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- Title
How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial.
- Authors
Wanner, Christoph; Nangaku, Masaomi; Kraus, Bettina J; Zinman, Bernard; Mattheus, Michaela; Hantel, Stefan; Schumacher, Martin; Ohneberg, Kristin; Schmoor, Claudia; Inzucchi, Silvio E
- Abstract
Introduction Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear. Methods We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimated glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy or death due to kidney disease) in EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure. Results In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid and urine albumin-to-creatinine ratio mediated 79.4%, 33.2% and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%) and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis. Conclusions Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease.
- Subjects
TYPE 2 diabetes; GLYCOSYLATED hemoglobin; FREE fatty acids; SYSTOLIC blood pressure; SODIUM-glucose cotransporter 2 inhibitors; EMPAGLIFLOZIN
- Publication
Nephrology Dialysis Transplantation, 2024, Vol 39, Issue 9, p1504
- ISSN
0931-0509
- Publication type
Article
- DOI
10.1093/ndt/gfae032