Abstract Background CLEAR Outcomes (N=13,970) showed bempedoic acid (BA) reduced MACE-4 by 13% in statin intolerant patients at high cardiovascular risk. Due to modest inhibition of organic anion transporter 2, BA is associated with mean increases in uric acid (UA) of ~0.8 mg/dL which are stable over time and reversible. Gout occurred in 3.2% BA and 2.2% placebo (PBO) patients over a median 40.6 months follow up. Additionally, gout was reported in 14.7% BA vs 19.4% PBO patients with history of gout, and in 7.7% BA vs 5.2% PBO patients with elevated baseline UA.(1) The clinical impact and timing of UA lowering medication (UAMED) use on the risk of gout is unknown. Purpose Assess the association of timing of UAMED use (baseline and new treatment) on incidence of gout in CLEAR Outcomes, and if baseline UA and/or gout history influence the results. We also assessed the effect of BA vs. PBO on MACE-4 by gout history. Methods The safety analysis dataset was used to report gout. For patients who started UAMED during the study, UA level change over time was plotted and stratified by presence of a gout event, with time 0 set at the start date of the UAMED. MACE-4 was analyzed using a proportional hazard model in the full analysis set. Results At baseline 375/7001 (5.4%) BA and 345/6964 (5.0%) PBO patients reported gout; 2158 (30.8%) and 2162 (31.0%), respectively, had a baseline UAupper limit of normal (ULN). In patients with prior gout who never received UAMED, gout rate was 2.2% BA vs 0.6% PBO (Table). In patients with prior gout and on UAMED at baseline, gout rate was 3.2% BA vs 9.1% PBO. For those with prior gout who initiated UAMED during the study, gout occurred in 0.5% vs 0%, respectively, after the UAMED was started. In patients with baseline UAULN but no history of gout, rates of gout were low after UAMED was started or in patients who were on a UAMED at baseline (Table). In patients with both prior gout and baseline UAULN, new UAMED use was 25.3% BA and 19.9% PBO with gout occurring in 11.6% BA and 8.9% PBO during the trial. Gout was less frequent in the patients with both who either used UAMED at baseline or after a UAMED was started during the trial (Table). Regardless of randomization to BA or PBO, addition of UAMED reduced UA levels (Figure). There was no evidence of heterogeneity on the effect of BA vs PBO on MACE-4 by those with history of gout (n=720) HR(adjusted) 0.87 (95% CI: 0.63-1.21) and those without (n=13,245) HR(adjusted) 0.87 (95% CI: 0.79-0.96). Conclusion Patients with elevated UA levels are at a higher risk of experiencing gout with bempedoic acid. However, further risk of gout may be reduced by pre-treatment with UAMED or initiation of UAMED after an episode of gout. Patients with a prior history of gout derive similar CV benefits with bempedoic acid as those without.Table 1.
Ray et al. (Sat,) studied this question.