Improving Multiple Outcomes With One Treatment

^{By Julie Gould}

Kiersten Combs, vice president of US Cardiovascular & Metabolic Disease, and Jim McDermott, vice president of US Medical Affairs and Metabolism, both at AstraZeneca, discuss recent study findings presented at the American Diabetes Association Scientific Sessions. They highlight how the use of Farxiga and other SGLT2 inhibitors impact payers and patient outcomes, as well as explain the benefits beyond controlling blood glucose by also looking at treating cardiovascular and renal disease.  

Can each of you tell us a little bit about yourself and your research interests?

Kiersten Combs:  My name's Kiersten Combs, and I am the VP of the US business that covers our cardiovascular metabolic commercial portfolio. Right now we have three promoted products within the portfolio, Farxiga and Bydureon in the diabetes space, and then Brilinta in the cardiovascular space.

Jim McDermott:  I'm Jim McDermott. I lead the medical affairs diabetes team, so looking after our diabetes portfolio. My research interest, actually, I've been working on Farxiga since 2007.

In 2007, we were the first-in-class SGLT2 in development. As I mentioned, we thought it was really novel in terms of treating diabetes, excreting glucose through the urine. It was all about A1C, all around glucose control.

Now, we've come such a long way with the outcomes trials and seeing the benefits on cardiovascular endpoints, renal endpoints. We do have two trials ongoing now outside of diabetes. One is looking at dapa, Farxiga in patients with chronic kidney disease.

What's really exciting about this for me is that it's no longer just looking at patients with type 2 diabetes, we're looking at non-type 2 diabetes patients who have chronic kidney disease. We're actually just completing a similar trial in patients with heart failure. Again, that's in patients with and without type 2 diabetes. As we were discussing earlier, we're talking about medications that were developed to control blood glucose.

Now, it's really beyond just controlling blood glucose and looking at treating cardiovascular and renal disease.

Can you briefly highlight why early intervention is so important among patients with type 2 diabetes?

KC: I think that if you look at the significant amount of the population that either has diabetes today or is prediabetic, obviously, the treatment of diabetes is going to be an important healthcare concern for the US.

What I think we're doing here at AstraZeneca is that we believe that treating patients with diabetes beyond just lowering of A1C ultimately increases those patients' health outcomes, specifically in the cardiovascular and renal space.

Then also, it will reduce the burden of cost on the US healthcare system. We, I think, at AstraZeneca are uniquely positioned in our portfolio to offer a wide variety of medicines that treat across the cardiovascular, metabolic, and renal space.

Also, as Jim was just talking about, we are studying dapagliflozin and Farxiga across the different therapeutic areas, I think, is really a unique position for us.

JM: Just from my perspective with regards to earlier intervention, you may be familiar with our large clinical outcome trial, DECLARE, with over 17,000 patients. It was very different than other trials in terms of the types of patients that we enrolled.

We had over 60 percent of the patient population that were patients without established disease. They obviously were type 2 patients, but they were not as sick, in terms of the patient populations that were studied in the other trials.

In fact, in that population, we had close to 50 percent had normal renal function, or eGFR above 90. This was very early on. In that trial, we actually showed the prevention of the onset of renal disease in patients within DECLARE.

To me, that really highlights the importance of early intervention. Also within DECLARE, we showed a significant impact in hospitalization for heart failure, again, in a patient population that did not have preexisting cardiovascular disease.

I think that really supports the use specifically of SGLT2s in early treatment with patients with type 2 diabetes. As you probably know, diabetes and blood pressure is the leading cause of chronic kidney disease (CKD), so I think results in DECLARE really support the importance of early treatment.

How does treatment with Farxiga improve patient outcomes? Can you highlight some of the recent study findings?

JM: I think with DECLARE, the largest trial, actually, within the class -- as I mentioned, over 17,000 patients -- in patients 60 percent did not have established cardiovascular disease, we saw a significant benefit on the composite of CV death and hospitalization for heart failure.

We were very excited about those results. We saw a 27 percent relative risk reduction in hospitalization for heart failure. We also saw a rather profound decrease in the renal composite. We had a renal composite that consisted of 40 percent or greater reduction in the eGFR, in the estimated glomerular filtration rate, end stage renal disease, CV death, or renal death.

Within that, we saw a 24 percent relative risk reduction. Again, as you recall, as I mentioned, these patients had really good renal function. The average was around 84 mLs per minute. That means close to 50 percent had a renal function above 90 mLs per minute.

It's really showing a positive impact in the prevention of renal disease. I think that was really exciting for us. Then we had some secondary analyses that we presented at ADA, again, around these renal data. I think it really highlights the importance of the opportunity for Farxiga in terms of the not just treating CKD, but also in the prevention of CKD.

KC: Just to build upon it from a patient perspective, when you think about the overall DECLARE result, and you think about heart failure today, it is one of the earliest complications that presents for patients with diabetes.

It's often undertreated and underdiagnosed, and therefore, it tends to be one of the most fatal complications that diabetic patients can have. I think that the DECLARE data is a really important piece of evidence for clinicians on why treating diabetic patients beyond just the A1C is an important component for them to consider.

JM: You're looking at patient populations, and those patients who have both heart failure and CKD have a much higher rate of mortality than the individual components, or anything like MI, stroke.

It's very, very significant. Now, you're looking at a class of agents that shows benefit on both conditions here.

Following the results of this study, how do you foresee prescribing practices changing for Farxiga prescriptions? Do you think there'll be an increase?

KC: I think we are highly encouraged by what we believe will be future prescribing of the SGLT2 class, and specifically Farxiga. I think when you talk to clinicians today, what's quite exciting is that it's not just primary care physicians who predominantly treat diabetes today that have taken note of this.

