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Randomized Controlled Trial

Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD

Kaitlin J Mayne et al. J Am Soc Nephrol. .

Abstract

Significance statement: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk.

Background: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population.

Methods: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach.

Results: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1).

Conclusions: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass.

Trial registration: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).

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Conflict of interest statement

The EMPA-KIDNEY bioimpedance substudy was initiated, designed, conducted, analyzed, and reported by the University of Oxford with a steering committee of experts. This paper has not been published previously in whole or part. The Clinical Trial Service Unit and Epidemiological Studies Unit (Oxford, UK) have a staff policy of not accepting honorarium or other payments from the pharmaceutical industry, except for the reimbursement of costs to participate in scientific meetings (see https://www.ctsu.ox.ac.uk/about/ctsu_honoraria_25june14–1.pdf). C. Baigent reports advisory or leadership role: Chair of the European Society of Cardiology Clinical Practice Guidelines Committee 2020–22, and other interests or relationships: trustee of the UK charity Alport-UK, which supports patients and families with Alport syndrome. S. Brenner reports participation on a nephrologist advisory board of Boehringer Ingelheim. V. Cejka reports support to attend meetings from Boehringer Ingelheim, Lilly, and the University of Oxford. V. Cejka also reports research funding: EMPA-KIDNEY study, PI in Wurzburg C. Wanner: The RENAL LIFECYCLE study(NCT05374291): PI in Wurzburg C. Wanner; HELIOS-B study (NCT04153149), PI in Wurzburg C. Morbach; CARDIO-TTRansform study (NCT04136171), and PI in Wurzburg S. Stork; honoraria: Pfizer; and other interests or relationships: financial support for travel and attendance of scientific congresses from Alnylam. D.Z.I. Cherney reports grant funding from AstraZeneca, Boehringer Ingelheim, CSL-Behring, Eli Lilly, Janssen, Merck & Co. Inc., Novo Nordisk, and Sanofi; and consulting fees from AbbVie, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, CSL-Behring, Eli Lilly, Gilead, Inversago, Janssen, Lexicon, Maze, Merck & Co. Inc., Mitsubishi-Tanabe, Novartis, Novo Nordisk, Otsuka, Prometic, Sanofi, and Youngene. D.Z.I. Cherney also reports honoraria: AbbVie, AstraZeneca, Bayer, BMS, Boehringer Ingelheim-Lilly, CSL-Behring, Janssen, Maze, Merck, Mitsubishi-Tanabe, Novartis, Novo Nordisk, Otsuka, Prometic, Sanofi, and Youngene; and advisory or leadership role: AstraZeneca, Bayer, BMS, Boehringer Ingelheim-Lilly, CSL-Behring, Janssen, Lexicon, Maze, Merck, Novartis, and Novo Nordisk. S.J. Davies reports consultancy: Ellen Medical; research funding: Baxter Healthcare; honoraria: Baxter Healthcare and Fresenius Medical Care; and advisory or leadership role: International Society of Peritoneal Dialysis (Member, co-chair PDOPPS Committee), International Society of Nephrology (Kidney Failure Strategy), President EuroPD, and Trustee Kidney Research UK. J.B. Green reports grant funding from Boehringer Ingelheim, Lilly, Merck, and Roche; consulting fees from Anji, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Merck, Novo Nordisk, Pfizer, Valo, and Vertex; honoraria for lectures from Boehringer Ingelheim; support to attend meetings from Bayer, Lilly, and Novo Nordisk; and writing support from Bayer. J.B. Green also reports research funding: Bluedrop; and honoraria: Anji, AstraZeneca, Bayer, Lilly, Novo Nordisk, Pfizer, Valo, and Vertex. W.G. Herrington was additionally funded by an MRC Kidney Research UK Professor David Kerr Clinician Scientist Award (MR/R007764/1). S.J. Hauske, D. Steubl, and M. Brückmann are employees of Boehringer Ingelheim International GmbH. W.G. Herrington also reports advisory or leadership role: NDT subject editor; UK Kidney Association, European Society of Cardiology & KDIGO guideline committee roles, and UK Renal Trial Network Chair. S.J. Hauske, D. Steubl, and M. Brückmann are employees of