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Effects of Thiazide Diuretics on Sympathetic Nervous System in Hypertension

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ClinicalTrials.gov Identifier: NCT00353652
Recruitment Status : Completed
First Posted : July 19, 2006
Results First Posted : December 29, 2014
Last Update Posted : February 6, 2019
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Wanpen Vongpatanasin, University of Texas Southwestern Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hypertension Drug: Study#1: chlorthalidone (CTD), titrated dose Drug: Study #1: spironolactone (SP), titrated dose Drug: Study# 2 chlorthalidone (CTD), fixed dose Drug: Study# 2 spironolactone (SP), fixed dose Drug: Study# 2 irbsesartan (IR), fixed dose Phase 4

Detailed Description:

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. Study# 1: All subjects were randomized to receive 3 months chlorthalidone (12.5-25 mg/d) or spironolactone (50-75 mg/d), using a single-blind 2-phase crossover design without washout between treatments. Each subject was followed every 4 wk for measurement of 24-h ambulatory BP and serum potassium (K). The doses of chlorthalidone and spironolactone were titrated to achieve 24-h ambulatory BP of less than 130/80mmHg in the same subject. During chlorthalidone treatment period, subject was given oral K supplementation according to a sliding scale to maintain serum K from 4.0-4.5 mmol/liter. Then, sympathetic nerve activity (SNA) is measured after 3 months of chlorthalidone and after 3 months of spironolactone. Arterial baroreflex sensitivity, glucose, and insulin are measured at baseline, after 3 months of chlorthalidone, and after 3 months of spironolactone. Insulin sensitivity will be measured using HOMA-IR. Study #2: All subjects are randomized to 3 months of fixed-dose Chlorthalidone 25 mg once daily alone, fixed-dose Chlorthalidone 25 mg once daily plus fixed-dose Spironolactone 25 mg once daily, and fixed-dose Chlorthalidone 25 mg once daily plus fixed-dose Irbesartan 150 mg once daily, using a single-blind 3-phase crossover design without washout between treatments. Then, SNA , Arterial baroreflex sensitivity, glucose, and insulin are measured after 3 months of each treatment phase.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 166 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Masking Description: Capsule was made to appear identical in appearance so that subjects are blinded to treatment assigned.
Primary Purpose: Treatment
Official Title: Neural Mechanisms of Thiazide-induced Insulin Resistance
Study Start Date : January 2005
Actual Primary Completion Date : January 2013
Actual Study Completion Date : January 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Study#1: chlorthalidone (CTD) first then spironolactone (SP)
Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months of chlorthalidone first (12.5-25 mg/d), using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment with spironolactone (25-75 mg/d)without washout period for 3 months. Following 3 month treatment period, the procedures listed below were performed. After completion of the study procedures, the medication is discontinued.
Drug: Study#1: chlorthalidone (CTD), titrated dose
Participants in study #1 will receive 3 months of chlorthalidone (12.5-25 mg/d) at the dose titrated to achieve 24-h ambulatory BP < 130/80 mmHg

Drug: Study #1: spironolactone (SP), titrated dose
Participants in study #1 will receive 3 months spironolactone (25-75 mg/d), at the dose titrated to achieve 24-h ambulatory BP < 130/80 mmHg.

Active Comparator: Study #1: spironolactone (SP) first, then chlorthalidone (CTD)
Participants in study #1 only received 2 interventions. All subjects are randomized to receive 3 months spironolactone first (25-75 mg/d), using a single-blind 2-phase crossover design. Then, the subject is transitioned to treatment with chlorthalidone(12.5-25 mg/d) without washout period. Following 3 month treatment period, the procedures listed below were performed. After completion of the study procedures, the medication is discontinued.
Drug: Study#1: chlorthalidone (CTD), titrated dose
Participants in study #1 will receive 3 months of chlorthalidone (12.5-25 mg/d) at the dose titrated to achieve 24-h ambulatory BP < 130/80 mmHg

Drug: Study #1: spironolactone (SP), titrated dose
Participants in study #1 will receive 3 months spironolactone (25-75 mg/d), at the dose titrated to achieve 24-h ambulatory BP < 130/80 mmHg.

