Effects of Hyperuricemia Reversal on Features of the Metabolic Syndrome

This study is being done to evaluate whether the medication, febuxostat, can improve the degree of insulin resistance and other features of the metabolic syndrome (high blood pressure, elevated insulin levels, excess body fat around the waist, and/or high cholesterol) by lowering uric acid levels in the blood.

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.

Adult patients (age > 21 years) with gout and hyperuricemia (serum uric acid > 7.0 mg/dl in men and >6.0 mg/dl in women) requiring uric acid lowering therapy.

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

Marin M, Maalouf NM. Effects of pharmacological reversal of hyperuricemia on features of the metabolic syndrome in patients with gouty arthritis. J Investig Med. 2018 Oct;66(7):1031-1036. doi: 10.1136/jim-2018-000728. Epub 2018 Apr 4.