Hello again. I'm joined by Dr. Pardeep Jhund from the University of Glasgow, who's a cardiologist. I'm Silvio Inzucchi, an endocrinologist from Yale University. We just heard the DELIVER trial results. Some questions emerge. The first is that, particularly as a diabetologist, and this reflects in primary care as well, we learn that HFpEF is increasingly common. How do we identify patients in our practices with HFpEF? Yes, that's a great question. If you're going to think, you're right, it's a question for everyone actually. It's not just about heart failure doctors, diabetologists, also for internal medicine and primary care, there's a lot of talk at the moment about how we identify these patients and get them into the fold so they can get these evidence-based treatments that we've shown to be beneficial in trials like DELIVER. Of course, part of the difficulty is, number one, thinking about this condition because heart failure is a great masquerader, it looks like lots of other conditions because some of the symptoms overlap with a lot of symptoms of other diseases that this patient population may have. They have lots of comorbidities like diabetes, also other things like obesity. Often, the patients complain of things like fatigue, tiredness, shortness of breath, exercise intolerance, sure, of course, hallmarks of heart failure, but also they maybe just describe to their other comorbidities like obesity, diabetes, chronic kidney disease.

The first problem is actually thinking about it, making sure that you have that awareness that this may be one of the diagnoses. That's, I think, most of the battle. Then you can go and look for other signs and symptoms that confirm the diagnosis. Other things like orthopnea, PND. Then the clinical examination is so important. I think in this day and age we forget that often that having to look for signs of congestion, raised jugular venous pressure, crackles in the chest, peripheral edema. They take you very far along the clinical diagnosis, because remember heart failure a clinical diagnosis. Then we can supplement that with things like natriuretic peptides, which are important in helping us determine if this is the heart that's causing these symptoms, because they're a very good rule-out test. Then we can move on to other imaging modalities like cardiac echo. Cardiography and cardiac MRI and then refer on to the heart failure specialist for further assessment, but having that awareness first of all is the important thing. First, thinking about the diagnosis. Absolutely.

The SGLT2 inhibitors are obviously gaining in popularity not only in diabetes and primary care but also in the cardiovascular community. They are now Class 1 recommendations in most of the HFrEF guidelines. Not so much in the HFpEF guidelines. What's your prediction? Yes, you're absolutely right. They are Class 1a recommendations for heart failure with reduced ejection fraction. They are one of the foundational therapies for heart failure with reduced ejection fraction now. I think that given the results of DELIVER that you've just shown and also EMPEROR-Preserved with empagliflozin that the guidelines will change and that we will see an indication for the SGLT2 inhibitors in heart failure with mildly reduced or preserved ejection fraction, because we've seen two trials now, they're almost identical in their benefit for this patient population.

For this specific question about SGLT2 inhibition, we don't have to worry about whether it's HFrEF or HFpEF any longer? Yes, well, that's one of the interesting things. This has been one of the few drugs that we have in heart failure where we've seen a benefit in both types of patients. That's a real leap forward because now for the first time I don't really have to worry about what the ejection fraction is in my patient before I think about reaching for a drug. I can give a drug to a patient with heart failure irrespective of their ejection fraction. That's the first time we've had that in heart failure. Really exciting to me. But it's still important to think about that distinction for other therapies? Absolutely. We're not saying throw out ejection fraction at all, because ejection fraction is still important for determining whether or not you're eligible for an angiotensin receptor-neprilysin inhibitor or sacubitril/valsartan or device therapies such as implantable cardioverter defibrillator, CRT. We still need the ejection fraction, but for an SGLT2 inhibitor, maybe it's not so important to know the ejection fraction.

This leads me to my last question, just to pick your brains. How does a drug that is a relatively modest A1c-reducing medication originally developed for type 2 diabetes, how in the world does a drug like this have such pervasive benefits in heart failure? Well, that's the multimillion-dollar question, and we could speak for hours about this, I'm sure. There's a few different postulated mechanisms, and it's hard to see how a drug that's been shown to be beneficial in diabetes, heart failure with reduced ejection fraction, preserved ejection fraction, and chronic kidney disease could have one mechanism of action that's beneficial to all of these different patient populations. With regards to heart failure, there's a few different things that seem to be going on in heart failure with reduced ejection fraction, we have evidence that it probably remodels the heart, reduces left ventricular volume size. May also reduce left ventricular hypertrophy, which is something that's important in, of course, HFpEF. There's also experimental evidence to show that it produces natriuresis as well, but whether that's important over the longer term we're not too sure because in our heart failure with reduced ejection fraction population, you'll remember in DAPA-HF, we showed, Silvio, that they don't really change their diuretic dose. It's maybe not a big thing as we go on. Also other diuretics don't seem to have this huge impact on mortality. Exactly, exactly. The other things that have been talked about are things like myocardial energetics and whether that's something that happens, changing the metabolism. Ketone hypothesis. Exactly. Changing the metabolism of myocardium and then a whole host of other things have all been postulated. To be honest, I don't think we know, and my own feeling is it's probably, as I've said, not one mechanism. It's hard to see one unifying mechanism for the broad range of conditions that these drugs seem to be beneficial for.

Thanks a lot. Thanks for joining me and thanks for joining us.

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