CMHC Pulse Blog

Theories abound on what’s driving the cardiovascular benefits seen in EMPA-REG, as an FDA advisory panel votes to support a claim of CV risk reduction on the SGLT-2 inhibitor empagliflozin’s label.

An advisory panel to the US FDA has voted, albeit narrowly, to allow the claim that treatment with the SGLT-2 inhibitor epagliflozin reduces the risk of cardiovascular death in patients with type 2 diabetes. Results of EMPA-REG, which were published last year, showed that the drug reduced cardiovascular death by 38% and reduced the combined risk of cardiac death, non-fatal myocardial infarction, and non-fatal stroke by 14%. The potential mechanisms by which empagliflozin works to reduce this cardiovascular risk are still not known, however, and were the focus of discussion at the recent ADA 2016 Scientific Sessions.

The improvements observed with empagliflozin with regard to glycemic parameters, lipids, or blood-pressure control were not sufficient to explain the results seen in EMPA-REG, according to lead investigator Silvio Inzucchi, MD, of Yale University, New Haven, Connecticut. But a number of theories have been suggested in the time since the trial results were reported. Among them:

  • Empagliflozin’s effects are primarily mediated “through effects on plasma volume and off-loading of the heart.” (Just 10% of patients in EMPA-REG were believed to have heart failure, however.)
  • A link to “fuel energetics, alterations in fat oxidation, and increases in ketones circulating that may be more efficient in some way for the ventricles to utilize”
  • Volume mechanism as represented by change in hematocrit: the hazard ratio for volume (hematocrit) was 0.791 for empagliflozin compared with placebo in EMPA-REG, correlating to a 51.8% change. (A rise in hematocrit of about 3% is equivalent to a change in plasma volume of about 7%.) As explained by Dr. Inzucchi, this rise, when cardiac output is maintained, may increase the oxygen-carrying capacity of the blood and enhance tissue oxygenation.
  • “Thrifty substrate paradigm:” this theory states that under conditions of mild, persistent hyperketonemia (which would occur with SGLT-2 inhibitor treatment), beta-hydroxybutyrate is freely taken up by the heart and other organs and oxidized in preference to fatty acids
  • A shift in myocardial and renal fuel metabolism away from energy-inefficient fat and glucose oxidation (in the hearts and kidneys of patients with type 2 diabetes) toward an energy-efficient superfuel such as ketone bodies, which improve myocardial/renal work efficiency and function

At this point these theories are only theories. But according to researchers, they may at least provide a partial explanation for the CV outcomes seen in EMPA-REG and warrant further study to determine the mechanisms behind the cardiovascular/renal benefits seen with empagliflozin (and potentially, other SGLT-2 inhibitors).

The CV outcomes that have been seen in such trials as EMPA-REG, as well as others including LEADER, will be the focus of discussion at the 11th Annual Cardiometabolic Health Congress, being held October 5-8, 2016, in Boston, MA. Session III: Diabetes Management, on Friday, October 7, 2016 will feature CMHC Chair Jay S. Skyler, MD, presenting “CV Outcomes Trials and Diabetes.”



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