COMMENTARY

SCORED and FIDELIO-DKD: Time for Cardiologists to Help, Not Hurt, the Kidney

Jennie J. Lin, MD, MSc; Jane E. Wilcox, MD, MSc

Disclosures

November 20, 2020

This transcript has been edited for clarity.

Jennie J. Lin, MD, MSc: Hello, everyone. On November 16, 2020, results from two major clinical trials looking at cardiovascular endpoints in chronic kidney disease (CKD) patients were released at the American Heart Association (AHA) Scientific Sessions.

As you know, CKD is a major risk factor for cardiovascular disease and mortality. Through multiple mechanisms, CKD can drive accelerated atherosclerosis, and cardiorenal physiology can certainly complicate heart failure and management.

Recently, other clinical trials for SGLT2 inhibitors, which exert pharmacologic effects primarily through kidney-driven mechanisms, have yielded very promising findings for the role of SGLT2 inhibitors in improving outcomes in heart failure and CKD. This further emphasized the importance of the kidney–heart connection in human health. It's in this context that the results from the SCORED trial and the cardiovascular portion of FIDELIO-DKD were announced.

My name is Jennie Lin, and I'm a physician scientist and attending nephrologist at Northwestern University in Chicago. I am joined in this discussion by Dr Jane Wilcox.

Jane E. Wilcox, MD, MSc: Hi, Jennie. Thanks so much. I'm Dr Jane Wilcox. I am an advanced heart failure and transplant cardiologist and a physician scientist here at Northwestern University in Chicago as well. I'm pleased to be with you.

Lin: Based on yesterday's reveal of SCORED, what were some of the top findings that came out?

SCORED Study of Sotagliflozin

Wilcox: I think this is a real game changer in the sense of SGLT2s as a class for heart failure or for cardiovascular disease. And then also with this novel compound sotagliflozin which, as you know, is an SGLT2 inhibitor, which mainly targets the kidney, but also an SGLT1 inhibitor, which we know less about. But there are receptors mostly in the gut, so it's targeting postprandial insulin surges and glucose absorption. There are also some SGLT1 effects that directly affect the myocardium, and so potentially that's the mechanism that drives the beneficial effects that we saw in the SCORED trial.

SCORED was a trial of over 10,000 patients with type 2 diabetes, and these were really patients who needed intensification of their regimen for diabetes. Their A1c by definition had to be greater than 7%, they had cardiovascular risk factors, and, as you know, mild to moderate or stage 3 kidney disease with a GFR between 25 and 60 mL/min/1.73 m2.

There was an average of 16 months of follow-up. The trial was actually stopped early because of a loss of funding around the time of COVID, and the primary endpoint was a composite endpoint of cardiovascular death, heart failure hospitalization, or urgent visit for heart failure.

Indeed, the trial was positive, favoring sotagliflozin. The number needed to treat was about 54 and the cumulative incidence was 8.3% vs 9.5%, so about a 23% reduction. [Editor's note: The hazard ratio was 0.74; 95% CI, 0.63-0.88; P < .001.] There was an early benefit as well that was seen within 3 months; the curve started to separate.

I think this adds to the SGLT2 story. Additionally, what I thought was really interesting is that we're learning more about the SGLT2 inhibitors and heart failure independent of diabetes. What we saw in SCORED was that there was also a reduction in ASCVD, or atherosclerotic events. Some have hypothesized that maybe this is due to the SGLT1 inhibitor. I don't think we really can say, but it's exciting to have a reduction in heart failure–driven events and also in atherosclerotic events.

Finally, I think the really exciting thing from the SCORED trial was that about 30% of patients actually had a history of heart failure, and they did a pooled analysis with the patients from SCORED and then also from SOLOIST, which was also presented yesterday at AHA by Dr Bhatt and colleagues. In over 700 patients with heart failure and preserved ejection fraction, there was, in fact, a signal for a benefit with sotagliflozin as well.

We're all looking for a drug that treats heart failure with preserved ejection fraction, so my Twitter is blowing up and it's very exciting. I think we await the larger trials of DELIVER HFpEF, which is looking at dapagliflozin, and EMPEROR-Preserved, which is looking at empagliflozin in the HFpEF space. So it's a really exciting night for heart failure and also for kidney disease, and for our patients.

