Urate Lowering Therapies and Left Ventricular Diastolic Dysfunction

Overview

Hyperuricemia is an additional risk factor for cardiovascular disease, associating with left ventricular diastolic dysfunction in individuals with metabolic syndrome. The effect of urate-lowering therapies on left ventricular diastolic dysfunction remains unclear. The study is conducted to investigate whether febuxostat or benzbromarone might improve left ventricular diastolic dysfunction in individuals with metabolic syndrome and hyperuricemia

Full Title of Study: “The Cardiovascular Effects of Febuxostat and Benzbromarone on Left Ventricle Diastolic Dysfunction in Individuals With Metabolic Syndrome and Hyperuricemia – an Open-label Non-blinded Randomized-controlled Clinical Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2021

Detailed Description

Between 1, July 2018 and 31, Dec 2018, consecutive individuals with metabolic syndrome hyperuricemia are candidates of the present study. After the eligible candidates sign the informed consent, they will receive blood tests with a fasting time of 8 hours at least. The investigators will randomize the study participants by pre-specified random codes with a 1:1:1 ratio to the three groups. The study medication, febuxostat or benzbromarone, will be administered orally on the next day after transthoracic echocardiography is performed. The control group will only receive dietary control. All participant will receive transthoracic echocardiography and blood tests at baseline and at 3 months. The visit will be scheduled at baseline and at the 3rd month. The blood tests include high-sensitivity C-reactive protein, high-sensitivity interleukin-1 beta, high-sensitivity interleukin-6, tumor necrosis factor alpha, Dickkopf-related protein 3, galectin-3, ST2, fibroblast growth factor 23, xanthine oxidase activity, and thioredoxin.

Interventions

  • Drug: Febuxostat 40 mg
    • Febuxostat 40 mg orally per day plus dietary control only
  • Drug: Benzbromarone 50mg
    • Benzbromarone 50mg orally per day plus dietary control only
  • Other: Control
    • Dietary control only

Arms, Groups and Cohorts

  • Experimental: Febuxostat 40mg
    • Febuxostat 40mg orally per day
  • Active Comparator: Benzbromarone 50mg
    • Benzbromarone 50mg orally per day
  • Other: Control
    • Dietary control only

Clinical Trial Outcome Measures

Primary Measures

  • Change of average E/e’
    • Time Frame: At day1 and at week 12
    • the mean change of average E/e’ in each group
  • Difference of average E/e’
    • Time Frame: At day1 and at week 12
    • the mean difference of average E/e’ between among three groups
  • Automate office blood pressure (AOBP)
    • Time Frame: At day1 and at week 12
    • the mean difference of AOBP among three groups

Secondary Measures

  • Change of xanthine oxidase activity
    • Time Frame: At day1 and at week 12
    • the mean change of xanthine oxidase activity in each group
  • Difference of xanthine oxidase activity
    • Time Frame: At day1 and at week 12
    • the mean difference of xanthine oxidase activity among three groups
  • Change of left ventricular mass index
    • Time Frame: At day1 and at week 12
    • the mean change of left ventricular mass index in each group
  • Difference of left ventricular mass index
    • Time Frame: At day1 and at week 12
    • the mean difference of left ventricular mass index among three groups
  • Change of tumor necrosis factor alpha
    • Time Frame: At day1 and at week 12
    • the mean change of tumor necrosis factor alpha in each group
  • Difference of tumor necrosis factor alpha
    • Time Frame: At day1 and at week 12
    • the mean difference of tumor necrosis factor alpha among three groups
  • Change of high-sensitivity interleukin-6
    • Time Frame: At day1 and at week 12
    • the mean change of high-sensitivity interleukin-6 in each group
  • Difference of high-sensitivity interleukin-6
    • Time Frame: At day1 and at week 12
    • the mean difference of high-sensitivity interleukin-6 among three groups
  • Change of thioredoxin
    • Time Frame: At day1 and at week 12
    • the mean change of Thioredoxin in each group
  • Difference of Thioredoxin
    • Time Frame: At day1 and at week 12
    • the mean difference of Thioredoxin among three group
  • Change of fibroblast growth factor 23
    • Time Frame: At day1 and at week 12
    • the mean Change of fibroblast growth factor 23 in each group
  • Difference of fibroblast growth factor 23
    • Time Frame: At day1 and at week 12
    • the mean difference of fibroblast growth factor 23 among three groups
  • Change of Dickkopf-related protein 3
    • Time Frame: At day1 and at week 12
    • the mean change of Dickkopf-related protein 3 in each group
  • Difference of Dickkopf-related protein 3
    • Time Frame: At day1 and at week 12
    • the mean difference of Dickkopf-related protein 3 among three groups
  • Change of galectin-3
    • Time Frame: At day1 and at week 12
    • the mean change of galectin-3 in each group
  • Difference of galectin-3
    • Time Frame: At day1 and at week 12
    • the mean difference of galectin-3 among three groups
  • Change of ST2
    • Time Frame: At day1 and at week 12
    • the mean change of ST2 in each group
  • Difference of ST2
    • Time Frame: At day1 and at week 12
    • the mean difference of ST2 among three groups

Participating in This Clinical Trial

Inclusion Criteria (all of the four criteria)

1. Aged between 40-75 years

2. Metabolic syndrome

3. Hyperuricemia, defined as a serum uric acid level of 7 mg/dl or more in men or 6 mg/dl or more in females, with a history of hyperuricemia within a year; or a serum uric acid level of 8 mg/dl or more in men or 7 mg/dl or more in females and it is hardly expected to be modified by dietary control; or persistent hyperuricemia after dietary control for 3 months

4. Not take any of urate-lowering therapies (benzbromarone, allopurinol, or febuxostat)

Exclusion Criteria

1. pregnancy

2. hypersensitivity to febuxostat or benzbromarone

3. acute gout

4. a history of urinary tract stone

5. chronic kidney disease stage IV or V

6. valvular heart disease with moderate or severe regurgitation

7. left ventricular ejection fraction of 40% or less

8. hypertrophic cardiomyopathy or dilated cardiomyopathy or infiltrative cardiomyopathy or constrictive cardiomyopathy

9. a history of congenital heart disease

10. a history of pulmonary hypertension

11. chronic atrial fibrillation or significant arrhythmia

12. a history of intracardiac device implantation

13. uncontrolled hypertension (systolic blood pressure > 160mm Hg or diastolic blood pressure > 100 mm Hg)

14. alanine Aminotransferase > 3 times upper limit)

15. acute infection

16. suspected or diagnosed with malignancy

17. a history of autoimmune disease

18. limited to or dependent on daily activities

19. life expectancy less than a year

20. Acute coronary syndrome or received a percutaneous coronary intervention or received a coronary artery graft bypass surgery or stroke within 3 months

21. Diabetes with insulin treatment or glucagon-like peptide 1 receptor agonist treatment

22. Anemia (hemoglobin < 11 mg/dl in mem or <10mg/dl in women)

Gender Eligibility: All

Minimum Age: 40 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • National Defense Medical Center, Taiwan
  • Provider of Information About this Clinical Study
    • Principal Investigator: Cheng-Wei Liu, Principal investigator – National Defense Medical Center, Taiwan
  • Overall Official(s)
    • Cheng-Wei Liu, M.D., Principal Investigator, 1.Tri-service General hospital, Songshan branch, Taipei, Taiwan
  • Overall Contact(s)
    • Cheng-Wei Liu, M.D., 886-2-27642151, issac700319@gmail.com

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