Boehringer Ingelheim International GmbH. L.S. Hooi reports support to attend meetings from the Malaysian Society of Nephrology and unpaid leadership roles as editor, the Malaysian Dialysis Transplant Registry; and chairman, Nephrology Medical Education Committee of the Malaysian Medical Council. L.S. Hooi reports other interests or relationships: editor, Malaysia Dialysis and Transplant Registry and Malaysian Society of Nephrology. P.K. Judge reports research funding: The UK HARP-III trial was funded by a grant to the University of Oxford from Novartis. D.F. Keane reports institutional grant funding from Baxter Healthcare for an Investigator Initiated Research Grant Award. D.F. Keane reports research funding: Baxter Healthcare Investigator Initiated Grant. M.J. Landray reports research funding: Apollo Tx, Boehringer Ingelheim, Moderna, Novartis, Regeneron, and Sanofi. J.S. Lees reports personal lectureship honoraria from AstraZeneca. P.B. Mark reports grant funding (paid to institution) from AstraZeneca and Boehringer Ingelheim; consulting fees (paid to institution) from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, and GSK; honoraria (paid to institution) from AstraZeneca, Boehringer Ingelheim, and Pharmacosmos; and personal payment from Novartis for participation on a Data Safety Monitoring Board or Advisory Board. P.B. Mark also reports consultancy: Pharmacosmos; and honoraria: Astellas, Bayer, GSK, and Pharmacosmos. K.J. Mayne reports research funding: MRC-UK—core funding paid to department. K.J. Mayne, N. Staplin, P.K. Judge, D. Preiss, J. Emberson, R. Dayanandan, R. Lee, J. Nolan, A. Omata, M.J. Landray, C. Baigent, R. Haynes, and W.G. Herrington report grant funding paid to their institution (the University of Oxford) from Boehringer Ingelheim and Eli Lilly, and funding from the United Kingdom Medical Research Council (MRC) (to the Clinical Trial Service Unit and Epidemiological Studies Unit; reference no., MC_UU_00017/3), the British Heart Foundation, National Institute for Health and Care Research Biomedical Research Council, and Health Data Research (UK). R. Pontremoli reports honoraria from Alfa-Sigma, AstraZeneca, Boehringer Ingelheim, Lilly, Menarini, MSD, Novartis, and Novo Nordisk. D. Preiss reports research funding: Novartis and Novo Nordisk. N. Staplin reports research funding: Novo Nordisk; and advisory or leadership role: associate editor for Nephrology Dialysis Transplant. J. Stegbauer reports grant funding and honoraria from AstraZeneca and Boehringer Ingelheim; and support to attend meetings from Boehringer Ingelheim (Annual meeting of the German Society of Nephrology). J. Stegbauer also reports research funding: German Research Foundation; honoraria: Bayer Life Science; advisory or leadership role: editorial board: Hypertension and Kidney360; and other interests or relationships: German Society of Nephrology, AHA High Blood Pressure, and German Society of Hypertension. K.R. Tuttle reports grant funding from the National Institutes of Health, NIH (NIDDK, NHLBI, NCATS, and NIMHD), the Centers for Disease Control and Prevention (CDC), Bayer, and Travere; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Novo Nordisk, Pfizer, and Travere; honoraria from AstraZeneca, Bayer, Lilly, and Novo Nordisk; support to attend meetings from Novo Nordisk; unpaid roles on Data Safety Monitoring/Advisory Boards for NIDDK and George Clinical; and unpaid leadership roles as Chair, Diabetic Kidney Disease Collaborative, American Society of Nephrology and Board of Directors, and Kidney Health Initiative. K.R. Tuttle reports consultancy: AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, and Travere; research funding: Bayer and Travere; and honoraria: Bayer, Boehringer Ingelheim, and Novo Nordisk. C. Wanner reports institutional grant funding from Boehringer Ingelheim and Sanofi; consulting fees from AstraZeneca and Astellas, Bayer, and Boehringer Ingelheim; honoraria for lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Vifor, Fresenius Medical Care, MSD, and Sanofi. C. Wanner also reports consultancy: CSL Vifor, GSK, MSD, and Novo Nordisk; honoraria: Amicus, Astellas, Chiesi, Eli Lilly, FMC, GSK, Novartis, Stadapharm, and Takeda; and other interests or relationships: European Renal Association (ERA).

