SGLT2 Inhibitor Evidence in Reducing CV Events

APRIL 15, 2018


Troy Trygstad, PharmD, MBA, PhD; Javier Morales, MD, FACP, FACE; and Dhiren Patel, PharmD, remark on the burden of cardiovascular events in patients with diabetes and highlight data supported by the EMPA-REG OUTCOME study and the CANVAS trial that suggest potential improvements in CV outcomes in patients treated with sodium-glucose cotransporter 2 inhibitors.

Troy Trygstad, PharmD, MBA, PhD: Let’s talk about real-world benefits—so, the data. Dr Morales, can we talk about the EMPA-REG findings?

Javier Morales, MD, FACP, FACE: I think so. I think it’s really important. It’s actually been in the mainstay since it was reported on at the EASD Annual Meeting. In 2009, the FDA mandated that all companies that produce antidiabetic agents undergo rigorous testing to determine cardiovascular outcome. The EMPA-REG study happened to be one of those studies in which a very high number of patients who were at increased risk of developing heart disease or stroke were enrolled in this trial. They had risk factors for coronary artery disease and cardiovascular events, so they were already on background therapy from a cardiovascular standpoint—and they had diabetes, so they were on medications for their diabetes, as well.

On top of standard of care, these patients were randomized to receive this sodium-glucose cotransporter 2 inhibitor, empagliflozin, versus placebo. This was actually an event-driven trial. The results were really eye-opening and compelling because we look at the major adverse cardiovascular events, or MACE. These constitute
cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. A reduction of 14% was noted for major adverse cardiovascular events. Cardiovascular mortality went down by 38%. And when we look at all-cause mortality, death of any cause, there was a reduction of 32%. This led to a standing ovation at the presentation.

Dhiren Patel, PharmD: The reason there was a standing ovation when we saw this released live was because of rosiglitazone and the issue that we had. All of these trials had to be undertaken by these manufacturers. We had a slew of them that were neutral in their findings. All of the DPP-4 inhibitor trials were neutral. When that first happened, we were like, “Oh, this is great. It’s not causing increased harm.” And that’s basically what that expectation was. When this came out, it was like, “Oh my, now we’re going in a positive direction.” You see some of this data, and now there is a label change where you see something that is preventing death. It’s a big deal, right? We can explain to patients that it’s not just for glycemic control. I usually tell patients that you die less, right?

Troy Trygstad, PharmD, MBA, PhD: So, patients may struggle a little bit with hemoglobin A1C?

Dhiren Patel, PharmD: Yes.

Troy Trygstad, PharmD, MBA, PhD: But they understand heart attack and death.

Dhiren Patel, PharmD: That’s it.

Javier Morales, MD, FACP, FACE: Back to the DPP-4 studies—even though they showed no benefit in terms of major adverse cardiovascular risk reduction, there was actually a warning that was issued for saxagliptin, as well as the other DPP-4 inhibitor. There was a little bit of an increase in risk of heart failure hospitalizations in these patients who were taking these drugs.

What’s very interesting is that when you looked at that SAVOR-TIMI 53 data, some of those patients who did have hospitalizations for heart failure already had a history of heart failure, and they may already have had renal insufficiency and an elevated BMP at entry level of the studies. So, there was a little bit of a signal, although we don’t know how that’s going to play out.

However, we did make mention about sugar in the urine and how it may be bad to have sugar in the urine. When we look at studies like the EMPA-REG study, we ended up stabilizing renal function in patients who were on these SGLT2 inhibitors. Furthermore, we saw very similar findings in patients who were in the CANVAS study, where there was stabilization of the GFR over the long term in these patients who were on the SGLT2 inhibitors—so there are more benefits that really aren’t quite explained.

Troy Trygstad, PharmD, MBA, PhD: What should we know about the CANVAS study?

Dhiren Patel, PharmD: The EMPA-REG was the first one that came out when we were looking at the SGLT2 class. The next ones were the CANVAS trials. Two of them were ongoing. We’re now starting to talk a little about looking beyond the glycemic benefits of this class, right? We heard a little bit about improvements in renal function. Unlike the DPP-4 inhibitors, you’re seeing improvements from the heart failure hospitalization standpoint, so some of these things started coming out. These signs were there from the EMPA-REG study.

The CANVAS trial was 2 different trials. One was just a regular trial. The other was the CANVAS-R trial, which was a renal study. In order for it to be powered and sufficiently read out, they ended up merging these 2 trials. The population was a little different. We heard Dr Morales talk a little about how the folks in the EMPA-REG trial were mainly 99%-plus for secondary prevention. All of these patients already had an event. You saw a different composition, or mix, in the CANVAS trials. You had more folks from a primary prevention standpoint.

We wanted an answer: “This is great—it works for those who already had an event” and “Well, does this work for someone who hasn’t had an event?” That mix was a little bit different—maybe 65/35 in terms of primary prevention and secondary prevention. You still saw that MACE reduction, which was pretty much identical to what you saw in EMPA-REG, but there were no individual components—those 3 components that you mentioned: nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. Together, it produced that 3-point MACE reduction, but, individually, each one wasn’t powered to have a claim like you saw with cardiovascular death.

Troy Trygstad, PharmD, MBA, PhD: Yes, that’s common. If I have a more complex population with a higher baseline of risk, I’m more likely to produce something that moves the needle. So, once you broaden that out to a broader population, you have to move the needle more to produce measurable outcomes.
 


