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Behind Empagliflozin’s Reduction in Cardiovascular Mortality

Mar 31, 2018

Post-hoc analysis of the breakthrough EMPA-REG Outcome trial demonstrated reduction in composite cardiovascular outcomes that can be seen with empagliflozin therapy.

The EMPA-REG trial was the groundbreaking trial that positioned not only empagliflozin but the entire class of SGLT2 inhibitors as the agents that provide reduction in CV death in individuals with type 2 diabetes who have cardiovascular disease. When added on to the already existing anti-hyperglycemic medications, empagliflozin provided a 14% decrease in composite cardiovascular outcomes of CV death, nonfatal stroke, and nonfatal MI, which was not seen with placebo. Moreover, hospitalizations due to heart failure exacerbations were also decreased in patients treated with empagliflozin, as was the all-cause mortality.  The drastic results of the EMPA-REG trial were responsible for labeling of empagliflozin by the FDA to include the reduction of CV death in patients with T2DM and established CV disease. The mechanisms behind which the empagliflozin reduced the CV events are not known. In order to uncover the mediators that lead to the above-mentioned benefit, researchers completed a post-hoc analysis of the EMPA-REG trial.

Subjects with T2D who were enrolled into the EMPA-REG trial received empagliflozin 10 mg, empagliflozin 25 mg, or placebo as well as their glucose-lowering medications they have been taking in the past. To analyze the potential mediators of the benefit with empagliflozin, variables that were measured in the trial were identified for the post-hoc analysis.  These included HbA1c levels, FPG, SBP, DBP, lipids, adiposity, renal function, volume status, and uric acid levels. A mixed-effects repeated-measured model was used to differentiate between the effects each treatment arm had on the longitudinal changes of each of the potential mediators. Researchers regarded the empagliflozin’s CV benefit both as a direct effect by the medication itself, or the indirect effect that occurs due to one of the potential mediators mentioned above.  The changes in variables were measured at baseline and post-baseline in order to determine their true treatment potential.

Over the course of the trial duration, subjects who were treated with empagliflozin had greater reductions in weight, A1c levels, waist circumference, uric acid, SBP and DBP compared to individuals treated with placebo. No differences were seen in heart rate. Conversely, empagliflozin treatment led to small increases in both LDL and HDL cholesterol levels. Study researchers discovered that increased FPG, heart rate and uric acid levels were responsible for amplified risk of cardiovascular death; on the other hand, increased SBP, HDL, cholesterol, eGFR, BMI and albumin reduced the risk of CV death.  When looking at the variable that had the greatest change from the baseline, hematocrit was found to be the strongest mediator of empagliflozin CV benefit. The hematocrit change accounted for a 51.8% change in the cardiovascular events, while fasting plasma glucose levels provided an effect of 19.1%.

Changes in the uric acid levels and renal function from the baseline attributed to approximately 15% of cardiovascular benefit, pinpointing to these mediators as the major variables that affected the cardiovascular death with empagliflozin, HR of 0.931. However, multivariable model results diminished some of the effects we have seen with uric acid, renal function, FPG and hematocrit. This may indicate that other variables may also have a modest effect on CV outcomes seen with empagliflozin that are complementary to the four major aforementioned variables.

The results discussed above were the most likely reasons behind the CV death reduction that was observed with empagliflozin but not placebo in the EMPA-REG trial. By following the hazard ratio rules, those that are closest to 1 are mainly responsible for the treatment effect, therefore, the 0.93 HR seen with hematocrit, renal function, uric acid, and fasting plasma glucose are the major mediators that led to the empagliflozin’s treatment effect. The hematocrit change from baseline provided the majority of the benefit, accounting for approximately 50% of the treatment group effect. It is interesting to note that SBP, DBP, heart rate, BMI or lipid levels did not lead to major treatment effects, which is unexpected because these variables are typically thought to be directly responsible for cardiovascular disease. Moreover, the multivariate analysis proved the empagliflozin benefit to be multifactorial.  The greatest limitation of the study is the ability to only hypothesize of possible relationships since the true cause-effect relationships is not known. Nonetheless, the results that were presented in the post-hoc analysis of the EMPA-REG trial allow clinicians to understand the mechanisms behind empagliflozin’s role in cardiovascular disease in type 2 diabetes.

Practice Pearls:

  • The hematocrit change from baseline played the greatest role in CV benefit that is seen with empagliflozin in patients with type 2 DM and established CV disease.
  • Other variables that influence the reduction in CV death include the fasting plasma glucose, uric acid levels and renal function.
  • The hematocrit change from baseline provided the majority of the benefit, accounting for approximately 50% of the treatment group effect.


Silvio Inzucchi, Bernard Zinman, David Fitchett, et al.  “How Does Empagliflozin Reduce Cardiovascular Mortality?  Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial.” Diabetes Care. 2018.  http://care.diabetesjournals.org/content/41/2/356.  Accessed on Jan 2018.

Bernard Zinman, Christoph Wanner, John Lachin, et al.  “Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes.” New England Journal of Medicine. 2015. http://www.nejm.org/doi/full/10.1056/NEJMoa1504720.  Accessed Jan 2018.

Lamija Zimic, PharmD(c), University of South Florida College of Pharmacy