Effects of Thiazide Diuretics on Sympathetic Nervous System in Hypertension
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Study#1: chlorthalidone (CTD), titrated dose; Study #1: spironolactone (SP), titrated dose; Study# 2 chlorthalidone (CTD), fixed dose; Study# 2 spironolactone (SP), fixed dose; Study# 2 irbsesartan (IR), fixed dose
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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.; 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.
Intervention MeSH terms: Chlorthalidone; Spironolactone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Blood Pressure, High