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

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01350388

Enrollment

Registered

2011-05-09

Start date

2011-05-31

Completion date

2013-12-31

Last updated

2016-10-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Kidney Disease, Diabetes

Keywords

Chronic Kidney Disease, Diabetes, Febuxostat, Inflammation, Hyperuricemia

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.

Interventions

DRUGFebuxostat

80 mg/day of febuxostat for 24 weeks

DRUGPlacebo

1 placebo tablet per day for 24 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Change in Urinary Concentrations of Transforming Growth Factor-beta1 (TGF-beta1) From Baseline to 24 Weeks	Baseline and 24 weeks	The percent difference in TGF-beta1 concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Change in Thiobarbituric Acid Reactive Substance (TBARS) Concentration in Adipose Tissue From Baseline to 24 Weeks	Baseline and 24 weeks	The percent difference in thiobarbituric acid reactive substance (TBARS) concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Change in Adiponectin Concentration in Adipose Tissue From Baseline to 24 Weeks	Baseline and 24 weeks	The percent difference in adiponectin concentration geometric mean values from baseline to 24 weeks was calculated for each arm

Secondary

Measure	Time frame	Description
Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 24 Weeks	Baseline and 24 weeks	The percent difference in plasma TNF-α concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 24 Weeks	Baseline and 24 weeks	The percent difference in plasma IL-6 concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 24 Weeks	Baseline and 24 weeks	The percent difference in plasma hsCRP concentration geometric mean values from baseline to 24 weeks was calculated for each arm

Countries

United States

Participant flow

Participants by arm

Arm	Count
Febuxostat Febuxostat: 80 mg/day of febuxostat for 24 weeks	40
Placebo Placebo: 1 placebo tablet per day for 24 weeks	40
Total	80

Baseline characteristics

Characteristic	Febuxostat	Placebo	Total
Age, Continuous	67 years STANDARD_DEVIATION 10	68 years STANDARD_DEVIATION 11	68 years STANDARD_DEVIATION 10
Estimated Glomerular Filtration Rate (eGFR)	52.2 milliliters per minute STANDARD_DEVIATION 15.3	54.8 milliliters per minute STANDARD_DEVIATION 19	53.5 milliliters per minute STANDARD_DEVIATION 17.2
Plasma Uric Acid Level	7.2 milligram per deciliter STANDARD_DEVIATION 1.5	7.1 milligram per deciliter STANDARD_DEVIATION 1.2	7.2 milligram per deciliter STANDARD_DEVIATION 1.4
Sex: Female, Male Female	16 Participants	12 Participants	28 Participants
Sex: Female, Male Male	24 Participants	28 Participants	52 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 40	0 / 40
serious Total, serious adverse events	1 / 40	3 / 40

Outcome results

Primary

Change in Adiponectin Concentration in Adipose Tissue From Baseline to 24 Weeks

The percent difference in adiponectin concentration geometric mean values from baseline to 24 weeks was calculated for each arm