ASSOCIATION OF KIDNEY AND CARDIOVASCULAR OUTCOMES IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: INSIGHTS FROM THE EMPA-REG OUTCOME TRIAL

Abstract

BACKGROUND In the EMPA-REG OUTCOME trial, empagliflozin (10 or 25mg once daily) reduced the risk of hospitalization for heart failure (HHF) as well as kidney events in patients with type 2 diabetes (T2D) and established cardiovascular (CV) disease by 35-39%. We aimed to evaluate the yet ill-defined bi-directional relationship between kidney and CV outcomes in this population. METHODS AND RESULTS Of the 2,061 patients on placebo in our analysis, 388 (18.8%) experienced a kidney event (progression to macroalbuminuria with UACR >300mg/g, doubling of serum creatinine with eGFR ≤45 ml/min/1.73 m², initiation of renal-replacement therapy or renal death). Low baseline eGFR, albuminuria ≥30mg/g, high uric acid and LDL-C were among the factors significantly associated with the risk of experiencing a kidney event, also prior HF but no coronary artery disease. Associations of kidney events and subsequent CV events and vice versa were explored using Cox regression with time-varying covariates and adjustment for various baseline factors. In the placebo arm, the occurrence of a non-fatal kidney event (excluding renal death) increased the risk of subsequent HHF (HR 2.40, 95% CI 1.42, 4.05) but not 3P-MACE (HR 1.30, 95% CI 0.89, 1.91) (panel A). Also, seemingly vice versa, HHF (HR 2.03, 95% CI 1.22, 3.39) but not myocardial infarction (MI) or stroke (HR 0.94, 95% CI 0.56, 1.56) increased the risk of subsequent kidney event in the placebo arm (panel B). The associations for kidney event following MI/Stroke were consistent in the pooled empagliflozin arm and in the overall population (panel B). For 3-P MACE following kidney event, the risk was significantly increased in the empagliflozin and overall groups although to a lesser extent and not significant from placebo (panel A). CONCLUSION Our results demonstrate strong and bidirectional inter-relationship between HHF and kidney events. Strategies to optimize the use of therapies such as empagliflozin, reducing both kidney and HF outcomes, are warranted, as their benefits may be thereby compounded. In the EMPA-REG OUTCOME trial, empagliflozin (10 or 25mg once daily) reduced the risk of hospitalization for heart failure (HHF) as well as kidney events in patients with type 2 diabetes (T2D) and established cardiovascular (CV) disease by 35-39%. We aimed to evaluate the yet ill-defined bi-directional relationship between kidney and CV outcomes in this population. Of the 2,061 patients on placebo in our analysis, 388 (18.8%) experienced a kidney event (progression to macroalbuminuria with UACR >300mg/g, doubling of serum creatinine with eGFR ≤45 ml/min/1.73 m², initiation of renal-replacement therapy or renal death). Low baseline eGFR, albuminuria ≥30mg/g, high uric acid and LDL-C were among the factors significantly associated with the risk of experiencing a kidney event, also prior HF but no coronary artery disease. Associations of kidney events and subsequent CV events and vice versa were explored using Cox regression with time-varying covariates and adjustment for various baseline factors. In the placebo arm, the occurrence of a non-fatal kidney event (excluding renal death) increased the risk of subsequent HHF (HR 2.40, 95% CI 1.42, 4.05) but not 3P-MACE (HR 1.30, 95% CI 0.89, 1.91) (panel A). Also, seemingly vice versa, HHF (HR 2.03, 95% CI 1.22, 3.39) but not myocardial infarction (MI) or stroke (HR 0.94, 95% CI 0.56, 1.56) increased the risk of subsequent kidney event in the placebo arm (panel B). The associations for kidney event following MI/Stroke were consistent in the pooled empagliflozin arm and in the overall population (panel B). For 3-P MACE following kidney event, the risk was significantly increased in the empagliflozin and overall groups although to a lesser extent and not significant from placebo (panel A). Our results demonstrate strong and bidirectional inter-relationship between HHF and kidney events. Strategies to optimize the use of therapies such as empagliflozin, reducing both kidney and HF outcomes, are warranted, as their benefits may be thereby compounded.