Medicine Matters diabetes

How will the DAPA-HF and DEFINE-HF results impact treatment decisions?

I'm quite sure they will impact treatment by time. At the present moment, I don't think they do because the guidelines from the European Society of Cardiology, in collaboration with the EASD, they were actually given out just a couple of weeks ago, so then the studies hadn't been presented.

We knew that dapagliflozin, as other similar compounds, have an impact on heart failure in patients with diabetes. What is new is that the two studies that has been presented since then show that it's not only people with diabetes, but also other people with heart failure, that are influenced by dapagliflozin in a positive way. And that is a very quickly onsetting action-- it takes only a week or two before you can see an impact.

Having said that, both in the DAPA Heart Failure Study and the study that was presented here today on biomarkers and dapagliflozin, they didn't really investigate people with heart failure who were claimed not to have diabetes very thoroughly. And we know that if these patients would have been subjected to an oral glucose tolerance test, one third of them would have had diabetes and 20% perhaps impaired glucose tolerance.

So that is sort of a gap in knowledge still. Were they really free from diabetes or glucose perturbations or not? And that has to be investigated in the future.

But what is remarkable now is that we, during the last few years, have got two types of drugs-- GLP-1 receptor agonists and SGLT2 inhibitors, which both were launched as glucose lowering drugs but rather should be seen as cardioprotective drugs with glucose lowering capabilities. And if you look at the new guidelines from the European Society of Cardiology, they say that if you have a patient with cardiovascular disease established, or at a very high risk for such disease, then you should start glucose lowering treatment with one of those compounds. And if you are going to choose between the GLP-1 receptor agonist and the SGLT2 inhibitors, if you have a patient which are prone to develop heart failure, I would certainly take the SGLT2 inhibitor, and if I am more worried for a progressive atherosclerosis, then perhaps a GLP-1 receptor agonist.

Do the results of these trials tell us anything not already covered by clinical practice guidelines?

The new thing was that they were actually acting both in people with and without diabetes, although we don't know how many there actually were in these studies. We also know that we have two studies-- the one presented today here and the DAPA Heart Failure Study presented at the ESC meeting two weeks ago-- that confirm the very rapid and very efficient action in people with imminent heart failure or with established heart failure. So it consolidates knowledge in a very nice way, and I am absolutely convinced that the use of these drugs will be much more common in the future.

We still need more mechanistic trials, and it's still difficult to understand why the most recently published data today, [DEFINE] you couldn't really identify patients by biomarkers. You just knew they got improved. They felt better, but you couldn't really point on exactly why and which biomarker that really told us that they would be better.

And another thing that was discussed today when I chaired the session was, why didn't they improve their exercise capability? Because I think it's a very short time study, and patients with heart failure are rather physically decompensated. They are not physically fit, and it takes longer time than a few weeks to re-establish your physical ability. So if they had studied physical activity exercise testing over a much longer time period, I think they would have found it had improved.

Why did dapagliflozin reduce the risk for cardiovascular outcomes and improve health status but not reduce NT-proBNP levels?

I think that the rapidity of onset, we have seen that before in heart failure treatment when we have interfered with neuroendocrine activation. So I believe that neuroendocrine activation is something which is very important for the SGLT2 inhibitors. That neuroendocrine activation is commencing by deloading from sodium and fluid, and therefore, your afterload and preload of the heart decreases rapidly. And if the heart is just taken off that for a while, it can recover and start to improve its capacity by time. Then it may be, in the long run, myocardial structure, function, metabolism that improves as well, but that is less certain.

Is it too early to say we have a new drug class for heart failure?

Probably, yes, by time-- certainly for people with diabetes already, and they are already in the guidelines. The new thing is whether you can use them or not in people without diabetes. In these studies, there are some patients who are really treated extremely well with every type of modern drug that exist, and the impact is actually derived beyond that effect. So I think they will appear even there, but it takes a longer time before you can establish a new indication.

Heart failure is a very difficult disease to have, and if you're in a situation where you think the patient is desperately ill and you cannot offer anything more, I think very many people will try to see whether they could improve them by addition of this as an ad hoc thing. But for systematic treatment, it will take a longer time in patients without diabetes.