Abstract
<h3>Introduction</h3> Cardiovascular and kidney disease are closely inter-related. In EMPA-REG OUTCOME, empagliflozin (10 or 25mg once daily) reduced the risk of hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes and established cardiovascular (CV) disease. <h3>Hypothesis</h3> We evaluated whether kidney events increase risk for subsequent HF or CV outcomes and vice versa. <h3>Methods</h3> Bi-directional associations of kidney events and subsequent CV events were explored using Cox regression with time-varying covariates. <h3>Results</h3> Of 2,061 placebo patients, 18.8% experienced a kidney event (progression to macroalbuminuria with urine albumin-creatinine ratio [UACR] >300mg/g, doubling of serum creatinine with estimated glomerular filtration rate [eGFR] ≤45 ml/min/1.73 m<sup>2</sup>, initiation of renal-replacement therapy or renal death). Factors significantly associated with risk of experiencing a kidney event included: low baseline eGFR, albuminuria ≥30mg/g, high uric acid and LDL-C, prior HF but no coronary artery disease. In placebo patients, occurrence of a non-fatal kidney event increased subsequent HHF risk (hazard ratio [95% CI]) (2.40 [1.42,4.05]) but not 3P-MACE (1.30 [0.89,1.91]) (panel A). Vice versa, HHF (2.03 [1.22,3.39]) but not myocardial infarction (MI)/stroke (0.94 [0.56,1.56]) increased subsequent kidney event risk in the placebo arm (panel B). For 3-P MACE following kidney event, risk was significantly increased in the empagliflozin and overall groups although to a lesser extent and not significant from placebo (panel A). <h3>Conclusions</h3> These findings demonstrate strong bi-directional 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 compounded.
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