Urate-lowering therapy in cardiovascular pharmacotherapy: from Mendelian randomization data to cardio–renal–metabolic risk modulation

Serum uric acid (SUA) and hyperuricaemia have re-emerged as determinants of cardiovascular (CV) risk beyond gout. This review integrates epidemiological, Mendelian randomization (MR), and pharmacological evidence to define the role of SUA and urate-lowering therapy (ULT) in contemporary CV pharmacotherapy.

We synthesized population-based studies, MR and drug-target MR analyses, and randomized trials of xanthine oxidase inhibitors (XOIs), uricosurics/URAT1 inhibitors, biologic uricases, and CV drugs with urate-modifying effects. Hyperuricaemia is prevalent and rising, often closely accompanying obesity, hypertension, diabetes, and chronic kidney disease (CKD). Higher SUA correlates with coronary artery disease, heart failure, stroke, cardio–renal–metabolic syndromes, and mortality, with non-linear risk relationships and sex- and age-specific thresholds. Mendelian randomization suggests a modest causal contribution of genetically elevated SUA to blood pressure, coronary disease, and advanced CKD, partly mediated via haemodynamic, renal, and inflammatory pathways. Pharmacologically, XOIs, URAT1 inhibitors, and uricases differ in kinetics and safety profiles. However, large trials and real-world cohorts show no consistent reduction in CV events when ULT is added to guideline-directed therapy in asymptomatic hyperuricaemia, stable ischaemic heart disease, chronic heart failure, or CKD. Observational data suggest that long-term, adequately dosed XOIs and high cumulative uricosuric exposure may reduce coronary risk.

Serum uric acid is a cardio–renal–metabolic biomarker and a plausible therapeutic target in selected cardio–renal–metabolic phenotypes. However, evidence does not support routine ULT for CV prevention in asymptomatic hyperuricaemia. Urate-lowering therapy should remain focused on gout and symptomatic hyperuricaemia, with phenotype-guided strategies to identify patients with asymptomatic hyperuricemia most likely to benefit.