You definitely see increased interest from specialists like cardiologists, nephrologists, and endocrinologists. I think that is a sign that you will see treatment paradigms shifting and those specialists trying to figure out, what is their role in both treating diabetes and/or the complications of diabetes.

A lot of the cardiovascular and renal disease that they treat is a side effect or a complication of the diabetes that their patients have. I think the other thing that makes us quite excited is that you see that guidelines are being updated, based on data like DECLARE and other data in the CV outcome space reading out in the SGLT2 class.

This is quite exciting, because it's not just the traditional diabetes guidelines that professional societies and their guidelines being updated. You also see cardiovascular societies updating their guidelines. It's happening faster than we've ever seen guidelines be updated before.

We know that guidelines are an important component to seeing a shift in treatment paradigms across all types of physicians. I think we definitely will see not only an increase in use of Farxiga based on the compelling data that we have, but really, an increase in the use of SGLT2s across the board.

JM: Now, it's almost like everybody's tripping over each other to update their guidelines. Just last year, ADA, it [the guidelines] were very glucose-centric.

Now, they've come out, along with the EASD, very specifically calling out those patients with either chronic kidney disease or heart failure should be considered to put them on an SGLT2 or a GLP1, rather than just managing their A1C. Then as I mentioned to you earlier, that's ADA, and then the cardiologists are updating their guidelines. As I mentioned, I'm attending a symposia this week where the nephrologists are really looking at the role of SGLT2s in kidney disease. I would anticipate, in the not-too-distant future, their guidelines may change as well.

How will these findings, use of Farxiga, and increased use of SGLT2s overall, impact payers?

KC: Today, Farxiga coverage is quite strong across the nation with payers. I think that there is a real opportunity here. Something that AstraZeneca feels quite proud about being a trailblazer in is working with payers to create value-based contracts that really put the clinical evidence of Farxiga on the line on how we can help their patient population.

I believe that use of these medicines will continue to evolve, and the impact to payers could be a very positive one. It can reduce the overall cost of treating these patients if we can treat earlier with medicine that not only lowers the A1C, but we also know have both cardiovascular and renal benefits for these patients.

JM: I would agree. They've expressed great interest in the results of DECLARE and our renal outcomes, because they are seeing these medications provide greater benefits that just controlling blood glucose.

Utilization, in terms of hospitalization for heart failure, CKD, obviously, there's a great benefit there, if we can lessen that burden.

What knowledge gaps still exist relating to Farxiga use and SGLT2s, and what do you think may be studied in the future?

KC: Just maybe the one point to say, I think for me, and for AstraZeneca overall, when you think about the DECLARE data that reads out, it is really just the start of what I think is a very robust clinical program for dapagliflozin and Farxiga.

If you look forward, we have four major outcome trials that will read out in the next four years. Jim, I know you talked a little bit about our dapa heart failure program, and also, that will read out later this year.

We also have a DAPA-CKD program reading out next year. Jim, maybe you can comment a little bit more on the investment that AstraZeneca is making, and why we're excited about the data that's to come for Farxiga.

JM: Thanks, Kiersten. As I mentioned, Julie, earlier, we do have this trial that'll be reading out before the end of this year. It's DAPA-HF. This is looking at dapa in patients with established heart failure, diagnosis of heart failure.

As I mentioned, this is in patients with and without diabetes. This will be the first trial, actually, to assess the potential benefit of Farxiga in patients with heart failure, but do not have type 2 diabetes. This is where I think we're really starting to see some opportunities, in cardiovascular disease, not only in patients with type 2, but patients without type 2.

Again, as Kiersten mentioned, the CKD trial, is in patients both with type 2 diabetes, but also those without type 2. I think what you're seeing is, we're branching beyond just patients with type 2 diabetes, but looking at potential benefits in cardiovascular and renal disease in those patients without type 2.

The other study we're doing, the first heart failure trial I mentioned was HEF-REF, or heart failure with reduced ejection fraction. We also have another heart failure trial in patients with preserved ejection fraction.

Today, there is really no good treatment for patients with preserved ejection fraction. In fact, what's also interesting is, women have greater risk of preserved ejection fraction than men. This is truly an area of unmet medical need.

It's the first time that we're going in, or SGLT2s are going into, this space, again, currently, where there is no good treatments for preserved ejection fraction. Again, it's patients with type 2, but also patients without type 2.

I think that's the area where, in terms of the future, what's really exciting, is really beyond type 2 diabetes.

Overall, is there anything else you would like to add that we may not have covered?

KC: I think the only thing I would add is -- and hopefully, you've heard it through these last few minutes of conversation -- I think that we are extremely excited about the future of Farxiga and the clinical evidence that we are generating at AstraZeneca.

It is a core strategic driver for our organization to become a cardiovascular, metabolic, renal organization, and as Jim just said, treat beyond just A1C. Really, truly offer medicines that treat the cardiometabolic complications that patients with type 2 diabetes have.

I think that DECLARE, in being the largest and the first CV outcome study in the class to reduce hospitalization of heart failure, is going to be the beginning of what is going to be a really long and exciting life cycle program for Farxiga.

As Jim says, as we move not to just treat diabetic patients, but we move to treat patients outside of diabetes who suffer from heart failure and renal disease.

JM: I would just add, based on the findings that we saw in DECLARE in terms of the benefits on hospitalization for heart failure and new onset or progression of renal disease, I'm very optimistic for our heart failure trials, as well as our CKD trial. I'm looking forward to seeing those results in the near future.