Changes in plasma glucose markers may mediate CV risk reduction with empagliflozin
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The reduction in risk for cardiovascular death in adults with type 2 diabetes and established cardiovascular disease seen with empagliflozin compared with placebo may be mediated with changes in markers of plasma glucose, according to results from an exploratory mediation analysis of the EMPA-REG Outcome trial.
“The type of glucose-lowering drug used in patients with type 2 diabetes and CVD can have a major influence on important clinical outcomes,” Silvio E. Inzucchi, MD, professor of endocrinology and director of the Yale Diabetes Center at Yale School of Medicine, told Endocrine Today.
Inzucchi and colleagues evaluated data from the EMPA-REG Outcome trial on 7,020 adults with type 2 diabetes and established CVD (mean age, 63 years; 72% men; mean HbA1c, 8%; mean BMI, 30.6 kg/m²) to determine the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin (Jardiance, Boehringer Ingelheim).
In the EMPA-REG Outcome trial, participants were randomly assigned to empagliflozin or placebo in addition to standard care during a median observation time of 3.1 years. Empagliflozin led to a 14% reduction in the risk for three-point major adverse CV events compared with placebo. After the results, the FDA expanded the indication for empagliflozin to include reducing the risk for CV death in patients with type 2 diabetes and established CVD.
Changes from baseline in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin on the reduction in risk for CV death compared with placebo. Further, changes in albumin and uric acid mediated 25.5% and 24.6% of the effects, respectively. HbA1c, fasting plasma glucose, weight, BMI, systolic blood pressure and diastolic BP, LDL and HDL cholesterol, triglycerides, free fatty acids, estimated glomerular filtration rate and urine albumin-to-creatinine ratio did not have any effects on the analyses. However, in multivariable models, combined changes from baseline in hematocrit, fasting glucose, uric acid and urine albumin-to-creatinine ratio provided 85.2% mediation on the effect of empagliflozin on the reduction in risk for CV death compared with placebo.
“The surprising and striking benefit of empagliflozin to reduce CV death in patients with type 2 diabetes and CVD has been the topic of extensive speculation as to underlying mechanisms,” Inzucchi said. “Our new data from the EMPA-REG Outcome study itself suggests that the drug’s effect may be mediated at least partially through a reduction in plasma volume, presumably with off-loading of failing or perhaps soon-to-fail ventricles. More mechanistic studies are needed to confirm our results, and they should also be corroborated within studies of other SGLT2 inhibitors. Since our was a retrospective, statistical analysis, it can only be considered as hypothesis-generating.” – by Amber Cox
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Silvio E. Inzucchi, MD, can be reached at silvio.inzucchi@yale.edu.
Disclosures: Inzucchi reports he has served on clinical trial steering or executive committees for AstraZeneca, Boehringer Ingelheim, Eisai, Novo Nordisk and Sanofi/Lexicon; as an adviser to Janssen and VTV Therapeutics; and on a data monitoring committee for Intarcia. Please see the study for all other authors’ relevant financial disclosures.