Effects of Febuxostat on Adipokines and Kidney Disease in Diabetic Chronic Kidney Disease

NCT ID: NCT01350388

Last Updated: 2016-10-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-05-31
• Study Completion Date: 2013-12-31

Brief Summary

Hyperuricemia is emerging as a risk factor for development of diabetes and metabolic syndrome. Recently, it was shown in in-vitro cell culture experiments that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. By targeting levels of uric acid with febuxostat it is hypothesized that the levels of oxidative stress in adipose tissue (obtained by fat biopsy) will decrease.

Primary aims of the study are to determine whether febuxostat therapy in overweight or obese, diabetic patients with stage 3 Chronic Kidney Disease (CKD) and high serum uric acid levels

1. will affect adipose tissue concentrations of thiobarbituric acid reactive substance (TBARS), a marker of oxidative stress

2. will affect adipose tissue expression and concentrations of adiponectin; and

3. will affect urinary concentrations of transforming growth factor (TGF)- B1.

Detailed Description

Hyperuricemia is highly prevalent in the US population and commonly clusters with obesity and metabolic syndrome. It remains controversial whether this reflects an epiphenomenon or connotes a causal role of hyperuricemia in metabolic syndrome. If indeed hyperuricemia plays a causal role in metabolic syndrome, it would be expected that hyperuricemia will impact on the molecular signals that mediate the effects of adiposity on inflammation and insulin resistance.

Adipokines, the protein hormones produced by the adipocytes, serve as the signals for the effects of adipocytes on insulin resistance, dyslipidemia, hypertension, inflammation and atherosclerosis. Adipokines include tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), plasminogen activator inhibitor (PAI-1), leptin, angiotensinogen and adiponectin. In obesity, the production of TNF-α, IL-6, PAI-1, leptin and angiotensinogen increases whereas the production of adiponectin decreases. Increased expression of pro-inflammatory TNF-α and IL-6 and decreased expression of anti-inflammatory adiponectin by adipocytes results in insulin resistance and inflammation.

As oxidative stress in adipose tissue is considered to play a critical role in dysregulation of adipokines production in obesity and that hyperuricemia induces oxidative stress in adipocytes, it is hypothesized that hyperuricemia alters adipose tissue production of adipokines; therefore, febuxostat therapy will decrease hyperuricemia and thereby, have beneficial effects on adipokine production by adipose tissue; the favorable effects on adipokine production by febuxostat therapy will result in decrease in plasma levels of markers of inflammation; and as a result of the above, urinary markers of kidney disease will improve.

Chronic Kidney Disease (CKD) patients with type 2 diabetes will be studies because this population has a high prevalence of hyperuricemia and likely represents a target population which might benefit from reduction of uric acid levels.

This is a placebo-controlled, double-blinded, randomized controlled trial to examine the effects of uric acid lowering with oral febuxostat on adipokines and markers of inflammation.

Conditions

Chronic Kidney Disease; Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Febuxostat

80 mg/day of febuxostat for 24 weeks

Group Type: ACTIVE_COMPARATOR

Febuxostat

Intervention Type: DRUG

80 mg/day of febuxostat for 24 weeks

Placebo

1 placebo tablet per day for 24 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

1 placebo tablet per day for 24 weeks

Interventions

Febuxostat

80 mg/day of febuxostat for 24 weeks

Intervention Type: DRUG

Placebo

1 placebo tablet per day for 24 weeks

Intervention Type: DRUG

Other Intervention Names

Uloric

Eligibility Criteria

Inclusion Criteria

• Age > 18 years
• BMI > 25 kg/m2
• type 2 diabetes
• serum uric acid ≥ 5.5 mg/dl in men and ≥ 4.6 mg/dl in women
• eGFR 30-60 mL/min/1.73m2

Exclusion Criteria

• History of gout
• concurrent use of azathioprine, mercaptopurine, theophylline, allopurinol, thiazolidinediones or warfarin
• concurrent use of metformin
• current antibiotic therapy
• pregnant women
• prisoners

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

Sponsors

Takeda

INDUSTRY

Sponsor Role: collaborator

University of Utah

OTHER

Sponsor Role: lead

Responsible Party

Srinvasan Beddhu

Srinivasan Beddhu, MD Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Srinivasan Beddhu, MD

Role: PRINCIPAL_INVESTIGATOR

University of Utah

Locations

University of Utah

Salt Lake City, Utah, United States

Countries

United States

References

Beddhu S, Filipowicz R, Wang B, Wei G, Chen X, Roy AC, DuVall SL, Farrukh H, Habib AN, Bjordahl T, Simmons DL, Munger M, Stoddard G, Kohan DE, Greene T, Huang Y. A Randomized Controlled Trial of the Effects of Febuxostat Therapy on Adipokines and Markers of Kidney Fibrosis in Asymptomatic Hyperuricemic Patients With Diabetic Nephropathy. Can J Kidney Health Dis. 2016 Dec 5;3:2054358116675343. doi: 10.1177/2054358116675343. eCollection 2016.

Reference Type: DERIVED

PMID: 28270924 (View on PubMed)

Other Identifiers

IRB_00044016

Identifier Type: -

Identifier Source: org_study_id