How URAT1 inhibitors can shape the future of chronic gout treatment: a narrative review of uricosurics past and present

Abstract

Gout is a common inflammatory arthritis preceded by chronically elevated levels of serum urate. In addition to leading to gouty flares, hyperuricemia can result in stone-like deposits of monosodium urate crystals (tophi) being deposited in joints and soft tissue, where they cause severe pain and damage. Although gout is an ancient disease with a well-characterized etiology, its treatment landscape has not kept pace with that of other rheumatic conditions. Therapy centers on lowering serum urate concentrations, with urate-lowering drugs falling into three categories: xanthine oxidase inhibitors (e.g., allopurinol, febuxostat) that reduce urate production by blocking the conversion of hypoxanthine to uric acid; uricosurics [primarily urate transporter-1 (URAT1) inhibitors, including probenecid, lesinurad] that promote the renal excretion of urate; and recombinant uricases (e.g., pegloticase) that convert uric acid to allantoin (a water-soluble compound that is more readily excreted). Some treatments have been available for decades, but are often limited by toxicities, primarily relating to the liver and kidneys. Recent research has focused on developing more potent and specific URAT1 inhibitors in the hope that these safety concerns can be overcome, and that better tolerated, more effective therapies can be made available. Newer uricosurics have different chemical structures from their predecessors, resulting in greater URAT1 selectivity in order to reduce off-target effects. Several of these have shown promising results in clinical trials and could prove to be viable alternatives to suboptimal existing therapies. Indeed, newer generation uricosurics may have the potential to become viable therapies in indications other than gout, such as some metabolic diseases. In this narrative review, we discuss the position of uricosurics (primarily URAT1 inhibitors) in the landscape of chronic gout treatment of the past, present, and future.

Keywords

Uricosurics / URAT1 / chronic gout / hyperuricemia / renal / safety

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