Troy Trygstad, PharmD, MBA, PhD; Javier Morales, MD, FACP, FACE; and Dhiren Patel, PharmD, remark on the burden of cardiovascular events in patients with diabetes and highlight data supported by the EMPA-REG OUTCOME study and the CANVAS trial that suggest potential improvements in CV outcomes in patients treated with sodium-glucose cotransporter 2 inhibitors.

Troy Trygstad, PharmD, MBA, PhD: Let’s talk about real-world benefits—so, the data. Dr Morales, can we talk about the EMPA-REG findings?

Javier Morales, MD, FACP, FACE: I think so. I think it’s really important. It’s actually been in the mainstay since it was reported on at the EASD Annual Meeting. In 2009, the FDA mandated that all companies that produce antidiabetic agents undergo rigorous testing to determine cardiovascular outcome. The EMPA-REG study happened to be one of those studies in which a very high number of patients who were at increased risk of developing heart disease or stroke were enrolled in this trial. They had risk factors for coronary artery disease and cardiovascular events, so they were already on background therapy from a cardiovascular standpoint—and they had diabetes, so they were on medications for their diabetes, as well.

On top of standard of care, these patients were randomized to receive this sodium-glucose cotransporter 2 inhibitor, empagliflozin, versus placebo. This was actually an event-driven trial. The results were really eye-opening and compelling because we look at the major adverse cardiovascular events, or MACE. These constitute
cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. A reduction of 14% was noted for major adverse cardiovascular events. Cardiovascular mortality went down by 38%. And when we look at all-cause mortality, death of any cause, there was a reduction of 32%. This led to a standing ovation at the presentation.

Dhiren Patel, PharmD: The reason there was a standing ovation when we saw this released live was because of rosiglitazone and the issue that we had. All of these trials had to be undertaken by these manufacturers. We had a slew of them that were neutral in their findings. All of the DPP-4 inhibitor trials were neutral. When that first happened, we were like, “Oh, this is great. It’s not causing increased harm.” And that’s basically what that expectation was. When this came out, it was like, “Oh my, now we’re going in a positive direction.” You see some of this data, and now there is a label change where you see something that is preventing death. It’s a big deal, right? We can explain to patients that it’s not just for glycemic control. I usually tell patients that you die less, right?

Troy Trygstad, PharmD, MBA, PhD: So, patients may struggle a little bit with hemoglobin A1C?

Dhiren Patel, PharmD: Yes.

Troy Trygstad, PharmD, MBA, PhD: But they understand heart attack and death.

Dhiren Patel, PharmD: That’s it.

Javier Morales, MD, FACP, FACE: Back to the DPP-4 studies—even though they showed no benefit in terms of major adverse cardiovascular risk reduction, there was actually a warning that was issued for saxagliptin, as well as the other DPP-4 inhibitor. There was a little bit of an increase in risk of heart failure hospitalizations in these patients who were taking these drugs.

What’s very interesting is that when you looked at that SAVOR-TIMI 53 data, some of those patients who did have hospitalizations for heart failure already had a history of heart failure, and they may already have had renal insufficiency and an elevated BMP at entry level of the studies. So, there was a little bit of a signal, although we don’t know how that’s going to play out.

However, we did make mention about sugar in the urine and how it may be bad to have sugar in the urine. When we look at studies like the EMPA-REG study, we ended up stabilizing renal function in patients who were on these SGLT2 inhibitors. Furthermore, we saw very similar findings in patients who were in the CANVAS study, where there was stabilization of the GFR over the long term in these patients who were on the SGLT2 inhibitors—so there are more benefits that really aren’t quite explained.

Troy Trygstad, PharmD, MBA, PhD: What should we know about the CANVAS study?

Dhiren Patel, PharmD: The EMPA-REG was the first one that came out when we were looking at the SGLT2 class. The next ones were the CANVAS trials. Two of them were ongoing. We’re now starting to talk a little about looking beyond the glycemic benefits of this class, right? We heard a little bit about improvements in renal function. Unlike the DPP-4 inhibitors, you’re seeing improvements from the heart failure hospitalization standpoint, so some of these things started coming out. These signs were there from the EMPA-REG study.

The CANVAS trial was 2 different trials. One was just a regular trial. The other was the CANVAS-R trial, which was a renal study. In order for it to be powered and sufficiently read out, they ended up merging these 2 trials. The population was a little different. We heard Dr Morales talk a little about how the folks in the EMPA-REG trial were mainly 99%-plus for secondary prevention. All of these patients already had an event. You saw a different composition, or mix, in the CANVAS trials. You had more folks from a primary prevention standpoint.

We wanted an answer: “This is great—it works for those who already had an event” and “Well, does this work for someone who hasn’t had an event?” That mix was a little bit different—maybe 65/35 in terms of primary prevention and secondary prevention. You still saw that MACE reduction, which was pretty much identical to what you saw in EMPA-REG, but there were no individual components—those 3 components that you mentioned: nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. Together, it produced that 3-point MACE reduction, but, individually, each one wasn’t powered to have a claim like you saw with cardiovascular death.

Troy Trygstad, PharmD, MBA, PhD: Yes, that’s common. If I have a more complex population with a higher baseline of risk, I’m more likely to produce something that moves the needle. So, once you broaden that out to a broader population, you have to move the needle more to produce measurable outcomes.
 
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