The association between urate-lowering therapies and treatment-related adverse events, liver damage, and major adverse cardiovascular events (MACE): A network meta-analysis of randomized trials

Abstract

Purpose: Hyperuricemia is a common disease that may lead to gout, renal damage, and cardiovascular events. Oral medication is the main treatment for hyperuricemia patients when lifestyle intervention fails. An evaluation of the safety of various urate-lowering therapies (ULTs) is integral to clinical decision-making. We constructed a network meta-analysis (NMA) to evaluate the safety of oral ULTs.

Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched up to April 1, 2021, for randomized controlled trials that examined the safety of ULTs. The language restriction was English. The three outcomes used to assess the safety of uric acid lowering medications were treatment-related adverse events, liver damage, and major adverse cardiovascular events (MACE).

Results: Thirty-two trials enrolling 23,868 individuals were included in the study. In terms of treatment-related adverse events, there were no statistically significant differences between five uric acid lowering medications and placebo: allopurinol (risk ratio (RR): 1.08; 95% credible interval (CrI): 0.91, 1.29), febuxostat (RR: 1.05; 95% CrI: 0.89, 1.25), lesinurad (RR: 1.19; 95% CrI: 0.85, 1.67), lesinurad combined with xanthine oxidase inhibitor (XOI, RR: 1.05; 95% CrI: 0.83, 1.32), and topiroxostat (RR: 1.01; 95% CrI: 0.83, 1.23). Topiroxostat likely increases risk of liver damage (RR: 2.65; 95%CI: 1.24, 5.70; NNH: 33.40) as compared with placebo. With regard to MACE, there were no statistically significant differences between three uric acid lowering medications and placebo: allopurinol (RR: 0.63; 95% CrI: 0.36, 1.34), febuxostat (RR: 0.69; 95% CrI: 0.38, 1.66), and lesinurad combined with XOI (RR: 0.56; 95% CrI: 0.23, 1.85). The rankings of different interventions were depicted by cumulative ranking curve (SUCRA).

Conclusions: Through NMA, we provide some evidence for the safety of ULTs. We found no statistically significant differences in their effects on treatment-related adverse events and MACE. However, topiroxostat likely increases the risk of liver damage.

Keywords: liver damage; major adverse cardiovascular events; network meta-analysis; treatment-related adverse events; urate-lowering therapy; xanthine oxidase inhibitor.