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Medicine Matters diabetes

The EMPEROR program if you ask why there are two different trials is a program that on the one hand looks for an indication in a setting that is typically known as heart failure with reduced ejection fraction with ejection fractions up to 40 percent and then is venturing into uncharted territory with the EMPEROR-Preserved trial with ejection fractions above 40 percent. There's a history of trials with ejection fraction about 40 percent HFpEF not to work and so there is some uncertainty in that area, whereas in the heart failure is reduced ejection fraction space for where the EMPEROR-Reduced trial recruited there is many many other previous trials and treatments that were successful; that means two patient cohorts exist this totally different requirements for background therapy also these treatment cohorts differ with their risk and with their other kind of therapy and so really we had to create two different trials because they use different definitions for severity of patients and background therapy and the result was the EMPEROR program with EMPEROR-Reduced up to 40 percent, EMPEROR-Preserved above 40 injection fraction patients being mainly included.



When you look at the success of a therapy and you find that the therapy works you very often as you do ask 'why does it work?' now unfortunately the science that we are practicing for the last 40 years, officially speaking, is only doing falsification that's why we have a null hypothesis and we reject it. We don't know exactly why these drugs work and trials like these are not really designed to discover it except that it might give us some hints that we call hypothesis generating. Here, we have for instance, the situation that hematocrit increases quite significantly but NT BNP levels do not significantly – from a clinical perspective – go down beyond five percent on average, that means this is unlike the typical effect seen with diuretic therapy, so I would mostly exclude diuretic effects that some speculate about. I think personally that the uric acid reduction is important and so that hints either in the direction of uric acid being important via some immune mechanisms or alternatively uric acid being important as a metabolic indicator of better insulin sensitivity of overall less catabolism going on so I personally think it's these metabolic pathway changes where maybe in addition you have also erythropoietin stimulation but in reality the fact of the matter is the valid finding of EMPEROR-Preserved is that the treatment works. The 'why?' Is for our debates and discussions and our—if you like—fireplace assessments but it's not for the validity of signs you can take directly from the trial I'm afraid.



The trials both showed strong reductions on the combined endpoint of cardiovascular death and heart failure hospitalizations that is what these trials were designed for the components of the primary endpoints in both cases point to an eight or nine percent reduction in cardiovascular mortality within the studies and a 25 percent-plus reduction in heart failure hospitalization. Why we didn't see a more direct relationship with the two? Well, frankly speaking, we don't know and technically speaking we didn't design the trials to achieve this so maybe we need to have longer running studies to have a significant impact on cardiovascular mortality. In EMPEROR-Preserved we saw a completely neutral all-cause mortality result.



I would say it's for the future for us a) to get a better understanding how these results come about but what we need to conclude is that drugs like empagliflozin modify particular cardiac outcomes and in the heart failure this reduced ejection fraction also renal outcomes but they do not modify the non-cardiovascular mortality, which made up half of all the mortality seen in EMPEROR-Preserved.



Maybe in the future we can do better with different medicines but heart failure hospitalization let's not underestimate this are a major burden for the disease status of patients, they predict future mortality, they cost a lot of money they, really impair quality of life. I think it's a great step forward that we actually have here such important changes in heart failure hospitalization rates with empagliflozin, both in preserved ejection fraction heart failure but also in reduced heart failure.



In patients with heart failure and a preserved ejection fraction, of course, until we now present this trial result no other study has presented convincing positive results in a prospective manner for any therapy, so here we now have more than 20 percent benefits, highly statistically significant and also working across a spectrum of subgroups for the primary endpoint analyzed. So if I have to write my guidelines I would make this one of the first pillars of therapy, clearly the researchers the physicians taking care of patients in the world in this trial, six thousand patients of them, already voted with their feet that they also want to give RASi therapy that they also want to give beta blocker therapy, each more than 80 percent in this cohort of patients, and they also want to use MRAs, particularly at the lower end of the spectrum of ejection fraction for these patients. So these are likely to be considered other pillars of the therapy but the evidence level for these other pillars is certainly not as strong as it is now for empagliflozin in heart failure with preserved ejection fraction.



Now, if you want to extend this to the guidelines on heart failure with a reduced ejection fraction, I think that these got it spot on right in patients with any type of heart failure you have two SGLT2 inhibitors that together got a 1A recommendation for the patients with diabetes and heart failure. If you take them in isolation you have three SGLT2 inhibitors that are recommended at a 1A level but for heart failure with a preserved ejection fraction we simply don't have that kind of differentiation yet and empagliflozin is the only drug with a meaningful number of patients with a big prospective trial to show this. I know that, of course, some people will argue there is data with sotagliflozin. It is certainly intriguing and really encouraging but by no means as good as the data there is for heart failure with reduced ejection fraction with uh sotagliflozin. So I'm not sure that the time is right for making recommendations also including this drug well and then dapagliflozin it's only maybe approximately eight months from now until we see the DELIVER study and that will be very important in the guideline that you want me to design to also know those results-- I would certainly wait to produce the guidelines to see them whether deliver-- delivers a similar message as EMPEROR-Preserved.