Effect of Urate-Lowering Therapy on Cardiovascular and Kidney Outcomes

Abstract

Background and objectivesSeveral clinical practice guidelines noted the potential benefits of urate-lowering therapy on cardiovascular disease and CKD progression; however, the effect of this regimen remains uncertain. In this systematic review, we aimed to evaluate the efficacy of urate-lowering therapy on major adverse cardiovascular events, all-cause mortality, kidney failure events, BP, and GFR.Design, setting, participants, & measurementsWe systematically searched MEDLINE, Embase, and the Cochrane databases for trials published through July 2020. We included prospective, randomized, controlled trials assessing the effects of urate-lowering therapy for at least 6 months on cardiovascular or kidney outcomes. Relevant information was extracted into a spreadsheet by two authors independently. Treatment effects were summarized using random effects meta-analysis.ResultsWe identified 28 trials including a total of 6458 participants with 506 major adverse cardiovascular events and 266 kidney failure events. Overall urate-lowering therapy did not show benefits on major adverse cardiovascular events (risk ratio, 0.93; 95% confidence interval, 0.74 to 1.18) and all-cause mortality (risk ratio, 1.04; 95% confidence interval, 0.78 to 1.39) or kidney failure (risk ratio, 0.97; 95% confidence interval, 0.61 to 1.54). Nevertheless, urate-lowering therapy attenuated the decline in the slope of GFR (weighted mean difference, 1.18 ml/min per 1.73 m2 per year; 95% confidence interval, 0.44 to 1.91) and lowered the mean BP (systolic BP: weighted mean difference, −3.45 mm Hg; 95% confidence interval, −6.10 to −0.80; diastolic BP: weighted mean difference, −2.02 mm Hg; 95% confidence interval, −3.25 to −0.78). There was no significant difference (risk ratio, 1.01; 95% confidence interval, 0.94 to 1.08) in the risk of adverse events between the participants receiving urate-lowering therapy and the control group.ConclusionsUrate-lowering therapy did not produce benefits on the clinical outcomes, including major adverse cardiovascular events, all-cause mortality, and kidney failure. Thus, there is insufficient evidence to support urate lowering in patients to improve kidney and cardiovascular outcomes.

Treating Hyperuricemia: The Last Word Hasn’t Been Said Yet

“…In line with these concerns are the results of a very recent meta-analysis including 28 prospective, randomized, controlled trials assessing the effects of ULT for at least six months on CV or kidney outcomes [ 39 ]. Chen Qi et al found that ULT was associated with the reduction of blood pressure and retardation of the decline in GFR overtime.…”

The dirty little secret of urate-lowering therapy: useless to stop chronic kidney disease progression and may increase mortality

“…Another approach to obtain further information is meta-analysis of already available trials. A recent meta-analysis that includes both PERL and CKD-FIX as well as 26 additional trials concluded that urate-lowering therapy did not show benefits on major adverse cardiovascular events [risk ratio (RR) 0.93 (95% CI 0.74–1.18)] and all-cause mortality [RR 1.04 (95% CI 0.78–1.39)] or kidney failure [RR 0.97 (95% CI 0.61–1.54)], thus confirming the futility of urate lowering on hard endpoints [ 59 ]. It should be noted that the meta-analysis was not limited to CKD patients or to trials with a kidney function primary endpoint.…”

“…Furthermore, no evidence for an acute effect of allopurinol on eGFR was observed in the first 16 weeks [mean between-group difference −0.89 mL/min/1.73 m 2 (95% CI −2.15–0.37)] of CKD-FIX [ 57 ]. Indeed, experience from other trials and a recent meta-analysis suggest that the difference in eGFR between the urate-lowering and control groups decreases rather than increases over time [ 45 , 59 ].…”

“…However, in the 3 years of follow-up, there was no significant difference in the mean eGFR slope between the febuxostat and non-febuxostat groups [−0.37 (95% CI −2.32–1.44) versus −0.69 (95% CI −2.63–1.39) mL/min/1.73 m 2 ; P = 0.606], which both had stable eGFR slopes that did not differ from the age-associated loss of eGFR. Overall, the meta-analysis reported a 0.68 mL/min/1.73 m 2 /year (95% CI 0.16–1.20)difference in eGFR slope for trials with a follow-up of at least 2 years (seven studies, n = 2734), but did not report on slope under control conditions and whether this was different from the age-associated loss of eGFR or even a negative slope [ 59 ]. Interestingly, the futility analysis in CKD-FIX considered a clinically meaningful difference to be 0.6 mL/min/1.73 m 2 /year [ 57 ].…”

Sex-Specific Association of Uric Acid and Kidney Function Decline in Taiwan

“…A meta-analysis of 1,134,073 participants showed a positive dose-response association between uric acid levels and cardiovascular disease mortality risk [ 11 ]. Hyperuricemia is common in chronic kidney disease (CKD) patients [ 12 ], and several studies have also shown a relationship between serum urate levels and kidney damage [ 13 , 14 , 15 , 16 ]. Urate-lowering therapy statistically significantly improved estimated glomerular filtration rate (eGFR) and serum creatinine and serum creatinine [ 17 ], and reduced the incidence of kidney failure events [ 18 ].…”