Various Mediators Influence the Improvement in HF Outcomes with Empagliflozin: The EMPA-REG OUTCOME Analysis
Introduction
The EMPA-REG OUTCOME trial has already demonstrated that addition of empagliflozin to the standard of care was associated with a risk reduction for major adverse cardiovascular events, including heart failure (HF) or hospitalization for HF (HHF) versus placebo in patients with type-2 diabetes mellitus (T2DM).
Aim
To determine various covariates that mediate the impact of empagliflozin on HHF or HF death.
Patient Profile
- Patients with T2DM and established atherosclerotic cardiovascular disease (n=7020)
- Glycated hemoglobin (HbA1c) was in the range of 7.0%-9.0% for drug-na?ve patients and in the range of 7.0%-10.0% for patients on glucose lowering therapy
- The estimated glomerular filtration rate (eGFR) was ≥30 ml/min/1.73 m2.
Methods
Study Design
- A post hoc analysis of the EMPA-REG OUTCOME trial
- EMPA-REG OUTCOME was a randomized, double-blind, multi-center global clinical.
Treatment Strategy
- Study participants were randomized to either empagliflozin (10 or 25 mg) or placebo.
Outcomes
- HHF
- HF death
Traditional Mediation Analysis
- A mediator had to fulfil the following criteria:
- Affected by active treatment
- Associated with the outcome
- Adjustment for it results in a reduced treatment effect compared with unadjusted analysis.
- The potential mediators included in the analysis were:
- Glycemia (HbA1c and fasting plasma glucose)
- Cardiovascular (CV) parameters (systolic blood pressure, diastolic blood pressure, and heart rate)
- Lipids (low-density-lipoprotein-cholesterol [LDL-C], high-density lipoprotein [HDL]-C, triglycerides, and free fatty acids)
- Adiposity (weight, body mass index [BMI], and waist circumference)
- Renal function (urine albumin-to-creatinine ratio [UACR], eGFR according to Modification of Diet in Renal Disease [MDRD], and CKD-EPI formulae)
- Markers that might represent volume status (hematocrit, hemoglobin, and albumin)
- Others (uric acid)
Results
- Lesser number of patients treated with empagliflozin vs. placebo experienced HHF (2.7% vs. 4.1%) and HF death (0.2% vs. 0.8%).
- Increases in heart rate, log UACR, waist circumference, and uric acid were associated with increased risk of HHF or HF death (Table 1).
- On the contrary, increases in HDL-C, eGFR, hematocrit, hemoglobin, and albumin were associated with reduced risk of HHF or HF death (Table 1).
|
Variable |
HR for HHF or HF death |
95% CI |
|
Heart Rate (bpm) |
1.059 |
1.036, 1.082 |
|
logUACR (1.0 measured on log-scale [log (mg/g)]) |
1.723 |
1.455, 2.039 |
|
Waist circumference (cm) |
1.040 |
1.008, 1.073 |
|
Uric acid (mg/dL) |
1.344 |
1.162, 1.553 |
|
HDL-C (mg/dL) |
0.965 |
0.941, 0.991 |
|
eGFR (MDRD) (mL/min/1.73 m2) |
0.957 |
0.941, 0.973 |
|
Hematocrit (%) |
0.912 |
0.859, 0.968 |
|
Hemoglobin (g/dL) |
0.687 |
0.569, 0.830 |
|
Albumin (g/dL) |
0.100 |
0.048, 0.209 |
CI: Confidence interval; eGFR: estimated glomerular filtration rate; HDL-C: High density lipoprotein cholesterol; HR: Hazard ratio; HF: Heart failure; HHF: Hospitalization for heart failure, MDRD: Modification of Diet in Renal Disease formula; UACR: urine albumin-to-creatinine ratio
- As per univariable analyses, change from baseline in hematocrit, hemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively.
- As per a multivariable analysis hemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated.
Conclusions
- Changes in hematocrit and hemoglobin were the most important mediators associated with reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin.
- Albumin, uric acid, and logUACR had comparatively smaller mediating impact, underscoring the probable role of multifactorial underlying mechanisms of empagliflozin on HF outcomes.
ESC Heart Fail. Oct 4, 2021 (Published Ahead of Print);doi: 10.1002/ehf2.13615.
