M JARDINE 1, C WANNER 2, M NANGAKU 3, B KRAUS 4,5,6, B ZINMAN 7, M MATTHEUS 8, S HANTEL 9, M SCHUMACHER 10, K OHNEBERG 10, SCHMOOR C11, S INZUCCHI 12
1NHMRC Clinical Trials Centre, The University Of Sydney , Specialist Renal Medicine Department, Concord Repatriation General Hospital, Camperdown, Australia, 2Würzburg University Clinic, Würzburg , Germany, 3Division of Nephrology and Endocrinology, Department of Hemodialysis and Apheresis, The University of Tokyo Hospital, Tokyo, Japan, 4Medical Affairs, Boehringer Ingelheim International GmbH, Ingelheim, Germany, 5Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany, 6Comprehensive Heart Failure Centre, University of Würzburg, , Germany, 7Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada, 8Biostatistics, Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany, 9Biostatistics, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany, 10Institute for Medical Biometry and Statistics and Clinical Trials Unit, Faculty of Medicine, and Medical Center, University of Freiburg, Freiburg, Germany, 11Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany , 12Section of Endocrinology, Yale University School of Medicine , New Haven, USA
Aim: Investigate factors mediating empagliflozin kidney benefits observed in EMPA-REG OUTCOME.
Background: Empagliflozin reduces kidney risk across kidney disease stages in heart failure or cardiovascular disease and type 2 diabetes; however, the underlying mechanisms are unclear.
Methods: Potential mediators of the empagliflozin treatment effect on the composite kidney outcome (first sustained eGFR [MDRD] ≥40% reduction from baseline, initiation of continuous kidney replacement therapy, or death due to kidney disease) were assessed post hoc in empagliflozin 10 mg, 25 mg, or placebo-treated participants. We performed Cox regression analyses with the updated mean of seventeen potential mediators as time-dependent covariates, plus landmark Cox regression analyses starting at Week 12 with potential mediator current change from baseline analysed as time-fixed covariates at Week 12; treatment group was adjusted for variable baseline values in both analyses. Variables with greatest mediating effect were added using a step-up procedure. Hazard ratios (HRs) for treatment were compared with unadjusted HRs, with mediation calculated as ratios of log-transformed HRs
Results: The composite kidney outcome treatment HR (95% CI) for the unadjusted Cox regression was 0.56 (0.42, 0.74). Haematocrit was the strongest time-dependent mediator: HR 1.00 (0.74, 1.35), 99.5% mediation. Uric acid mediated 33.2% and urine albumin-to-creatinine ratio mediated 31.0%. The unadjusted Week 12 landmark analysis HR (95% CI) was 0.54 (0.40, 0.72). Haematocrit was the strongest mediator: HR (95% CI) 0.69 (0.50, 0.95), 40.7% mediation. HbA1c, systolic blood pressure and free fatty acids mediated 28.3%, 16.8%, and 16.5%, respectively (combined mediation with haematocrit: 78.9%).
Conclusion: Haematocrit strongly mediated empagliflozin kidney benefits in T2D and CVD patients. It will be important to understand how haematocrit changes underpin the kidney benefits of SGLT2 inhibition.
Professor Meg Jardine is the Director of the NHMRC Clinical Trials Centre, the University of Sydney and Kidney Health Research Director. Her interests include the integration of clinical care and research endeavours, and the promotion of learning health system principles to contribute to the efficient delivery. She has experience in the design and conduct of national and international trials and is particularly interested in response-adaptive techniques as a solution to many of the challenges facing trials in kidney disease. She is a specialist nephrologist at Concord Repatriation General Hospital.