechanisms of Thiazide-Induced Insulin Resistance”

Thiazide medications are often prescribed for individuals with high blood pressure, but research has shown that they may increase an individual's risk of developing diabetes. While it is unknown exactly how thiazide causes this response, it is likely that the nervous system is somehow involved. This study will evaluate the role of the nervous system in sugar metabolism, as well as determine the effect of thiazide and other medications on individuals with high blood pressure.

Study Type: Interventional

Study Design: Prevention, Randomized, Single Blind (Subject), Placebo Control, Crossover Assignment, Safety/Efficacy Study

Study Primary Completion Date: June 2009

Thiazide medications, including chlorthalidone, are commonly prescribed for individuals with high blood pressure because they are inexpensive, effective at lowering blood pressure, and able to reduce the risk of heart failure and stroke. Despite these advantages, research has shown that thiazide medications may increase an individual's risk of developing diabetes. The exact mechanism that causes this remains unknown. Thiazide appears to increase sympathetic nervous system activity, thereby decreasing glucose reuptake and metabolism by skeletal muscle tissues. In turn, this tends to contribute to glucose intolerance and the development of diabetes. More research, however, is needed to confirm this link. Spironolactone, another blood pressure medication, does not pose the same risk for developing diabetes and may prove beneficial as a primary treatment for high blood pressure. The purpose of this study is to determine the role of the sympathetic nervous system in glucose metabolism in individuals with high blood pressure, as well as compare the effectiveness of thiazide, spironolactone, and other antihypertensive medications in reducing blood pressure. Results from this study may initiate the development of future clinical trials involving spironolactone as a primary treatment for reducing blood pressure.

This study will enroll individuals with high blood pressure. Participants will be assigned to one of eight treatment groups. Depending on the assigned group, participants will receive chlorthalidone, spironolactone, quinapril, irbesartan, eplerenone, or a combination of these drugs, with or without placebo. Participants will attend four to six study visits over a period of 16 to 28 weeks. All participants will attend a baseline study visit, which will include a physical examination, a medical history review, vital sign measurements, and blood and urine collection. Small electrodes will be used to measure muscle nerve activity. In addition, blood pressure will be monitored continuously for 24 hours prior to the start of the study. Depending on the assigned treatment group, study visits may include blood collection, blood pressure monitoring, an electrocardiogram (ECG) to record heart activity, nerve function monitoring, and/or plasma volume measurements. Participants' baroreflex sensitivity may also be measured by monitoring nerve ending responses within the heart and blood vessels. Insulin sensitivity will be measured with a glucose tolerance test and by evaluating skeletal muscle glucose uptake.

Intervention(s) in this Clinical Trial

• Drug: Chlorthalidone
  • 12.5-25 mg taken orally, once daily
• Drug: Spironolactone
  • 50-75 mg taken orally, once daily
• Drug: Eplerenone
  • 50-100 mg taken orally, once daily
• Drug: Quinapril
  • 20 mg taken orally, once daily
• Drug: Irbesartan
  • 150 mg taken orally, once daily

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1A
• Experimental: 1C
• Experimental: 2
• Experimental: 3

Primary Measures

• Sympathetic nerve activity
  • Time Frame: Measured at 6 months
    Safety Issue?: No
• 24-hour ambulatory blood pressure
  • Time Frame: Measured at 6 months
    Safety Issue?: No
• Insulin sensitivity
  • Time Frame: Measured at 6 months
    Safety Issue?: No
• Forearm blood flow
  • Time Frame: Measured at 6 months
    Safety Issue?: No
• Baroreflex sensitivity
  • Time Frame: Measured at 6 months
    Safety Issue?: No
• C-reactive protein
  • Time Frame: Measured at 6 months
    Safety Issue?: No
• Inflammatory cytokines
  • Time Frame: Measured at 6 months
    Safety Issue?: No

Secondary Measures

• Electrolytes
  • Time Frame: Measured at 6 months
    Safety Issue?: No
• Body weight
  • Time Frame: Measured at 6 months
    Safety Issue?: No

Inclusion Criteria:

• Untreated stage 1 primary hypertension (systolic blood pressure between 140 to 159 mm
• Hg and diastolic blood pressure between 90 to 99 mm Hg)

Exclusion Criteria:

• Cardiopulmonary disease, as determined by medical history or by physical examination
• Serum creatinine greater than or equal to 1.5 mg/dL
• Diabetes mellitus or other systemic illness
• Left ventricular hypertrophy by echocardiography or ECG
• Hypersensitivity to chlorthalidone, spironolactone, eplerenone, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blocker, insulin, Evans blue dye, or clonidine
• History of substance abuse (other than tobacco)
• History of gouty arthritis
• History of ACE inhibitor-induced cough or angioedema
• Evidence of secondary hypertension
• Pregnant

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Overall Clinical Trial Officials and Contacts

Wanpen Vongpatanasin, MD Principal Investigator University of Texas Southwestern Medical Center at Dallas  

Overall Contact: Wanpen Vongpatanasin, MD 214-648-7950 Wanpen.Vongpatanasin@UTSouthwestern.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00353652

Study ID Number: 413

ClinicalTrials.gov Identifier: NCT00353652

Health Authority: United States: Food and Drug Administration