Active Comparator: Study# 2 CTD alone 1st, CTD+ SP 2nd, CTD+IR 3rd
Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD (25 mg/d) plus fixed-dosespironolactone (SP) 25 mg daily for 3 months, then fixed-dose CTD (25 mg/d) plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months. After completion of the study procedures, the medication is discontinued.
Drug: Study# 2 chlorthalidone (CTD), fixed dose
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Drug: Study# 2 spironolactone (SP), fixed dose
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Drug: Study# 2 irbsesartan (IR), fixed dose
Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

Active Comparator: Study# 2 CTD alone 1st, CTD+IR 2nd, CTD+SP3rd
Subjects are randomized to receive 3 months of fixed-dose chlorthalidone (CTD, 25 mg/d) alone first, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD 25 mg/d plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months, followed by fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily for 3 months. After completion of the study procedures, the medication is discontinued.
Drug: Study# 2 chlorthalidone (CTD), fixed dose
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Drug: Study# 2 spironolactone (SP), fixed dose
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Drug: Study# 2 irbsesartan (IR), fixed dose
Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

Active Comparator: Study# 2 CTD+SP1st, CTD alone 2nd, CTD+IR 3rd
Subjects are randomized to receive fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily for 3 months, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD 25 mg/d alone for 3 months, then fixed-dose CTD 25 mg/d plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months. After completion of the study procedures, the medication is discontinued.
Drug: Study# 2 chlorthalidone (CTD), fixed dose
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Drug: Study# 2 spironolactone (SP), fixed dose
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Drug: Study# 2 irbsesartan (IR), fixed dose
Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

Active Comparator: Study# 2 CTD+SP1st, CTD+IR 2nd, CTD alone 3rd
Subjects are randomized to receive fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily for 3 months, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD 25 mg/d plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months, then fixed-dose CTD 25 mg/d alone for 3 months. After completion of the study procedures, the medication is discontinued.
Drug: Study# 2 chlorthalidone (CTD), fixed dose
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Drug: Study# 2 spironolactone (SP), fixed dose
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Drug: Study# 2 irbsesartan (IR), fixed dose
Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

Active Comparator: Study# 2 CTD+IR 1st, CTD alone 2nd, CTD+SP 3rd
Subjects are randomized to receive fixed-dose CTD 25 mg/d plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD 25 mg/d alone for 3 months, then fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily for 3 months. After completion of the study procedures, the medication is discontinued.
Drug: Study# 2 chlorthalidone (CTD), fixed dose
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Drug: Study# 2 spironolactone (SP), fixed dose
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Drug: Study# 2 irbsesartan (IR), fixed dose
Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

Active Comparator: Study# 2 CTD+IR 1st, CTD+SP 2nd, CTD alone 3rd
Subjects are randomized to receive fixed-dose CTD 25 mg/d plus fixed-dose irbsesartan (IR, 150 mg daily) for 3 months, using a single-blind 3-phase crossover design. Then, subjects are treated with fixed-dose CTD (25 mg/d) plus fixed-dose spironolactone (SP) 25 mg daily for 3 months, followed by fixed-dose CTD 25 mg/d alone for 3 months. After completion of the study procedures, the medication is discontinued.
Drug: Study# 2 chlorthalidone (CTD), fixed dose
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Drug: Study# 2 spironolactone (SP), fixed dose
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Drug: Study# 2 irbsesartan (IR), fixed dose
Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.




Primary Outcome Measures :
  1. Sympathetic Nerve Activity [ Time Frame: Measured at 3 months ]

Secondary Outcome Measures :
  1. 24-hour Ambulatory Systolic Blood Pressure [ Time Frame: Measured at 3 months ]
  2. Insulin [ Time Frame: 3 months ]
    fasting plasma insulin

  3. HOMA-IR [ Time Frame: 3 months ]
    assessment of insulin resistance calculated by multiplying fasting plasma insulin (mU/l) with fasting plasma glucose (mmol/l) divided by 22.5.

  4. Sympathetic Baroreflex Sensitivity [ Time Frame: 3 months ]
    slope relating percent change in SNA (% change in total activity from baseline) to diastolic BP.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00353652


Locations
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United States, Texas
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States, 75390
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
Sponsors and Collaborators
University of Texas Southwestern Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Wanpen Vongpatanasin, MD University of Texas, Southwestern Medical Center at Dallas
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Wanpen Vongpatanasin, M.D., University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT00353652    
Other Study ID Numbers: 413
R01HL078782-02 ( U.S. NIH Grant/Contract )
First Posted: July 19, 2006    Key Record Dates
Results First Posted: December 29, 2014
Last Update Posted: February 6, 2019
Last Verified: February 2019
Keywords provided by Wanpen Vongpatanasin, University of Texas Southwestern Medical Center:
Blood Pressure, High
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Chlorthalidone
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents
Antihypertensive Agents
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action