Effects of Thiazide Diuretics on Sympathetic Nervous System in Hypertension

Study Overview
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Brief Summary
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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
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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.

Official Title
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Neural Mechanisms of Thiazide-induced Insulin Resistance

Conditions
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Hypertension

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study#1: chlorthalidone (CTD) first then spironolactone (SP)<br>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<br>* 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<br>Drug: Study #1: spironolactone (SP), titrated dose<br>* 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.<br>|
| Active Comparator: Study #1: spironolactone (SP) first, then chlorthalidone (CTD)<br>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<br>* 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<br>Drug: Study #1: spironolactone (SP), titrated dose<br>* 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.<br>|
| Active Comparator: Study# 2 CTD alone 1st, CTD+ SP 2nd, CTD+IR 3rd<br>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<br>* Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.<br>Drug: Study# 2 spironolactone (SP), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.<br>Drug: Study# 2 irbsesartan (IR), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.<br>|
| Active Comparator: Study# 2 CTD alone 1st, CTD+IR 2nd, CTD+SP3rd<br>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<br>* Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.<br>Drug: Study# 2 spironolactone (SP), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.<br>Drug: Study# 2 irbsesartan (IR), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.<br>|
| Active Comparator: Study# 2 CTD+SP1st, CTD alone 2nd, CTD+IR 3rd<br>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<br>* Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.<br>Drug: Study# 2 spironolactone (SP), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.<br>Drug: Study# 2 irbsesartan (IR), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.<br>|
| Active Comparator: Study# 2 CTD+SP1st, CTD+IR 2nd, CTD alone 3rd<br>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<br>* Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.<br>Drug: Study# 2 spironolactone (SP), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.<br>Drug: Study# 2 irbsesartan (IR), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.<br>|
| Active Comparator: Study# 2 CTD+IR 1st, CTD alone 2nd, CTD+SP 3rd<br>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<br>* Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.<br>Drug: Study# 2 spironolactone (SP), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.<br>Drug: Study# 2 irbsesartan (IR), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.<br>|
| Active Comparator: Study# 2 CTD+IR 1st, CTD+SP 2nd, CTD alone 3rd<br>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<br>* Participants in study #2 will receive 3 months of fixed-dose of CTD, at 25 mg/d.<br>Drug: Study# 2 spironolactone (SP), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose SP at 25 mg daily.<br>Drug: Study# 2 irbsesartan (IR), fixed dose<br>* Participants in study #2 will receive 3 months of fixed-dose IR at150 mg daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sympathetic Nerve Activity |  | Measured at 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour Ambulatory Systolic Blood Pressure |  | Measured at 3 months | 
| Insulin | fasting plasma insulin | 3 months | 
| HOMA-IR | 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 | slope relating percent change in SNA (% change in total activity from baseline) to diastolic BP. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood Pressure, High