Cardiovascular Outcomes Trials in Diabetes

SEPTEMBER 05, 2018


Troy Trygstad, PharmD, MBA, PhD; Javier Morales, MD, FACP, FACE; and Dhiren Patel, PharmD, provide an overview of the cardiovascular outcomes trials for diabetes and remark on the importance of recognizing a diabetes patient who is at risk for cardiovascular disease.


Troy Trygstad, PharmD, MBA, PhD: Dr. Morales, we’re having this conversation today, how do diabetes and cardiovascular relate to each other and how important it is to be thinking about how they relate to each other. When you think of the medication armament that’s available, what thoughts do you have about treating both of these disease states at the same time? What’s changed over the last few years? Or, what’s most contemporary?

Javier Morales, MD, FACP, FACE: Well, I think we need to establish, first, whether or not the patient is at increased risk for a cardiovascular event. When it comes to managing patients with type 2 diabetes, we basically could use anything, out of the box, that we want. But, we need to take into consideration risks of hypoglycemia, risks of weight gain with intensification, and whether or not cardiovascular risk exists. In 2009, the rosiglitazone story unfolded. The need for cardiovascular outcomes studies evolved. Nowadays, most of these agents that are released for the management of diabetes are studied for cardiovascular risk reduction or elimination.

Most of these new drugs include the DPP-4 inhibitors, which belong to this class called incretins. The incretin effect is nothing more than the induction of insulin secretion out of the beta cell, in response to an oral glucose challenge relative to an intravenous glucose challenge. This is mediated through the release of an endogenous peptide called GLP-1. Unfortunately, GLP-1 has a half-life of about 2.5 minutes. That’s because of a ubiquitous enzyme called DPP-4. So, you could inhibit DPP-4 and allow GLP-1 to remain at physiologic levels, but what happens is that in patients with type 2 diabetes, not only do they have insulin resistance, but they also have incretin resistance. So, if you supplement them with pharmacologic or super physiologic doses of GLP-1, you’re going to get a better response out of the beta cell.

So, let’s take a look at their safety, for instance. When we look at the DPP-4 inhibitor trials for cardiovascular safety, we had the TECOS, SAVOR-TIMI-53, and EXAMINE studies. In essence, these studies failed to demonstrate any significant benefit, but they also demonstrated safety. In other words, there was no improvement in cardiovascular outcomes, which means that they caused no harm. However, if we look at alogliptin and saxagliptin, they were both issued a label warning for the possibility of heart failure. But, looking more into the detail of this study, you could see that some of these patients already had preexisting heart failure, renal insufficiency, and elevated BNP at entry of the study, which are risk factors for the development of heart failure. But, nonetheless, the DPP-4 inhibitors, for the most part, really don’t cause any harm in terms of cardiovascular risk.

Let’s look at the GLP-1s. So, if you look at GLP-1 receptor agonists, they’re broken down into short-acting and long-acting. The short-acting GLP-1 is exendin–4-based exenatide, which is dosed as twice-daily. There weren’t cardiovascular outcomes studies, other than if you look at the FREEDOM study. That was exenatide, but it was infused. It was a little different. You have another short-acting GLP-1, called lixisenatide, available as monotherapy in Europe. It is only used in combination therapy in the United States—co-formulated with a basal insulin. That cardiovascular study demonstrated noninferiority. In other words, it was safe to use. It did not worsen cardiovascular status or events.

Now, let’s look at the long-acting GLP-1 receptor agonists. The long-acting GLP-1 receptor agonists really have a duration of action of at least 24 hours or longer. These are broken down further into exendin–4-based versus analogs of GLP-1. So, if we’re looking at the exendin–4-based, you have the EXSCEL study, which looked at long-acting exenatide LAR. It demonstrated noninferiority. In other words, it was safe to use, but it didn’t reduce cardiovascular events. It didn’t cause any harm.

Now, when we look at the analogs, you have the LEADER study. The LEADER study looked at an analog of GLP-1, called liraglutide. In the high-risk population that liraglutide was studied in, a 13% reduction in major adverse cardiovascular events was demonstrated. So, here we have a GLP-1 receptor agonist that showed benefit in terms of cardiovascular risk reduction. There’s another long-acting GLP-1 receptor agonist, called semaglutide, studied in the SUSTAIN-6 study, which was already published. It showed noninferiority in terms of cardiovascular event rate, but there is a dedicated cardiovascular trial that has been designed and is already in effect because the SUSTAIN-6 study had too few numbers of events. Even though there was a 26% reduction in MACE (major adverse cardiovascular events), it really didn’t meet statistical superiority.

