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How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial
Christoph Wanner1, Masaomi Nangaku2, Bettina J Kraus3,4,5
1Department of Medicine, Würzburg University Clinic, Würzburg, Germany.
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.
Insights
Changes in hematocrit and hemoglobin levels significantly mediated the kidney benefits of sodium-glucose cotransporter-2 (SGLT2) inhibition in patients with type 2 diabetes and cardiovascular disease. These findings clarify mechanisms of SGLT2 inhibitors for kidney protection.
Area of Science:
- Cardiovascular Medicine
- Nephrology
- Endocrinology
Background:
- Mechanisms of kidney benefits from sodium-glucose cotransporter-2 (SGLT2) inhibitors in heart failure and/or type 2 diabetes (T2D) with cardiovascular disease remain unclear.
- SGLT2 inhibitors are increasingly used for cardiorenal protection.
Purpose of the Study:
- To investigate the factors mediating the kidney benefits of empagliflozin in patients with T2D and cardiovascular disease.
- To identify key hematological and metabolic changes responsible for empagliflozin's renal protective effects.
Main Methods:
- Post hoc analysis of the EMPA-REG OUTCOME trial data.
- Evaluation of mediating factors using time-dependent covariates and a Week 12 landmark approach in Cox regression.
- Multivariable analyses to determine the combined mediation effect of key variables.
Main Results:
- Hematocrit changes demonstrated the strongest mediation (99.5%) in univariable time-dependent analyses.
- Hemoglobin (79.4%), uric acid (33.2%), and urine albumin-to-creatinine ratio (31.0%) also showed significant mediation.
- In Week 12 landmark analyses, hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%), and free fatty acids (16.5%) were key mediators, combining for 78.9% mediation.
Conclusions:
- Increases in hematocrit and hemoglobin are the primary mediators of empagliflozin's kidney benefits in T2D patients with cardiovascular disease.
- These findings highlight the importance of hematological changes in the cardiorenal protective effects of SGLT2 inhibitors.
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