Thank you for the privilege of talking about the benefits and evolving insights on SGLT2 inhibitors across the spectrum of left ventricular ejection fraction in heart failure. The question is, can we set priorities?

Well, first of all, let's talk about heart failure across the spectrum of left ventricular ejection fraction. The ESC 2021 guidelines, which are very consistent with the universal definition, as well as the American 2022 guidelines, all classify heart failure by ejection fraction into these three main bins. We have heart failure with reduced ejection fraction with an EF less than 40 percent, less than or equal to 40 percent. We have heart failure with preserved ejection fraction or HFpEF of ejection fraction, 50 percent and above. And then those in between now called heart failure with mildly reduced ejection fraction.

So, let's start with perhaps the most obvious. HFrEF: the SGLT2 inhibitors are undoubtedly beneficial in this group of patients. In fact, they have become one of the four foundational therapies for patients with HFrEF. And these are based on the landmark data from the DAPA-HF and EMPEROR-Reduced trials. And you can see here the meta-analysis of their primary endpoints of heart failure hospitalization or events and cardiovascular death where you see a robust 25 percent relative risk reduction. And if we look at the components of the primary endpoint, again, remarkable consistency with especially marked reduction in heart failure hospitalizations. Now, please remember that, the benefits of these therapies are realized very quickly and these are data from DAPA-HF, where you see there's a significant benefit already shown at 28 days from initiation. In fact, look at that hazards ratio, it's almost half, which means we would double the risk of worsened health status or heart failure hospitalization or cardiovascular death, if we delay initiation.

Now, what about heart failure with a higher ejection fraction? Let's just talk about anything above 40% now and that was the population studied in the EMPEROR-Preserved trial of empagliflozin versus placebo in these patients. Now, of course, we are all celebrating that it was the first robustly positive outcomes trial in these patients with the primary composite of first heart failure hospitalization or cardiovascular death robustly reduced by empagliflozin. And this was mainly driven by a reduction in heart failure hospitalization.

So is the story over like that? Well, these are ejection fraction above 40 percent. So who are these patients? Well, there was a subgroup analysis, pre-specified by ejection fraction. And as you can see here it is pretty consistent. And the point estimates are all to the left of one and there was no significant interaction by ejection fraction. However, if you squint a bit, perhaps it's looking like, it's slanting. To address this issue the authors actually did a focused analysis in patients with ejection fraction of 50 percent or above. So, what we call HFpEF as I've reviewed before. And indeed, even if analyzed in this restricted population, you would find a robust reduction in the primary endpoint as shown here, 17 percent reduced risk of the composite of cardiovascular death or heart failure hospitalization. But put this together with this pooled analysis across EMPEROR-Reduced and EMPEROR-Preserved, where if you look across the ejection fraction spectrum, and if you look at the y-axis and realize that, if it falls below one, it says benefit, but as it approaches the one there could be attenuation of benefit and this was the suggestion in this analysis here, that could be attenuation of the benefit of heart failure hospitalization in those with an ejection fraction of 65 percent or above. But the field is still trying to grapple with this, because if you were to analyze now these data with ejection fraction as a continuous variable, we see a line that pretty much stays under the line of unity. But as you can see there appears to be a bit of a slant, with perhaps more benefit with a lower ejection fraction. But again, no significant interaction.

What we really need, of course, is more data. And you will soon hear about the DELIVER trial, which we already know, read out as positive. But what we really need to understand is, is there a difference across the higher ejection fraction range? We will soon find out.

In the meantime, the guidelines are thankfully quite consistent. And here are the foundational medications that I've represented on each row: HFrEF, HFmrEF and HFpEF and in each row split into the ESC 2021 guidelines and the American 2022 guidelines.

Very easy to remember for HFrEF, definitely class 1 recommendations for these medications, including the SGLT2 inhibitors. Now, where it differs is the SGLT2 inhibitors in those above 40% and because the American guidelines were published after the EMPEROR-Preserved study, you can see that this has been upgraded to a 2a across that entire spectrum,but no mention in the ESC 2021 guidelines which were published before EMPEROR-Preserved.

Does the story end there? Definitely not. Remember the question is, can we prioritize? It is a Class 1 recommendation by both ESC and the American guidelines that in patients with heart failure and diabetes Type 2, SGLT2 inhibitors are indicated. So remember if the patient has diabetes, you should be using an SGLT2 inhibitor. Another class 1 guidelines consistent recommendation, consistent in European and American guidelines, is in a patient who has been hospitalized, that we should be really optimizing their therapy before discharge.

Now remember those two groups and why do we say that? Well, this is a trial, not quite of SGLT2 inhibitors alone, but of the SGLT 1 and 2 inhibitor, sotagliflozin, in those patients with recent heart failure hospitalizations, but all of whom had type 2 diabetes and as you can see, there was a robust reduction in the primary endpoint of total cardiovascular deaths, HF hospitalizations or urgent heart failure visits. Now this trial had to be prematurely terminated, because of covid and so on, but still very intriguing suggestion that in these hospitalized patients whether your ejection fraction is below or above 50%, you do benefit.

The EMPULSE trial is another study that addresses this group of patients at high risk with a recent heart failure hospitalization, in fact, the initiation of the SGLT2 inhibitor during hospitalization, was related to benefit to the patient as quantified by a hierarchical endpoint and quantified by the win ratio.

And finally, another reason we treat our patients, is importantly to make them feel better. And in this very remarkable study called PRESERVED-HF. Dapagliflozin was initiated in patients with heart failure and preserved ejection fraction and compared to placebo, it significantly improved the primary outcome of KCCQ clinical summary score. This was a quite remarkable improvement. And in fact in a responder analysis, many more patients felt better and fewer patients felt worse when they received dapagliflozin then placebo. And this is not only for the clinical summary score, but also for the other components of KCCQ shown here. And finally importantly, although it was a secondary endpoint, dapagliflozin also improved six-minute walk distance.

And so, SGLT2 inhibitors in the spectrum of ejection fraction in heart failure, can we set priorities? I would say that as we await to DELIVER results, we have the class 2A recommendations for those with heart failure and ejection fraction above 40%. But regardless of ejection fraction, don't forget to treat these patients if they have diabetes, if they are hospitalized and at high risk and perhaps if they have impaired quality of life, the SGLT2 Inhibitors are something we may consider. And finally, I think with the DELIVER study, we will be able to finally answer the question of: is it mainly restricted to those with an ejection fraction of perhaps less than 65 percent?

Thank you.

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