Diabetes: Shifting Mindset for Cardiovascular Benefits

John Anderson, MD: In Stockholm in September of 2015, there had been an announcement that, for the very first time, there was actually a cardiovascular benefit with one of the SGLT2 inhibitors. Remember, this came on top of 3 trials with DPP-4 inhibitors that had shown they met their primary endpoint for safety, but they did not show any cardiovascular benefit. And so, in Stockholm on a Thursday night, it was like a rock concert, with people trying to get in this room. No one knew the data except, of course, the investigators themselves. When they first got to the stage and presented the trial, they got to the results and showed a 13% reduction in 3-point MACE: that’s M-A-C-E, major adverse cardiovascular events. Everybody politely clapped. Good, they met their primary endpoint. The next thing they showed was the cumulative plot of cardiovascular death that showed a 38% reduction in cardiovascular death in the empagliflozin-treated group.

People were stunned. That’s an absolute risk reduction of 2.2%. In a cardiovascular outcomes trial, that is enormous. That was the first trial that let us know the SGLT2 inhibitor, empagliflozin, had really positive cardiovascular benefits. The other thing that was interesting was that these curves did not take a year to separate. These curves separated immediately and were statistically significant within 50 days of the onset of giving empagliflozin to that group. In addition, something that did not go into the empagliflozin label that has since come about from the FDA is a 35% reduction in admissions for heart failure. So, this was a game changer. This was a real game changer. And that’s why empagliflozin is the first drug in the United States that got the FDA approval for reduction of cardiovascular death in addition to an indication for type 2 diabetes for glycemic lowering.

This EMPA-REG trial was designed to try to not focus on glucose lowering. So, by the end of the trial, the difference in A1C was maybe 0.4%. The difference in systolic blood pressure was 3 or 4 mm Hg. Clearly, they were 2 points that did not drive this cardiovascular outcome. They combined both the 10- and the 25-mg dose of empagliflozin to get their results. The other interesting thing was that there was an actual reduction in progression to renal events, some 40%-plus reduction in renal events. That is why you’re now seeing a lot of chronic kidney disease and renal trials being done, which will probably, in the next couple of years, give us even more information about whether or not there’s renal protection in these medicines.