Steven Nissen, MD, provides an overview of the learnings about heart failure from clinical studies in medications indicated for diabetes.
Neil Minkoff, MD: Steven is clearly 1 of the big experts in terms of the next topic of conversation, which is that medications indicated for diabetes have changed over the years, but the requirement in getting to cardiovascular outcomes has been a big push. That’s changed a lot over the past decade. What have we learned? Why did this happen, and what have we learned from it?
Steven Nissen, MD: Let me just say that this has been a huge change. Going back more than a decade ago, which seems like yesterday, we had concerns. I certainly had great concerns that the primary thing we were doing to improve diabetes drugs was to find out that they lowered blood sugar. I made the point over several years that lowering blood sugar was probably an inadequate standard. It has a relationship to macrovascular disease—no question about it—but how you lower blood sugar is probably as important as how much.
Three shocks to the system led to the changes. Two of them, we were involved with. One was rosiglitazone, which was the No. 1 selling diabetes drug and is still being debated to this day. The recent paper out of your group at Yale School of Medicine, Nihar, shows that without question, this drug increased cardiovascular events, particularly heart failure. Then a drug called muraglitazar almost came to market, but we found the same thing. Then there was the ACCORD trial, which showed that more intensive glucose lowering led to worse outcomes.
I presented to the FDA a proposal that they should do outcome trials and that we should not approve these drugs simply on the basis of their blood sugar–lowering effects. To my surprise, I was able to convince a panel of diabetologists that maybe we were right and that we needed outcome trials. It was a big battle. A lot of people in industry said that we would never have any more diabetes drugs and that all innovation would stop if we required outcome trials as part of the approval process. But we went forward with it. I’m not going to get into the 2-stage approach that we proposed. But 1 of the things we discussed at that 2008 FDA advisory panel was that if we did large cardiovascular outcome trials with diabetes drugs, we might just find drugs that actually lowered morbidity and mortality. There would be the potential to uncover benefits that we would not otherwise discover.
For me, the pivotal moment came in 2015. It took a long time. It takes a long time to do outcome trials. When I was unblinded to the EMPA-REG OUTCOME trial, I was not a participant, but I did learn of the results fairly early on. The EMPA-REG OUTCOME study that Bernie Zinman did showed that there was a reduction in mortality with empagliflozin. If you look at the trial carefully, even though it wasn’t the primary intent, the most striking benefit of empagliflozin was reduction in heart failure. It was about a 35% reduction in heart failure hospitalization. We didn’t know if that was a one-off, but next thing we knew, similar results were seen in the CANVAS trial for canagliflozin and in the DECLARE-TIMI58 trial for dapagliflozin.
In the diabetes population, we initially learned that the SGLT2 inhibitors reduced mortality, other cardiovascular events, and very strikingly reduced heart failure in patients with diabetes. For me, it was the reward for all the hard work and, frankly, a little abuse I took from people who said, “Why are you making us do these outcome trials?” I got beaten up by the diabetes community for many years over this. But at the end of the day, we learned some really important lessons. It was a very successful endeavor to require that we look at outcomes, not just at blood sugar lowering for diabetes drugs. The SGLT2 inhibitors were a home run in their ability to reduce hospitalization for heart failure.