Lin: That's absolutely right, and the kidney community was definitely very jazzed based on the CREDENCE trial earlier this year, as well as DAPA-CKD, which showed a benefit even in nondiabetic kidney disease. And we were able to look at patients with a lower GFR, which was a great finding and definitely very exciting for the field.

From a cardiovascular standpoint, do you feel that this is more of a class effect? You did mention that there may be some benefit from the SGLT1 inhibition. Do you feel like there's going to be a particular drug that you favor over the other in terms of gliflozins?

Wilcox: I don't know. I think we need to see more data, especially from EMPEROR-Preserved and DELIVER HFpEF. In terms of heart failure with reduced EF, these are really well-tolerated medicines. I've been using dapagliflozin and empagliflozin in my patients and found them to have good clinical outcomes and to be clinically well tolerated, with minimal side effects.

I do think there's a class effect. The SGLT1 inhibitor needs to be looked into more mechanistically to see if that really is driving more of these ASCVD outcomes. There are some data that it decreases the sympathetics in the myocardium and maybe increases the ischemic signal for driving increased angiogenesis. There's a little bit of hand waving, I think, at least in terms of what I know, but I think we need to figure out more about the mechanism.

For our patients, especially with reduced ejection fraction heart failure independent of diabetes status, it works really well, and oftentimes I'm able to substitute a guideline-directed medical therapy for heart failure — or soon to be — in place of a diuretic, which we know can cause hypokalemia and other things. It's really been an exciting time for patients.

FIDELIO-DKD and Finerenone

Lin: Moving on to the second trial that we're going to be discussing today, which is FIDELIO-DKD. The initial findings, especially the kidney-oriented outcomes, were already presented at Kidney Week 2020, which happened at the end of October, and it was accompanied by a publication in The New England Journal of Medicine.

This particular result that was released yesterday was based on a study published in Circulation and is a prespecified subgroup analysis of FIDELIO-DKD, really looking at the effect of preexisting cardiovascular disease on composite outcomes for both kidney and heart.

FIDELIO-DKD was designed to test the hypothesis that finerenone slows the progression of CKD and reduces cardiovascular morbidity and mortality among patients with advanced CKD and type 2 diabetes. All of these patients were already on an optimized renin-angiotensin system blockade because it's standard of care and it would not be ethical to remove people off of the standard of care.

What's special about finerenone is that it's a nonsteroidal, selective, mineralocorticoid receptor antagonist, and it is hypothesized that overactivation of the mineralocorticoid receptor drives inflammation and fibrosis. Blocking it could potentially intervene in terms of those pathways of disease.

With inflammation and fibrosis, you get deleterious effects on the heart, kidney, and vasculature. The hypothesis was that the mineralocorticoid blockade would attenuate some of that and improve outcomes. For the nonsteroidal part, one of the benefits is to reduce the side effects of hyperkalemia and gynecomastia.

The trial design was a randomized, double-blinded, interventional trial, and it consisted of 5734 patients randomized to either finerenone or placebo. The population was basically type 2 diabetic adult patients already on an ACE or ARB, with a potassium less than 4.8, and the GFR range from 25 to 75 mL/min/1.73 m2. Where things get a little bit different is that the urinary albumin-to-creatinine ratio had to be between 300 and 5000 mg/g, but if it was between 30 and 300 mg/g, a patient needed to also have evidence of microvascular complications of diabetes, which was documented as diabetic retinopathy in the medical history.

Exclusion criteria included nondiabetic CKD, so, for example: glomerular nephritis, a urinary albumin-to-creatinine ratio greater than 5000 mg/g, an A1c greater than 12%, HFrEF with NYHA class II to IV symptoms, and also extremes of blood pressure.

The composite cardiovascular outcome that was looked at was defined as death from cardiovascular causes, nonfatal MI, hospitalization for heart failure, and nonfatal stroke. The composite kidney outcome was defined as death from kidney causes, kidney failure, and sustained decrease of at least 40% in eGFR from baseline.

The punchline is that the effect of finerenone on the composite cardiovascular outcome was not modified by history of prior cardiovascular disease, and they defined cardiovascular disease as an atherosclerotic event in terms of coronary artery disease, stroke, and peripheral artery disease.

The composite kidney outcome was lower in the finerenone group, with a more pronounced effect in patients with a history of cardiovascular disease, and the authors discuss some hypotheses for why that may have been the case. Not surprisingly, there was a significant reduction in urinary albumin-to-creatinine ratio, irrespective of baseline cardiovascular disease.

