Effects of Thiazide Diuretics on Sympathetic Nervous System in Hypertension
Neural Mechanisms of Thiazide-induced Insulin Resistance
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Texas
-
Dallas, Texas, United States, 75390
- University of Texas Southwestern Medical Center
-
Dallas, Texas, United States, 75390
- University Of Texas Southwestern Medical Center At Dallas
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Single
Arms and Interventions
Participant Group / 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.
|
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
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.
|
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
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.
|
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.
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.
|
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.
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.
|
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.
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.
|
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.
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.
|
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.
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.
|
Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.
Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.
Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Sympathetic Nerve Activity
Time Frame: Measured at 3 months
|
Measured at 3 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
24-hour Ambulatory Systolic Blood Pressure
Time Frame: Measured at 3 months
|
Measured at 3 months
|
|
|
Insulin
Time Frame: 3 months
|
fasting plasma insulin
|
3 months
|
|
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.
|
3 months
|
|
Sympathetic Baroreflex Sensitivity
Time Frame: 3 months
|
slope relating percent change in SNA (% change in total activity from baseline) to diastolic BP.
|
3 months
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Wanpen Vongpatanasin, MD, University of Texas, Southwestern Medical Center at Dallas
Publications and helpful links
General Publications
- 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.
- 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.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Hypertension
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Natriuretic Agents
- Membrane Transport Modulators
- Diuretics
- Hormone Antagonists
- Mineralocorticoid Receptor Antagonists
- Diuretics, Potassium Sparing
- Sodium Chloride Symporter Inhibitors
- Spironolactone
- Chlorthalidone
Other Study ID Numbers
- 413
- R01HL078782-02 (U.S. NIH Grant/Contract)
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