#4139 EFFECTS OF EMPAGLIFLOZIN ON FLUID OVERLOAD IN CHRONIC KIDNEY DISEASE: AN EMPA-KIDNEY BIOIMPEDANCE SUBSTUDY

Abstract

Abstract Background and Aims The EMPA-KIDNEY trial showed that, compared to placebo, empagliflozin 10 mg once daily reduced the risk of kidney disease progression or cardiovascular death in 6609 patients with chronic kidney disease at risk of progression. We aimed to assess effects of empagliflozin on bioimpedance-measured fluid overload and adiposity in a subset to better understand the mechanisms of cardiovascular benefits of sodium glucose co-transporter-2 inhibitors. Method This EMPA-KIDNEY substudy added Body Composition Monitor (BCM) measurements at randomization and the 2 and 18 month follow-up visits to the trial's main protocol-specified procedures. The primary outcome was Absolute Fluid Overload (a parameter reflecting overhydration, derived from extracellular and intracellular resistance). Pre-specified subgroup analyses of the primary outcome were by sex, diabetes status, estimated glomerular filtration rate (eGFR) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) at baseline. The key secondary analysis was a composite of death from heart failure, heart failure hospitalisation or development of new moderate (>7%, ≤15%) or severe (>15%) BCM-measured Relative Fluid Overload. Tertiary outcomes included weight, anthropometry, and other BCM-measurements of body water and adiposity. The primary outcome was analysed used mixed-model repeated measures (MMRM) methods. The key secondary outcome used time-to-first event methods. Results A total of 660 EMPA-KIDNEY participants were recruited into this substudy. Mean age was 64 years, 205 (31%) were female and 245 (37%) had diabetes. Mean (SD) eGFR was 36 (12) ml/min/1.73m2 and median (Q1-Q3) NTpro-BNP was 211 (93-581) ng/L. Mean (SD) Absolute Fluid Overload at baseline was 0.4 (1.6) L, 19% had moderate fluid overload and 5% fulfilled criteria for severe fluid overload at baseline. Compared to placebo, the mean study average absolute difference in Absolute Fluid Overload was -0.24L (95% CI -0.38, -0.11), with similar differences at 2 months and 18 months (Figure 1). This difference was similar in men and women, in people with and without diabetes, and across the spectrum of eGFR and NT-proBNP studied (Figure 2). The number of key secondary outcomes was low and there was no significant difference in the risk of this outcome between treatment groups (35/332 [10%] vs 38/328 [12%], hazard ratio 0.91 [95% CI 0.57, 1.45], p = 0.69). Conclusion In patients with chronic kidney disease, empagliflozin reduced bioimpedance-measured fluid overload irrespective of diabetes status or level of eGFR. This effect persisted for at least 18 months with no evidence of attenuation over time. Funding Boehringer Ingelheim, Eli Lilly and others; Clinicaltrials.gov:NCT03594110.