Chronic gout is caused by persistent hyperuricemia. Sustained serum uric acid (sUA) levels above 7 mg/dL in adult men and 6 mg/dL in adult women can lead to the deposition of monosodium urate (MSU) crystals, triggering pain, inflammation and tissue damage in joints, synovium, tendons, and kidneys. Episodes of inflammation of acute gout attaches in joints result severe and excruciating pain.

If hyperuricemia is inadequately controlled over the long term, persistent accumulation of urate crystals can lead to detectable aggregates of MSU crystals, known as tophi, resulting in tophaceous gout, the most severe form of chronic gout. Tophi can cause bone erosion, synovial thickening, joint deformity, and, in severe cases, loss of joint function and impaired renal function [1].

In addition to causing recurrent flares, joint damage, and tophaceous disease, gout is associated with important systemic comorbidities, including chronic kidney disease (CKD), hypertension, metabolic syndrome, obesity, and cardiovascular disease. These comorbidities contribute substantially to the overall burden of illness and underscore the importance of sustained long-term urate control.

Cardiovascular risk is also an important component of gout. Gout flares and sustained hyperuricemia are associated with increased cardiovascular morbidity and mortality. Large cohort studies and systematic reviews indicate that gout independently elevates the risk of major cardiovascular events and all-cause mortality.

Specifically, gout has been linked to heightened risks for myocardial infarction (hazard ratio [HR], 1.39; 95% CI, 1.27–1.52; P < 0.001), cerebral infarction (HR, 1.36; 95% CI, 1.26–1.46; P < 0.001), cerebral hemorrhage (HR, 1.50; 95% CI, 1.33–1.71; P < 0.001), and all-cause mortality (HR, 1.07; 95% CI, 1.02–1.12; P = 0.004) [2].

Moreover, major adverse cardiovascular events (MACE) increased significantly following discontinuation of urate-lowering therapy (ULT) compared with continuing ULT, both within 1 month (HR, 7.40; 95% CI, 5.38–10.17) and within 6 months (HR, 5.22; 95% CI, 4.26–6.39).

Additionally, within 6 months after discontinuation of ULT, cardiovascular mortality was higher than non-cardiovascular mortality (45.7% vs. 27.9%; P = 0.0001) [3]. Furthermore, gout was associated with a 44% higher risk of developing atrial fibrillation (AF) after adjustment for other risk factors, including obesity, smoking, alcohol use, blood pressure, diabetes, cholesterol, and kidney disease. The association was particularly pronounced among non-obese individuals and those with CKD, with approximately 75% and 149% higher risks of AF, respectively [4]. Collectively, these findings underscore the substantial cardiovascular burden associated with gout and highlight the importance of sustained urate control and long-term adherence to ULT.

Clinical guidelines recommend maintaining a target sUA level of < 6.0 mg/dL. Some guidelines recommend a target sUA level of < 5.0 mg/dL for tophaceous gout patients. Notably, patients achieving the conventional therapeutic sUA target of < 6.0 mg/dL had an overall 9% lower risk of heart attack and stroke, whereas intensive urate lowering to sUA < 5.0 mg/dL conferred more favorable clinical benefits, including a more pronounced decrease in tophus size and a 23% relative risk reduction in major adverse cardiovascular events [5, 6]. Despite available therapies, a substantial proportion of patients fail to maintain this target due to inadequate efficacy, safety concerns, treatment intolerance, or poor compliance. This difficulty in achieving long-term disease control underscores the need for additional treatment options.