The diabetes world was stunned and delighted in 2015 when the diabetes medication empagliflozin (Jardiance) was proven to reduce cardiovascular death by a whopping 38%.   This was an unexpected finding, as no diabetes medication had ever before been shown to decrease the risk of cardiovascular events.  The protective ability of empagliflozin starts very early, suggesting that it is not an effect on atherosclerosis (hardening of the arteries) per se, as this process takes a longer time. It has been a puzzle to understand exactly what is behind the protective abilities of empagliflozin.

A recent publication by Inzucchi and colleagues describes an analysis of the EMPA REG data to try to shed some light on this interesting question.  They conducted an exploratory mediation analysis, examining many different variables, to see which ones contributed to the CV event reduction.
They found that changes in hematocrit and hemoglobin mediated about half of the benefit of empagliflozin.  (This may be because a higher hematocrit means that there is less plasma volume, and/or increased oxygen delivery to the heart.)  Smaller mediation effects were seen for uric acid levels, fasting blood sugar, and A1C (a diabetes ‘report card’ blood test).   The combination of
hematocrit, fasting blood sugar, uric acid, and protein in the urine (urine albumin:creatinine ratio) mediated most of the beneficial effect of empaglifozin.So, we learn what we suspected – that there are multiple and complex mechanisms at play by which empagliflozin reduces cardiovascular risk. There may well be additional mechanisms at play that were not measured, or measurable, in the EMPA REG study.

Empagliflozin was the first type 2 diabetes medication that was shown to decrease the risk of cardiovascular events.  Its cousin in this class called SGLT2 inhibitors, canagliflozin (Invokana), has
also been shown to protect against cardiovascular events, but canaglifozin was also found to increase the risk of amputations and bone fracture.  Two medications of a different class (GLP1 receptor agonists), called liraglutide (Victoza) and semaglutide (Ozempic) also have a protective benefit.

Disclaimer: I receive honoraria as as continuing medical education speaker and consultant from the makers of empagliflozin (Boehringer-Ingelheim and Eli Lilly), canagliflozin (Janssen), liraglutide and semaglutide (Novo Nordisk).  I am involved in research of SGLT2 inhibitors and GLP1 receptor agonists as treatments for diabetes. 

Follow me on twitter! @drsuepedersen © 2018