Hi. Today, I will be talking about evidence on SGLT2 inhibition. Where we are and what can we expect?

Here are my disclosures.

Well, I think we all know that there are still some unanswered questions. Despite the incredible success of SGLT2 inhibitors. First: "Is the benefit of SGLT2 Inhibitors similar across the full spectrum of ejection fraction in heart failure?" Second: "Are SGLT2 Inhibitors as effective in hospitalized patients and recently hospitalized patients as they are in outpatients?" Third: "Is addition of SGLT2 Inhibitors beneficial to patients with heart failure and "improved" Left Ventricular Ejection Fraction (LVEF)?" In other words, those who had a prior LVEF less than 40%. Fourth: "Can SGLT2 Inhibitors reduce cardiovascular death in patients with heart failure and a Left Ventricular Ejection Fraction greater than 40%?" And finally: "Can SGLT2 Inhibitors improve symptoms in patients with heart failure with mildly reduced and preserved Ejection Fraction?"

Let's first get the elephant in the room out of the way. We all know that the Top Line results of the DELIVER trial were announced last month, DELIVER met its primary endpoint of a composite of cardiovascular death or worsening heart failure in patients with mildly reduced and preserved ejection fraction. I am not going to talk about the results of DELIVER today. So instead I am going to tell you about what we can expect with DELIVER. What the baseline results of DELIVER look like, and what we're hoping to be able to show at an upcoming conference.

So first, let's talk about the design and baseline characteristics of patients in the DELIVER trial. This is the design of DELIVER. In order to get in this trial, patients had to be 40 years of age or older. They had to have New York Heart Association Class 2 to 4 heart failure, a Left Ventricular Ejection Fraction of greater than 40% and evidence of structural heart disease. What I mean by that is either left ventricular hypertrophy (LVH) or left artrial (LA) enlargement. They also had to have evidence of elevation of natriuretic peptide 300 for patients in sinus rhythm and 600 for patients in atrial fibrillation. They could be either ambulatory or hospitalized and they could have had prior Left Ventricular Ejection Fraction less than 40%. This is a group that has been excluded from all other clinical trials in this area. Patients were randomized to either Placebo or Dapagliflozin 10 milligrams once daily.

We ended up randomizing 6263 patients. The primary endpoint with the time to the first composite of cardiovascular death or heart failure event. Meaning either a heart failure hospitalization or an urgent heart failure visit. And this primary endpoint was assessed, both in the full population, everybody. And simultaneously in the patients with an ejection fraction under 60%, we split the alpha between those two groups, secondary end points included, total heart failure events, and cardiovascular death in both populations. Change in KCCQ total symptom score by eight months in the full population. And then cardiovascular death and all-cause mortality. Also in the full population and, of course, we also did a sensitivity analysis looking at COVID-19.

The DELIVER design, compared to other trials, is unique. And the main thing that is unique about DELIVER, is that it is larger. We have more patients with heart failure with mildly reduced and preserved ejection fraction, than any trial thus far. We did require structural heart disease and elevation of natriuretic peptides similar to what we did in the PARAGON study. The LVEF is over 40%. This is lower than in many of the prior trials, but similar to EMPEROR-Preserved and the endpoint was a combination of cardiovascular death, heart failure hospitalization and urgent heart failure visit, which was a little bit different from EMPEROR-Preserved, which did not have urgent heart failure visit in their endpoint.

Here are the baseline characteristics of DELIVER compared with the other HFpEF trials. And I'm not going to go through, of course, all of these numbers. But what you can see here is that DELIVER was remarkably similar to many of the other studies, we had a lower percentage of women in DELIVER as they had in EMPEROR-Preserved than in some of the other trials because our Left Ventricular Ejection Fraction was in fact lower. We had about 70% of patients who are New York Heart Association class 2, 45% of patients with diabetes, 26% of patients were hospitalized within the last 12 months, and we had a subacute population, patients who were either enrolled in the hospital or hospitalized within 30 days that made up 10% of our patients. And then, as I have said, we allowed patients with an improved LVEF that represented 18% of our population. Our mean LVEF was 54% and our mean NT-proBNP was approximately 1,000.

These patients were on RAAS inhibitors, a very high percentage on ACE inhibitors and ARBs we even had some patients on ARNIs and about 40% of our patients were on MRAs, which is the highest percent of any of the trials on MRAs. The medication use in these patients, you can see in DELIVER and EMPEROR-Preserved. We had the most MRAs of any trial so far And DELIVER really and EMPEROR-Preserved were the only trials that had any use of ARNIs.

Now, we have known that patients who are recently hospitalized seem to have a higher event rate and they also seem to benefit from therapies to a greater extent, than patients who are more chronic when they are enrolled in trials. We saw this in the PARAGON trial and it was also seen in the SOLOIST and SCORED HFpEF cohorts using sotagliflozin. We have enrolled patients in DELIVER who were either in hospital or within 30 days of hospitalization, you can see that the mean age here of these patients was about the same as the other patients there are a couple of other things though that are different, including the fact that they had a higher use of mineralocorticoid receptor antagonist and also they had a higher NT-proBNP.

The other sub group that is going to be very important, is this group of patients with heart failure, with so-called improved LVEF. We used to call this recovered LVEF. This is recently been defined in the guidelines as any patient who had a previous LVEF less than or equal to 40% and a follow-up measurement of greater than 40%. We had 18% of patients in DELIVER. This is what they look like on the right and you can see here that there are some really important differences in this group. They were more likely to be New York Heart Association Class 2, they were less likely to be women. Their mean NT-proBNP was identical. Their ejection fraction was a little bit lower, about five points lower than patients who are not enrolled in this group and there were some important differences in medications. They were more likely to be on the kind of medications that we use for heart failure with reduced ejection fraction.

Well importantly, we've also seen in other trials that as ejection fraction goes up, the benefit of therapies seems to decline. We saw that with candesartan in CHARM, with the mineralocorticoid receptor spironolactone in TOPCA and we saw that with sacubitril/valsartan in the PARADIGM and PARAGON programs. So, in EMPEROR-Preserved although the study was overall positive. There was at least a suggestion on these post hoc analyses of heterogeneity by Left Ventricular Ejection Fraction. As you can see in these two slides. This is a question that is obviously very important and we hope to be able to answer with DELIVER. Why might this be? Because we think that as ejection fraction goes up, the contribution of the cardiac effects, The cardiac benefit of our therapies actually goes down And so, our cardiovascular therapies may not be as effective as ejection fraction goes up. We are going to find that out in DELIVER. We certainly know that patients with heart failure, with reduced and mildly reduced ejection fraction, seem to respond to therapy with many of the drugs that we have currently used for treating heart failure with reduced ejection fraction. I think that the group in the upper area, what we call heart failure with normal ejection fraction, is right now, our discomfort zone and we hope to answer that question with DELIVER, which is the largest and broadest trial in heart failure with mildly reduced and preserved ejection fraction.

As I said, we have two ways we can win in the full population and with the patients who have an ejection fraction under 60%. DELIVER should elucidate whether SGLT2 Inhibition, like other therapies, shows attenuation in patients, with normal left ventricular ejection fraction. DELIVER will further assess benefit of SGLT2 Inhibitors, in hospitalized, or recently hospitalized patients and we will assess the benefit in this group with improved LVEF, a group excluded from other trials.

Stay tuned.

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