Additional Data Supporting SGLT2 Inhibitors in Practice

Troy Trygstad, PharmD, MBA, PhD; Dhiren Patel, PharmD; and Javier Morales, MD, FACP, FACE, highlight additional studies exploring the potential for treating patients with diabetes with sodium-glucose cotransporter 2 inhibitors.

Troy Trygstad, PharmD, MBA, PhD: Are there any hot-off-the-press studies or any emerging studies that are coming out to address the broader circles of patients and population management?

Dhiren Patel, PharmD: We have some studies, such as CVD-REAL, that are retrospective studies. These studies tell us a little bit. The most definitive one, which is still ongoing, is probably the DECLARE trial with dapagliflozin. It is slated to read out this year. The trial is powered enough—it has 17,000-plus patients—to answer that question of, are we going to see a benefit from a primary prevention standpoint? Until that becomes available, we probably won’t have definitive cardiovascular outcomes trial research, but we have stuff like CVD-REAL, which was a retrospective look through all of them, to kind of see if there was benefit. It was very in line with what we saw from the other completed cardiovascular trials, even though almost 80% to 85% of it was primary prevention. But, again, it’s different.

Troy Trygstad, PharmD, MBA, PhD: As an expert, then, what does the CVD-REAL study add, in your opinion?

Dhiren Patel, PharmD: I’m curious, Dr. Morales, about your thoughts on this? Would you now start to think that some of these effects of these sodium-glucose cotransporter 2 inhibitors are more of a class effect, after seeing what you’re seeing with CVD-REAL, where you’re seeing the heart failure hospitalization consistently, the renal data consistent…?

Javier Morales, MD, FACP, FACE: There are a lot of things that we really don’t understand about these SGLT2 inhibitors and why it is that we see these results. On the one hand, if we look at the effect on systolic blood pressure, they all have a favorable effect on blood pressure. When it comes down to it, they have a thiazide-like property. They can actually augment diuresis to some degree. Perhaps this could help to explain why we’re seeing heart failure benefits…?

The other side is, it does offer a little bit of concentration. To some degree, LDLs [low-density lipoproteins] do go up. We know that lower LDLs always translate to greater outcome. So, from a mechanistic standpoint, SGLT2 inhibitors do offer a significant amount of benefit. The data are the data. Why we’re seeing the data is probably not just because of a, b, or c but probably because of all of the above.

The CVD-REAL data were kind of interesting because that study looked at various SGLT2 inhibitors in comparison with the DPP-4 class. It was a retrospective analysis. It looked at hospitalization for heart failure, as well as risk of death reduction, which wound up being about 51%, so it was actually quite interesting. Now we consider whether the class in general may offer significant cardiovascular protection and may be indicated for risk reduction altogether.

Troy Trygstad, PharmD, MBA, PhD: I have 2 quick thoughts on that. First, 51% is a big number, right? As we’re having this discussion, it strikes me that when we think about cholesterol, diabetes, heart disease, and metabolic syndrome, there’s generally this intersection between these. Previously, we would bucket them into disease states, but they’re really sort of tributaries that come, for many patients, into the same flow of pathophysiology. Interestingly enough, when you have these drugs that affect 2 or more parts of that trifecta, maybe we don’t quite understand exactly what the mechanism is. But we know that we need something that addresses 2 of the 3, if not all 3, of those concerns, and so, it is fascinating, as we learn more about the pathophysiology. We end up with more therapies, and we have to think about how we look at these studies. Do we think of them as cardiovascular studies, diabetes studies, or hypercholesterolemia studies, or are we thinking about these therapies and these conditions as sort of joined?

Dhiren Patel, PharmD: That’s what it should be. I’m from the same school of thought. I think that a little bit of everything is helping. If we look at CVD-REAL and compare it with all other glucose-lowering therapy, they looked at all 3 SGLT2 inhibitors that were on the market and found this increased benefit. Again, it was a little bit more pronounced than what we saw in the cardiovascular outcomes trials, but this told us that we’re trending in the right direction. There wasn’t anything different or anything that was conflicting. It was really comforting to know that, but I think there’s a glucuretic effect or a little bit of a hemodynamic effect going on there. The heart failure hospitalization numbers were right in line with what we had seen in EMPA-REG, as well as in CANVAS. This is the first time that we have a drug class that’s not just managing 1 thing, right?

It’s not just lowering the A1C. We haven’t even talked about A1C reduction—think about that. When we’re talking about a diabetes drug, it has modest efficacy. A lot of the attractive features of it, as we talked about, include that it lowers your blood pressure a little bit. It causes some weight loss. It helps those with a history of heart failure. So, you’re managing renal disease. You know you’re managing that patient from a more holistic standpoint. You are not just saying, “I’m only going to be working with you on your sugars. This can help you with your other comorbid conditions.”