Emerging Urate-Lowering Drugs and Pharmacologic Treatment Strategies for Gout: A Narrative Review

Abstract

Hyperuricemia with consequent monosodium urate crystal deposition leads to gout, characterized by painful, incapacitating inflammatory arthritis flares that are also associated with increased cardiovascular event and related mortality risk. This narrative review focuses on emerging pharmacologic urate-lowering treatment (ULT) and management strategies in gout. Undertreated, gout can progress to palpable tophi and joint damage. In oral ULT clinical trials, target serum urate of < 6.0 mg/dL can be achieved in ~ 80-90% of subjects, with flare burden reduction by 1-2 years. However, real-world ULT results are far less successful, due to both singular patient nonadherence and prescriber undertreatment, particularly in primary care, where most patients are managed. Multiple dose titrations commonly needed to optimize first-line allopurinol ULT monotherapy, and substantial potential toxicities and other limitations of approved, marketed oral monotherapy ULT drugs, promote hyperuricemia undertreatment. Common gout comorbidities with associated increased mortality (e.g., moderate-severe chronic kidney disease [CKD], type 2 diabetes, hypertension, atherosclerosis, heart failure) heighten ULT treatment complexity and emphasize unmet needs for better and more rapid clinically significant outcomes, including attenuated gout flare burden. The gout drug armamentarium will be expanded by integrating sodium-glucose cotransporter-2 (SGLT2) inhibitors with uricosuric and anti-inflammatory properties as well as clinically indicated antidiabetic, nephroprotective, and/or cardioprotective effects. The broad ULT developmental pipeline is loaded with multiple uricosurics that selectively target uric acid transporter 1 (URAT1). Evolving ULT approaches include administering selected gut anaerobic purine degrading bacteria (PDB), modulating intestinal urate transport, and employing liver-targeted xanthine oxidoreductase mRNA knockdown. Last, emerging measures to decrease the immunogenicity of systemically administered recombinant uricases should simplify treatment regimens and further improve outcomes in managing the most severe gout phenotypes.