Fitchett D, Inzucchi SE, Zinman B, et al. - Among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease who received treatment with empagliflozin, the most crucial mediators of the decrease in hospitalization for heart failure (HHF) and death from heart failure (HF) were: alterations in hematocrit and hemoglobin. In this population, smaller mediating impacts of albumin, uric acid, and logUACR (log urine albumin-to-creatinine ratio) were evident.

• The EMPA-REG OUTCOME trial showed reduction in the risk of death from HF or HHF with empagliflozin vs placebo in patients with T2DM and established CV disease.

• In this post hoc analysis, the degree to which covariates mediated the impacts of empagliflozin on HHF or HF death was assessed.

• Certain criteria were defined to be fulfilled by a mediator.

• Elevated risk of HHF or HF death was observed in relation to increases in heart rate, logUACR, waist circumference, and uric acid.

• A decreased risk of HHF or HF death was evident with increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, hematocrit, hemoglobin, and albumin.

• Univariable analyses showed that 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin vs placebo was mediated by change from baseline in hematocrit, hemoglobin, albumin, uric acid, and logUACR, respectively.

• Multivariable analysis involving hemoglobin, logUACR, and uric acid was shown to mediate 85% of risk reduction with similar outcomes when updated means were assessed.