Bertram Pitt, MD: Interpreting Data from FIDELIO-DKD and FIGARO-DKD

This article was originally published on PracticalCardiology.com.

Backed by data from the FIDELIO-DKD trial, finerenone (Kerendia) received approval from the US FDA for reducing the risk of sustained eGFR decline, kidney failure, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in patients with chronic kidney disease associated with type 2 diabetes in July 2021. Now, data from the FIGARO-DKD trial is helping to further inform use of the nonsteroidal mineralocorticoid receptor antagonist in clinical settings.

Presented at European Society of Cardiology (ESC) Congress 2021 and simultaneously published in the New England Journal of Medicine, results of FIGARO-DKD provide evidence suggesting use of finerenone was associated with a 13% reduction in the primary composite end point in a population of patients with diabetes and less advanced chronic kidney disease.

With an interest in learning more about the results of the trial and what it means for clinicians as well as patients, Practical Cardiology reached out to principal investigator Bertram Pitt, MD, professor of medicine emeritus at the University of Michigan, for more perspective on the results.

Finerenone Q&A with Professor Bertram Pitt

Practical Cardiology (PC): Can you briefly describe the results of FIGARO and how they contribute to our understanding of finerenone?

Pitt: Finerenone is a nonsteroidal mineral corticoid receptor antagonist and it was studied in patients with diabetic kidney disease in the FIDELIO trial that was published last November in the New England Journal of Medicine. That was a trial of 5approximately 5500 patients who had severe kidney disease and type two diabetes. And in that trial, finerenone 10 to 20 milligrams showed a significant reduction in progression of renal disease, as well as reduction in cardiovascular endpoints.

Now, the FIGARO-DKD trial is also in people with type two diabetes and kidney disease. But it's milder kidney disease, there's some overlap, but 62% of the people in FIGARO had a normal GFR above 60, but they had an increase in urinary albumin creatinine ratio at least greater than 30.

So, this is looking at a group of people that many cardiologists don't even pay attention to. I know many diabetologists will certainly do this, they always get a UACR, but many of us in cardiology just don't do that. So, this is a group that's often overlooked, but this was 62% of the FIGARO trial. I should also add that we excluded people with heart failure and reduced ejection fraction because MRAs class one indication for HFrEF. There were a few people, about 7%, who had heart failure, but those probably were heart failure and preserved ejection fraction.

They had a run-in period where they were optimized on RAS inhibitors to maximum-tolerated target doses and 100% of people were on an ACE or an ARB—they were very well-treated. And after the run-in period, then they were randomized to finerenone 10 to 20 milligram, depending upon the renal function, and that was up titrated; by the end of the trial the mean dose was approximately 17 mg.

The bottom line of the primary endpoint, which is a composite of cardiovascular death, nonfatal MI, nonfatal stroke, and heart failure hospitalization, was reduced significantly by 13%. The main driver of that, however, was a 29% reduction in heart failure hospitalization. So, what this mainly did is prevented heart failure hospitalization. As I mentioned, a lot of these people had a normal GFR and this suggests that we really should be paying much more attention to these people with a normal GFR and looking at their UACR and that was very important.

We had a secondary renal outcome and the primary outcome was a 40% reduction EGFR that trended positive but didn't quite reach significance. That endpoint was chosen because that was an end point favored by the FDA and AMA at one time. It has now been shown that that's not a very sensitive endpoint and the more sensitive endpoint is a 57% reduction in EGFR—that was significantly reduced, but probably more importantly, we significantly reduced the progression to end-stage renal disease and dialysis. So, we really help these patients.

Now, having said all these good things, obviously, people who are randomized to MRA have an increase in potassium and we had twice the amount of potassium increase. But really, this was fantastically well-tolerated. Although we had twice as much hyperkalemia with finerenone as placebo, the people who dropped out because of hyperkalemia were really minimal. There was 1.2%, who had a stop on finerenone versus 0.4% on placebo. So, that's less than 1% to drop that.

So, we have a drug, a nonsteroidal MRA, that is really well-tolerated, effective in preventing heart failure in the scope of mild renal disease, and, certainly at the very least, trending towards reducing progression of renal disease, but it certainly reduced end-stage renal disease and the more rigorous outcome of 57% reduction in eGFR.

As we look across the spectrum of renal disease and type two diabetes, when we have FIDELIO and FIGARO, I think we can confidently say that finerenone works across the entire spectrum of renal disease to prevent progression of renal disease, as well as heart failure hospitalization and cardiovascular outcomes. To me, this is a pretty important trial.

PC: Should these results expand the potential patient population for finerenone in real-world settings?

Pitt: Well, in FIDELIO they were in pretty bad renal disease and, now, this is milder. So, we have the spectrum of people with type two diabetes and renal disease, but even with a normal GFR if they have an increase in UACR—and you should be looking, that's one of the messages from this because you can really do something to these patients. I think in the end, finerenone is going to be very good. Additionally, SGLT2 inhibitors are great and, probably they're going to add together and maybe even with a GLP-1 RA. It may be very interesting to pair with a GLP-1 RA because the SGLT2 inhibitors don't reduce stroke in diabetes and we didn't reduce stroke, but the GLP-1 RAs tend to do that. So, that may be a nice combination, but there's a lot of work to be done. I think we now have several drugs that we think affect the progression of renal disease in diabetics, as well as nondiabetics. So, this is just an exciting time.

PC: Do you think the most important responsibility when it comes to these newer agents is understanding how they work sort of in conjunction with one another?

Pitt: Well, I think that's going to be the future trials. As I said, so far it looks like finerenone works on top of the SGLT2 inhibitors and the GLP-1 RA, but it's small numbers and I think those are trials we have to do in the future or someone has to do to see if there's really additive effects and can we give our patients even more by having them on 1 or 2 or 3 of these agents.

Editor’s note: This transcript has been edited for clarity.