Dhiren Patel, PharmD: To add to that, at that point for that specific trial, they were looking to show that there was no increased harm?

Javier Morales, MD, FACP, FACE: That’s correct.

Dhiren Patel, PharmD: And then, they were going to embark on a larger cardiovascular outcome trial, similar to what you saw in LEADER?

Javier Morales, MD, FACP, FACE: Hopefully, we’ll have some data with dulaglutide, which is another once-weekly GLP-1, in the REWIND study. That’s also an analog of native GLP-1.
Now, let’s switch gears and look at the SGLT2 inhibitors. You have EMPA-REG—empagliflozin. Again, these medications are all added on to standard of care for preexisting cardiac disease as well as diabetes. The EMPA-REG study was a positive study. It showed a 14% reduction in major adverse cardiovascular events. The CANVAS study, which looked at canagliflozin, also demonstrated a 13% reduction in major adverse cardiovascular events. And, if we look at heart failure hospitalizations with another SGLT2 inhibitor, dapagliflozin, we saw a reduction in heart failure hospitalizations with an ongoing cardiovascular trial that’s currently in effect. It should be finishing reasonably soon. So, these newer agents may not induce significant harm, in terms of treating patients with established coronary disease, but may offer significant benefit. In these drugs that do offer a reduction in cardiovascular outcomes, maybe we should be reaching for these agents, first, in those at high risk?

Troy Trygstad, PharmD, MBA, PhD: We’ve had a lot of innovation in the space of diabetes over the past decade. We’ve transitioned in 2 ways. Way number 1 is, we are now thinking about what therapies treat diabetes, that have a dual benefit in improving or reducing cardiovascular risk—improving the circumstance. That goes along with an increased recognition, over time, that we can’t separate out diabetes and cardiovascular disease into 2 separate buckets, and that neither of the 2 shall meet. So, we’ve had a sort of therapeutic evolution, along with the evolution of how we think, epidemiologically, in how we treat patients. Is that a fair summary?

Javier Morales, MD, FACP, FACE: Oh, I think so. I couldn’t have said it better myself.
 


Troy Trygstad, PharmD, MBA, PhD; Javier Morales, MD, FACP, FACE; and Dhiren Patel, PharmD, provide an overview of the cardiovascular outcomes trials for diabetes and remark on the importance of recognizing a diabetes patient who is at risk for cardiovascular disease.


Troy Trygstad, PharmD, MBA, PhD: Dr. Morales, we’re having this conversation today, how do diabetes and cardiovascular relate to each other and how important it is to be thinking about how they relate to each other. When you think of the medication armament that’s available, what thoughts do you have about treating both of these disease states at the same time? What’s changed over the last few years? Or, what’s most contemporary?

Javier Morales, MD, FACP, FACE: Well, I think we need to establish, first, whether or not the patient is at increased risk for a cardiovascular event. When it comes to managing patients with type 2 diabetes, we basically could use anything, out of the box, that we want. But, we need to take into consideration risks of hypoglycemia, risks of weight gain with intensification, and whether or not cardiovascular risk exists. In 2009, the rosiglitazone story unfolded. The need for cardiovascular outcomes studies evolved. Nowadays, most of these agents that are released for the management of diabetes are studied for cardiovascular risk reduction or elimination.

Most of these new drugs include the DPP-4 inhibitors, which belong to this class called incretins. The incretin effect is nothing more than the induction of insulin secretion out of the beta cell, in response to an oral glucose challenge relative to an intravenous glucose challenge. This is mediated through the release of an endogenous peptide called GLP-1. Unfortunately, GLP-1 has a half-life of about 2.5 minutes. That’s because of a ubiquitous enzyme called DPP-4. So, you could inhibit DPP-4 and allow GLP-1 to remain at physiologic levels, but what happens is that in patients with type 2 diabetes, not only do they have insulin resistance, but they also have incretin resistance. So, if you supplement them with pharmacologic or super physiologic doses of GLP-1, you’re going to get a better response out of the beta cell.

