Hi, I'm Francesco Giorgino. I'm Professor of Endocrinology at University of Bari Aldo Moro in Italy. The VERTIS CV is an important study, of course. It's around another SGLT2 inhibitor, ertugliflozin, which was tested for its safety and also efficacy in a population at very high risk of cardiovascular disease in order to see whether it would specifically reduce the incidence of major adverse cardiovascular events. So the people that were enrolled in this trial were all patients with established cardiovascular disease. And the drug was compared with standard of care.
Now, there are some, I think, disappointing results from this study. And these are the lack of the superiority that was seen for the primary endpoint, which was a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. So this particular endpoint was not inferior with the ertugliflozin versus placebo, but was also not reduced with the drug, as compared with placebo. So this is somehow disappointing because we could have expected-- we could have expected-- a reduction of this particular endpoint.
Another kind of disappointing result based on the previous trial is the lack of superiority on a secondary endpoint, which was, again, a composite of cardiovascular death and hospitalization for heart failure. It was a trend for a reduction of this endpoint in the initial period of the study, of the trial. But then at the end, this was not statistically significant.
So these are some elements of disappointment. But at the same time, I think the study is consistent with previous cardiovascular outcome trials of the class of SGLT2 inhibitors. So if we look at the reduction of hospitalization for heart failure, this was there. In VERTIS CV, there was a 30% reduction, which was statistically significant, so very convincing and very much aligned on the previous results with SGLT2 inhibitors.
Again, another kind of consistent result is the reduction of the renal composite, which actually did not achieve the statistical significance for the way the endpoint was conceived, which was a composite of renal death, dialysis, and doubling of serum creatinine. But if we look at, for example, the behavior of the EGFR throughout the study, which was a fairly long study-- so between two and three years of follow-up-- there was clearly some effect of ertugliflozin, because the EGFR, which dropped initially, as it happens with all SGLT2 inhibitors, was more stabilized over time, and definitely at the end was maintained to a higher level of kidney function as compared to placebo.
So I think the take-home message of this trial is that the more recognized, I think, benefits of the SGLT2 inhibitors are confirmed with ertugliflozin, namely, the ability to reduce hospitalization for heart failure and to affect the kidney function in a favorable manner. At the same time, we have to recognize that this study, together with EMPA-REG, is a study that has enrolled a very high-risk population, the highest-risk population, together with EMPA-REG, when exposed to SGLT2 inhibitors. So I think this evidence is clinically relevant.
I think this trial is also interesting because in a high-risk population, it shows a safety profile of the molecule which is consistent with the class. There are some imbalances and some side effects, like, for example, the amputations. But at the same time, the statistical analysis that was shown by the authors of the study, by the steering committee members, was pretty convincing in showing that this is something that is not statistically so significant in terms of impact, anyway, that events were relatively rare.
The only thing that hits me a little bit in terms of adverse event profile is the fact that there was a statistically significant increase in the urinary tract infections, which is something that has been seen, but not always seen in previous studies. Actually, it was more not evident than evident in previous studies. So maybe this is some kind of, I think, interesting warning that should raise the attention, not exclusively on the genital infections, but also on the possibility to have some little excess urinary tract infections.
This is a difficult question to answer because, of course, if we have to consider the scientific evidence, we have to recognize that in other trials with different molecules, and specifically if we consider the results of EMPA-REG with empagliflozin, there was a major effect in that study on cardiovascular death. Even there was an effect on all-cause death. So if we want to reduce cardiovascular death individual individuals with established cardiovascular disease, you should use empagliflozin. You cannot use ertugliflozin because there is no evidence for this particular endpoint.
And similarly, if we consider the MACE, the Major Adverse Cardiovascular Events, or the composite endpoint of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death, this was reduced significantly, again, in EMPA-REG. It was the primary endpoint in this study, as in the CANVAS program, and also was reduced in the CANVAS program by canagliflozin. So if we are going to use these drugs for the reduction of the MACEs, we should stick with the trials that show evidence for superiority. And these trials are EMPA-REG and the CANVAS program, as I mentioned.
But if we want to consider what is probably-- as I probably alluded to, a more widely recognized benefit of the class, which is very much in regard to the reduction of hospitalization for heart failure, reduction of the severity of heart failure, and the effects on the kidney in the long term, I think that, in this respect, the data of VERTIS do not differ from previous trials. Actually, they confer what was found in all of the other trials with the three molecules that have preceded the evidence with ertugliflozin. So the class benefit, in my opinion, is not much changed after knowing the results of the VERTIS CV.
I think we still need to understand better how these drugs work. It is possible that the different results of these distinct cardiovascular outcome trials could be due to the population features, the study design, the way the study was conducted. But at the same time, the possibility that there could be some different mechanism of action, some fine-tuning of the way by which these drugs affect heart tissue or the kidney tissue or activate systemic changes that translate into organ benefit cannot be excluded. So I think that we need more research, because it would be valuable, anyway. Maybe beyond the understanding of how these drugs work, we need more research to really clarify what is the mechanistic basis for the benefit on the heart failure, for the benefit on the kidney.
There are, of course, some hypotheses that have been supported by experimental data. But at the same time, we still don't know which is the major or which are the major mechanistic changes that are behind the observed clinical effects. And at the same time, especially at the molecular level, we should understand whether there could be some differences between the individual molecules in terms of activating the inhibition of SGLT2 or by activating or targeting other molecules that have been suggested.