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Medicine Matters diabetes

The DAPA-HF trial was the first trial that was done in patients with well characterized heart failure. And this looked at the effect of dapagliflozin, ensured a significant benefit with reductions in hospitalizations and cardiovascular death. That was the first trial and included a substantial number of people who had heart failure but didn't have diabetes.



EMPEROR-Reduced was a similar trial, quite similar in setup, that was using the drug empagliflozin. They also showed significant benefits in the primary composite outcome which is a combination of hospitalization for heart failure and cardiovascular death. So we now have two large trials which show ostensibly same, and it also included plenty of people who didn't have diabetes, and it showed reductions. So there's consistency of benefit in these two outcome trials.



EMPEROR-Reduced also added to the data because it had people who were a bit sicker than in DAPA-HF. So they had an average of slightly lower ejection fraction and higher peptides which as markers of severity of disease. So it extended the type of patient that would benefit from this intervention.



These two studies are consistent in the results, and we know from the type of patient who was included that the benefits were in top of evidence-based therapies. So it was in top of ACE inhibitors, ARBs sacubitril/valsartan All the standard treatments for heart failure were in place, and this gave consistent benefit. So we now have two trials, and on the basis of these two trials the guidelines for management of patients both with and without diabetes who have heart failure should now be changed.



I think it's important to say that it is not definitely a class effect at present. We have these two molecules which have shown benefit. And so specifically for heart failure it should be these two drugs which should be recommended. Following on from EMPEROR-Reduced, there was a meta analysis performed by the investigators combining the data from the two trials. They then looked at different subgroups, and they looked according to severity of heart failure symptomatic severity in patients in NYHA class 3 and 4. Did not quite have the same benefit, but the important thing to say is they still showed benefit.



Will it cost unity? It was only just across unity. So there might be less benefit in those with the most severest forms of heart failure, and that's because hemodynamically things are changed. And often arrhythmias are what kill patients in this group of patients. So when we think about the clinical application of this finding it really means that we should be starting to use SGLT2 inhibitors in heart failure patients as early as possible, and not leaving it until they've got the more severe forms of heart failure.



When we look at the trials in diabetes, we see that it was EMPA-REG outcome that was reductions in cardiovascular death. But now there are diabetes CVOTs there was no consistent reductions in death, although they're worse in some subgroups. If we look at the heart failure trials, it was the DAPA-HF that showed cardiovascular death benefits, but not consistently in EMPEROR-Reduced.



And then in the renal trials, we've also seen reductions in cardiovascular death. So although some individual trials haven't shown benefits I think when you look at it widely all the trials in diabetes, in heart failure, and in renal disease we see there are reductions in cardiovascular death, as well as some other important outcomes. So I think overall it is consistent.



The two studies DAPA-HF and EMPEROR-Reduced were in patients with stable disease at the time they were enrolled, and they were all patients who had a reduced ejection fraction. Now in diabetes patients you have the type of heart failure with preserved ejection fraction (HFpEF) are more common. And so we need information to see whether the benefits that were seen in the patients with reduced ejection fraction would also extend to that group of patients.



And there are two large trials, DELIVER trial with dapagliflozen and EMPEROR-Preserved without the empagliflozin which are currently running and will address that.



The other thing I think would be helpful to know is could there be benefits in patients who've got acute heart failure? So that at the time somebody's admitted to hospital with an acute heart failure could there be immediate benefits from starting an SGLT2 inhibitor? Again there are studies starting to be done which will take a wee bit longer, I think, to get results from in that group of patients. So the data we've got is fantastic, but there still are some unanswered questions.