So, let’s take a look at their safety, for instance. When we look at the DPP-4 inhibitor trials for cardiovascular safety, we had the TECOS, SAVOR-TIMI-53, and EXAMINE studies. In essence, these studies failed to demonstrate any significant benefit, but they also demonstrated safety. In other words, there was no improvement in cardiovascular outcomes, which means that they caused no harm. However, if we look at alogliptin and saxagliptin, they were both issued a label warning for the possibility of heart failure. But, looking more into the detail of this study, you could see that some of these patients already had preexisting heart failure, renal insufficiency, and elevated BNP at entry of the study, which are risk factors for the development of heart failure. But, nonetheless, the DPP-4 inhibitors, for the most part, really don’t cause any harm in terms of cardiovascular risk.

Let’s look at the GLP-1s. So, if you look at GLP-1 receptor agonists, they’re broken down into short-acting and long-acting. The short-acting GLP-1 is exendin–4-based exenatide, which is dosed as twice-daily. There weren’t cardiovascular outcomes studies, other than if you look at the FREEDOM study. That was exenatide, but it was infused. It was a little different. You have another short-acting GLP-1, called lixisenatide, available as monotherapy in Europe. It is only used in combination therapy in the United States—co-formulated with a basal insulin. That cardiovascular study demonstrated noninferiority. In other words, it was safe to use. It did not worsen cardiovascular status or events.

Now, let’s look at the long-acting GLP-1 receptor agonists. The long-acting GLP-1 receptor agonists really have a duration of action of at least 24 hours or longer. These are broken down further into exendin–4-based versus analogs of GLP-1. So, if we’re looking at the exendin–4-based, you have the EXSCEL study, which looked at long-acting exenatide LAR. It demonstrated noninferiority. In other words, it was safe to use, but it didn’t reduce cardiovascular events. It didn’t cause any harm.

Now, when we look at the analogs, you have the LEADER study. The LEADER study looked at an analog of GLP-1, called liraglutide. In the high-risk population that liraglutide was studied in, a 13% reduction in major adverse cardiovascular events was demonstrated. So, here we have a GLP-1 receptor agonist that showed benefit in terms of cardiovascular risk reduction. There’s another long-acting GLP-1 receptor agonist, called semaglutide, studied in the SUSTAIN-6 study, which was already published. It showed noninferiority in terms of cardiovascular event rate, but there is a dedicated cardiovascular trial that has been designed and is already in effect because the SUSTAIN-6 study had too few numbers of events. Even though there was a 26% reduction in MACE (major adverse cardiovascular events), it really didn’t meet statistical superiority.

Dhiren Patel, PharmD: To add to that, at that point for that specific trial, they were looking to show that there was no increased harm?

Javier Morales, MD, FACP, FACE: That’s correct.

Dhiren Patel, PharmD: And then, they were going to embark on a larger cardiovascular outcome trial, similar to what you saw in LEADER?

Javier Morales, MD, FACP, FACE: Hopefully, we’ll have some data with dulaglutide, which is another once-weekly GLP-1, in the REWIND study. That’s also an analog of native GLP-1.
Now, let’s switch gears and look at the SGLT2 inhibitors. You have EMPA-REG—empagliflozin. Again, these medications are all added on to standard of care for preexisting cardiac disease as well as diabetes. The EMPA-REG study was a positive study. It showed a 14% reduction in major adverse cardiovascular events. The CANVAS study, which looked at canagliflozin, also demonstrated a 13% reduction in major adverse cardiovascular events. And, if we look at heart failure hospitalizations with another SGLT2 inhibitor, dapagliflozin, we saw a reduction in heart failure hospitalizations with an ongoing cardiovascular trial that’s currently in effect. It should be finishing reasonably soon. So, these newer agents may not induce significant harm, in terms of treating patients with established coronary disease, but may offer significant benefit. In these drugs that do offer a reduction in cardiovascular outcomes, maybe we should be reaching for these agents, first, in those at high risk?

Troy Trygstad, PharmD, MBA, PhD: We’ve had a lot of innovation in the space of diabetes over the past decade. We’ve transitioned in 2 ways. Way number 1 is, we are now thinking about what therapies treat diabetes, that have a dual benefit in improving or reducing cardiovascular risk—improving the circumstance. That goes along with an increased recognition, over time, that we can’t separate out diabetes and cardiovascular disease into 2 separate buckets, and that neither of the 2 shall meet. So, we’ve had a sort of therapeutic evolution, along with the evolution of how we think, epidemiologically, in how we treat patients. Is that a fair summary?

Javier Morales, MD, FACP, FACE: Oh, I think so. I couldn’t have said it better myself.
 
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