How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

Abstract

OBJECTIVEIn the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio [HR] 0.62 [95% CI 0.49, 0.77]). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin. RESEARCH DESIGN AND METHODSEffects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed. RESULTSChanges in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA 1c . In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death. CONCLUSIONSIn this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.Empagliflozin, a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, was the first glucose-lowering agent to demonstrate a reduction in cardiovascular (CV) death in patients with type 2 diabetes and high CV risk (1). In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, over a median observation time of 3.1 years, treatment

Empagliflozin reduces Ca/calmodulin‐dependent kinase II activity in isolated ventricular cardiomyocytes

“…In addition, empagliflozin exerts the same beneficial cardiovascular effects after adjustment for ischaemic risk factors (blood pressure, low‐density lipoprotein cholesterol, HbA1c) . In a mediation analysis of this trial, changes in haematocrit (and haemoglobin) but not HbA1c appeared to be the variables with the largest impact on the risk of cardiovascular death . This argues strongly against glycaemic control as the underlying cardio‐protective mechanism .…”

“…Interestingly, in a non‐diabetic mouse model of afterload‐induced HF, empagliflozin prevented worsening of left ventricular function . Overexpression and activation of Ca 2+ /calmodulin‐dependent kinase II (CaMKII) are hallmarks of HF and also found in diabetic patients, leading to increased diastolic Ca 2+ leak from the sarcoplasmic reticulum (SR) and reduced SR Ca 2+ load, causing contractile dysfunction and arrhythmias . Interestingly, CaMKII is activated by increased cytosolic Ca 2+ concentrations.…”

ADVANCE in context: The benefits, risks and feasibility of providing intensive glycaemic control based on gliclazide modified release

“…Despite this, small but significant differences in HbA1c, in favour of the groups allocated to SGLT‐2 inhibitors or GLP‐1 agonists, were observed, with greater differences in HbA1c in the GLP‐1 agonist trials. A follow‐up mediation analysis of the EMPA‐Reg trial has further suggested that only a modest proportion (23%‐29%) of the overall cardiovascular benefit was attributable to glucose lowering . A further mediation analysis of the SUSTAIN 6 trial has also raised concerns regarding the magnitude and rapidity with which glucose levels are lowered given the unexpected increased risk of retinopathy reported .…”

Effects of empagliflozin treatment on cardiac function and structure in patients with type 2 diabetes: a cardiac magnetic resonance study

“…It is thought that the rapid onset of benefit seen may be due to plasma volume and preload reduction, and notably there was a 5% increase in haematocrit in the EMPA‐REG OUTCOME trial. Our findings are consistent with the results of a recent mediation analysis of the EMPA‐REG OUTCOME trial showing that haematocrit mediated around 50% of the effect of empagliflozin versus placebo on the risk of cardiovascular death …”