Effects of Hyperuricemia Reversal on Features of the Metabolic Syndrome

The metabolic syndrome (MS) is characterized by a constellation of metabolic features
including dyslipidemia, hyperglycemia, hypertension, obesity, and insulin resistance. This
cluster of features is strongly associated with type 2 diabetes, atherosclerotic
cardiovascular disease, and increased cardiovascular and all-cause mortality. Hyperuricemia
(elevated serum uric acid) is associated with insulin resistance and features of the MS in
cross-sectional epidemiological studies. However, it remains unclear whether this association
is causal or simply coincidental. If hyperuricemia CAUSES insulin resistance, then lowering
serum uric acid by pharmacological means may result in improved insulin sensitivity and
reversal of features of the metabolic syndrome. In some recent small studies, lowering serum
uric acid with allopurinol was associated with improvement in some of the features and/or
complications of the MS: Allopurinol use resulted in reduction in blood pressure in
adolescents and improvement in exercise capacity in patients with chronic stable angina. A
low urine pH is strongly associated with insulin resistance, and individual features of the
metabolic syndrome. Similarly, a low fractional excretion of uric acid is also associated
with metabolic syndrome feature. We therefore would like to examine the effect on febuxostat
on these two parameters which have been linked with the metabolic syndrome.

The goal of this study is to evaluate whether pharmacological lowering of serum uric acid
with the medication febuxostat is associated with improvement in the degree of insulin
resistance and various features of the metabolic syndrome.

Inclusion Criteria:

- Age > 21 years

- Gout

- Hyperuricemia (serum uric acid > 7.0 mg/dl in men and >6.0 mg/dl in women).

Exclusion Criteria:

- Current treatment with insulin, azathioprine, mercaptopurine, or theophylline.

- Treatment with febuxostat, allopurinol or other uricosuric agents (including losartan,
probenecid) within the past year

- Uncontrolled hypertension (clinic systolic blood pressure > 160 mmHg or diastolic
blood pressure > 90 mmHg within the past 6 months)

- Uncontrolled diabetes mellitus (HbA1c > 7%)

- estimated GFR < 60 ml/min by MDRD

- Elevated liver function tests (AST or ALT greater than 3 times the upper limit of
normal)

- Pregnancy