Urate-lowering effects of losartan: a meta-analysis of randomised controlled trials and target trial emulation

Common in hypertensive patients, hyperuricaemia is often exacerbated by guideline-recommended antihypertensive therapies such as thiazide diuretics. Losartan is known as an angiotensin II receptor type 1 antagonist with a uricosuric effect, but the magnitude of its efficacy in lowering urate has not been quantified versus a placebo-reference. We sought to quantify the urate-lowering effect of losartan versus placebo using two complementary approaches. We first conducted a meta-analysis of randomised controlled trials (RCTs) to quantify the effect of losartan on serum urate levels versus placebo. We then applied a target trial emulation framework in the UK Biobank as a secondary source of data and a replication experiment. The meta-analysis of six prospective randomised controlled trials (RCTs), including 1119 losartan-treated patients and 1093 controls, demonstrated that losartan reduced serum urate levels by approximately 0.29 mg/dL relative to placebo (95% CI: -0.46 to -0.12, p = 0.0009). In the target trial emulation, 23 losartan-treated individuals showed a reduction in serum urate of approximately 0.35 mg/dL (95% CI: -0.66 to -0.03, p = 0.03) when compared with 92 matched controls, and after accounting for 12 potential confounders including established urate-lowering therapies. Our results provide evidence for a modest yet consistent urate-lowering potential of losartan. This modest biochemical effect (~0.3 mg/dL) may be an attractive option to mitigate the diuretic-induced urate elevation. Thus, losartan can be considered as a favourable antihypertensive choice for patients managed with diuretics or those who are at risk of hyperuricaemia/gout.