Figures

None
Graphical abstract
Figure 1
Figure 1
Relationship of the derived “Fluid Overload” parameter to body weight and tissue mass. Based on the three-compartment model described by Chamney et al. *Excess ECW accumulates both in tissues and in the blood (although blood volume is not specifically conceptualized in the three-compartment model), so changes in Fluid Overload could reflect changes in excess ECW that might be residing in adipose tissue, lean tissue, or both. †Refers to normally hydrated lean and adipose tissue mass. Total body water (TBW) is the sum of ECW and ICW, although TBW is not conceptualized in the three-compartment model. The figure is not to scale because compartment proportions vary between individuals and “Fluid Overload” is usually smaller than depicted (and can be a negative value in fluid depletion). The mean baseline values in the EMPA-KIDNEY substudy were total body weight 88.8 kg, “Fluid Overload” 0.4 L, lean tissue mass 38.8 kg, and adipose tissue mass 49.6 kg. In the EMPA-KIDNEY substudy, mean total ECW at baseline was 18.7 L and ICW 20.4 L. ECW, extracellular water; ICW, intracellular water.
Figure 2
Figure 2
Effects of empagliflozin on mean bioimpedance-derived absolute “Fluid Overload” by time. The value at time 0 is the average across all randomized participants. Follow-up means (and their CIs) are derived from a repeated measures mixed model adjusted for baseline values, age, sex, diabetes, eGFR, and uACR. Follow-up values are plotted at the median follow-up day in each time window. There was no significant interaction between treatment allocation and time (P = 0.11). The study average is the between-group difference (empagliflozin minus placebo) in weighted averages of both time points (see Supplemental Methods). Analyses excluded 40 consenting participants with no valid follow-up measurements. Median (Q1–Q3) follow-up since randomization for empagliflozin versus placebo groups at the 2-month visit: 64 (57–74) versus 64 (57–75) days, Wilcoxon rank sum P = 0.871; and at the 18-month visit: 540 (519–555) versus 532 (505–554) days, P = 0.026. CI, confidence interval; uACR, urinary albumin-creatinine ratio.
Figure 3
Figure 3
Effects of empagliflozin on mean bioimpedance-derived absolute “Fluid Overload” (in liters) by prespecified substudy subgroups. Study-average differences are adjusted for baseline values of the dependent variable (in continuous form) and for any differences in key baseline characteristics (categories of age, sex, diabetes, eGFR, and urinary albumin-creatinine ratio) between treatment groups and weighted in proportion to the amount of time between follow-up visits (see Supplemental Methods). Analysis excluded 40 consenting participants with no valid follow-up measurements (3 deaths before first follow-up measurement, 28 with no measurement performed, and 9 excluded because of inadequate data quality). Further details are available in Supplemental Table 5. NT-proBNP, N-terminal pro B-type natriuretic peptide; SE, standard error.
Figure 4
Figure 4
Full trial cohort: effects of empagliflozin on weight and systolic BP overall and by key bioimpedance substudy prespecified subgroups. Study-average differences are adjusted for baseline values of the dependent variable (in continuous form) and for any differences in key baseline characteristics (categories of age, sex, diabetes, eGFR, urinary albumin-creatinine ratio, and region) between treatment groups and weighted in proportion to the amount of time between follow-up visits (see Supplemental Methods). Each analysis includes all individuals with at least one follow-up measurement of the outcome variable with mean imputation of missing baseline measurements. For comparison, between-group differences in the substudy cohort were −0.7 (95% CI −1.3 to −0.1) kg and −3.3 (−5.5 to −1.2) mm Hg for weight and systolic BP, respectively.
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