Effects of Thiazide Diuretics on Sympathetic Nervous System in Hypertension

NCT ID: NCT00353652

Last Updated: 2019-02-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 166 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-01-31
• Study Completion Date: 2013-01-31

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.

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.

Conditions

Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Study#1: chlorthalidone (CTD), titrated dose

Intervention Type: DRUG

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

Study #1: spironolactone (SP), titrated dose

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

Study#1: chlorthalidone (CTD), titrated dose

Intervention Type: DRUG

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

Study #1: spironolactone (SP), titrated dose

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

Study# 2 chlorthalidone (CTD), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Study# 2 spironolactone (SP), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Study# 2 irbsesartan (IR), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

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.

Group Type: ACTIVE_COMPARATOR

Study# 2 chlorthalidone (CTD), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Study# 2 spironolactone (SP), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Study# 2 irbsesartan (IR), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

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.

Group Type: ACTIVE_COMPARATOR

Study# 2 chlorthalidone (CTD), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Study# 2 spironolactone (SP), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Study# 2 irbsesartan (IR), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

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.

Group Type: ACTIVE_COMPARATOR

Study# 2 chlorthalidone (CTD), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Study# 2 spironolactone (SP), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Study# 2 irbsesartan (IR), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

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.

Group Type: ACTIVE_COMPARATOR

Study# 2 chlorthalidone (CTD), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Study# 2 spironolactone (SP), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Study# 2 irbsesartan (IR), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

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.

Group Type: ACTIVE_COMPARATOR

Study# 2 chlorthalidone (CTD), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Study# 2 spironolactone (SP), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Study# 2 irbsesartan (IR), fixed dose

Intervention Type: DRUG

Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Study# 2 chlorthalidone (CTD), fixed dose

Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.

Intervention Type: DRUG

Study# 2 spironolactone (SP), fixed dose

Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.

Intervention Type: DRUG

Study# 2 irbsesartan (IR), fixed dose

Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Texas Southwestern Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Wanpen Vongpatanasin

M.D.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wanpen Vongpatanasin, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas, Southwestern Medical Center at Dallas

Locations

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Countries

United States

References

Raheja P, Price A, Wang Z, Arbique D, Adams-Huet B, Auchus RJ, Vongpatanasin W. Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients. Hypertension. 2012 Aug;60(2):319-25. doi: 10.1161/HYPERTENSIONAHA.112.194787. Epub 2012 Jun 25.

Reference Type: DERIVED

PMID: 22733474 (View on PubMed)

Kontak AC, Wang Z, Arbique D, Adams-Huet B, Auchus RJ, Nesbitt SD, Victor RG, Vongpatanasin W. Reversible sympathetic overactivity in hypertensive patients with primary aldosteronism. J Clin Endocrinol Metab. 2010 Oct;95(10):4756-61. doi: 10.1210/jc.2010-0823. Epub 2010 Jul 21.

Reference Type: DERIVED

PMID: 20660053 (View on PubMed)

Other Identifiers

R01HL078782-02

Identifier Type: NIH

Identifier Source: secondary_id

View Link

413

Identifier Type: -

Identifier Source: org_study_id