Plasma Volume Changes May Mediate Effects of Empagliflozin
Findings suggest reduced CV mortality risk mediated by effects on markers of plasma volume
Findings suggest reduced CV mortality risk mediated by effects on markers of plasma volume
The reduction in risk of cardiovascular (CV) death with empagliflozin is most mediated by changes in hematocrit and hemoglobin, according to research published online Dec. 4 in Diabetes Care.
Silvio E. Inzucchi, M.D., from Yale University in New Haven, Conn., and colleagues assessed the effects of potential mediators, identified post hoc, on the risk of CV death with empagliflozin compared with placebo among participants in the EMPA-REG OUTCOME trial involving 7,020 patients with type 2 diabetes and established cardiovascular disease.
The researchers found that changes in hematocrit and hemoglobin from baseline mediated 51.8 and 48.9 percent, respectively, of the effect of empagliflozin on the risk of CV death versus placebo. Uric acid, fasting plasma glucose, and hemoglobin A1c showed smaller mediation effects (maximum, 29.3 percent). When the effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin-to-creatinine ratio were incorporated into a model, the combined changes from baseline provided 85.2 percent mediation of the effect of empagliflozin on CV death, while updated mean analyses provided 94.6 percent mediation.
"In 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," the authors write.
Several authors disclosed financial ties to pharmaceutical companies, including Boehringer Ingelheim and Eli Lilly and Co., which funded the EMPA-REG OUTCOME trial.
Abstracts
How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial
Silvio E. Inzucchi, Bernard Zinman, David Fitchett, Christoph Wanner, Ele Ferrannini, Martin Schumacher, Claudia Schmoor, Kristin Ohneberg, Odd Erik Johansen, Jyothis T. George, Stefan Hantel, Erich Bluhmki and John M. Lachin
Diabetes Care 2017 Dec; dc171096. https://doi.org/10.2337/dc17-1096
Abstract
OBJECTIVE In the 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 METHODS Effects 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.
RESULTS Changes 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 HbA1c. 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.
CONCLUSIONS In 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.
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