Empagliflozin and uric acid metabolism in diabetes: A post hoc analysis of the EMPA-REG OUTCOME trial

Abstract

Aim: To evaluate the effect of empagliflozin on uric acid (UA) levels, antigout medication and gout episodes in the EMPA-REG OUTCOME trial (NCT01131676).

Materials and methods: A total of 7020 patients with type 2 diabetes (T2D) were randomized to either empagliflozin (10 or 25 mg) or placebo. The effects of empagliflozin versus placebo on UA concentration were assessed using mixed linear models. A composite outcome of new prescription of antigout medication or gout episode was studied with Cox proportional hazards models.

Results: Empagliflozin reduced serum UA levels versus placebo: week 52 adjusted mean treatment difference = -0.37 (95% confidence interval [CI] -0.42, -0.31) mg/dL; this was more pronounced in patients with baseline UA ≥ 7.0 mg/dL versus <7.0 mg/dL: week 52 adjusted mean treatment difference = -0.56 (95% CI -0.68, -0.43) and -0.30 (95% CI -0.37, -0.24) mg/dL, respectively. Among 6607 patients not taking antigout medications at baseline, 5.2% had a gout episode or initiated antigout treatment versus 3.6% in the placebo and empagliflozin groups, respectively: hazard ratio 0.67 (95% CI 0.53, 0.85; P = 0.001). Both components of the composite outcome contributed to the reduction with empagliflozin in the composite. Risk reduction was similar with both empagliflozin doses.

Conclusions: Empagliflozin reduced UA levels and the composite of gout episodes or prescription of antigout medication. These clinically important findings expand the utility of empagliflozin as a potential antigout treatment in patients with T2D, beyond its well-established cardio-renal benefits.

Keywords: antigout treatment; empagliflozin; gout; type 2 diabetes; uric acid.

Conflict of interest statement

J.P.F. is a consultant for Boehringer Ingelheim. S.E.I. reports membership on scientific/research advisory boards for Boehringer Ingelheim, AstraZeneca, Intarcia, Lexicon, Janssen, Sanofit, Merck & Co. and Novo Nordisk, has received research supplies to Yale University from Takeda, and has participated in medical educational projects, for which unrestricted funding from Boehringer Ingelheim, Eli Lilly, and Merck & Co. was received by Yale University. C.W. has received honoraria for consultancy and lecturing from AstraZeneca, Bayer, BI, GlaxoSmithKline, Eli Lilly and Company, Merck Sharp & Dome, Mundipharma, Sanofi Genzyme and Takeda. B.Z. received consulting fees from Boehringer Ingelheim, Novo Nordisk and Eli Lilly. M.M., T.M. and D.S. are Boehringer Ingelheim employees.

© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Effect of empagliflozin (10 and 25 mg doses pooled) versus placebo on uric acid (UA) levels (mg/dL) over time (on‐treatment). Mixed‐effect model repeated measures analyses included the continuous fixed effects of baseline UA and baseline glycated haemoglobin at each visit and discrete fixed effects for treatment at each visit, sex, region, baseline estimated glomerular filtration rate, baseline body mass index and last projected visit

FIGURE 2

Time to new onset of gout or antigout medication during on‐treatment phase, for patients not on antigout medication at baseline. Hazard ratio (HR) based on Cox proportional hazards model with terms for age, sex, geographic region, baseline glycated haemoglobin, baseline estimated glomerular filtration rate, baseline body mass index and treatment. CI, confidence interval

FIGURE 3

Effect of empagliflozin on new onset of gout or initiation of antigout medication during follow‐up (on‐treatment). †Per 1000 patient‐years. ‡Based on Cox regression with terms for age, sex, geographic region, baseline body mass index, baseline glycated haemoglobin, baseline estimated glomerular filtration rate, and treatment. §Analysis performed in patients not on antigout medication at baseline (n = 6607). ¶Analysis performed in all patients (n = 7020). CI, confidence interval; HR, hazard ratio