There was more hyperkalemia in the finerenone group — I think about twice as much as the placebo. Although the thought is that the finerenone would lead to less hyperkalemia than spironolactone, there was still a difference compared with the placebo group.

This is also an exciting result for the kidney community, although one of the comments that has been floating around quite a bit is that the benefit ended up being less than what was found for the SGLT2 inhibitor trials before. Also, this was not looking at patients without diabetes, and so this is also very different from the patient population looked at in DAPA-CKD most recently.

Kidney and Heart Hand in Hand

Wilcox: I don't necessarily think of them as mutually exclusive, sort of either/or. Do you think that we'll be prescribing both of these drugs in concert? There are some data that SGLT2 might actually allow you to take an MRA. In SOLOIST, a significant number of patients were on spironolactone, given that they had heart failure and they were hospitalized, so they had an indication. We didn't see hyperkalemia, and in fact we saw a little bit of hypokalemia. I wonder if this is an opportunity for combined therapy for patients.

Lin: Potentially. It would be interesting to see whether there would be a benefit if we end up seeing such trial results. In terms of going for first line, I would think that the SGLT2 inhibitors would still be first line over finerenone, especially for people without diabetes. It would be interesting to see about synergistic effects, and what I'm also waiting for on both accounts is whether they can replace ACE inhibitors.

Wilcox: That's an interesting thought. I love this idea of guideline-directed medical therapy for the kidney. The kidney has but one natural predator, and that's us cardiologists. We drive up diuretics and you nephrologists are like, "Please stop." I do think that we can get on the same page with this idea that with the SGLT2 inhibition, you're preserving renal function. It's sort of GDMT [guideline-directed medical therapy] for the kidney, and instead of this yin and yang, we're both on the same page, which is fun.

Lin: It's like this concept that the kidney and heart hold hands, and you want them to be siblings that are loving each other and getting along and not fighting. I think one of the lessons from the SGLT2 inhibitors is that there is a connection. There are some final common pathways that matter. To be able to see benefit for both organ systems, even though at the end of the day it didn't turn out to be the gangbusters glucose-lowering drug that it was originally designed to be — all of these great benefits to the other organ systems have been phenomenal.

At the European Society of Cardiology conference, when they were announcing the DAPA-CKD results, they were saying that we should start thinking about this, not in terms of organ systems but rather in terms of systemic disease in general.

I really like that approach, and at the very least, for patients on the heart failure service who have CKD, there's at least something that could be beneficial to both. There have been studies showing that maybe creatinine is not an endpoint that we should be looking at for diuresis. But on the other hand, we do get very worried about kidney perfusion and don't have better biomarkers for that in clinical practice. I do think that it's an exciting time. What these drugs are showing is that we really need to focus on what the pathways and mechanisms are that really benefit both.

Wilcox: Absolutely. That's why I'm actually super-excited about DELIVER-HF with DAPA and EMPEROR-Preserved. In HFpEF, we started with this diastolic heart failure idea, looking at the myocardium, and now the vast majority of the cardiology community really looks at HFpEF as a heterogeneous disease that is driven by comorbidities and driven by the periphery. It's obesity, CKD, even a BNP deficiency in some.

With the signal in SCORED and with that pooled data with SOLOIST, where there actually may be a benefit in HFpEF where we see that cardiorenal interaction all the time, I think that reflects that same idea that you were talking about, where we're treating the systemic process with a drug that inhibits this pathway. We might really have a therapy for HFpEF, which would be a game changer.

Lin: That would be amazing, and we definitely need a lot more work on the HFpEF front. That certainly is very important for the kidney community as well.

Do you have any other closing thoughts?

Wilcox: The SGLT2 inhibitor is the new statin.

Lin: That makes sense, and it's definitely an exciting time for that.

Wilcox: We see the effects across the spectrum now. We're seeing it in patients, having a cardiologist hat on, in DAPA-CKD or in CREDENCE in patients who are at risk for cardiovascular events, now to patients who are hospitalized with heart failure in SOLOIST.

I think having a class effect across the spectrum is really exciting, and again, it speaks to that systemic process rather than treating an isolated cell in the myocardium. Maybe we could even be pushing the needle and looking at prevention in patients who are at risk for kidney disease or at risk for some early forms of heart failure. It would be interesting to see if those data might be coming down the pike.

Lin: Absolutely. Definitely, preventive strategies are very much needed and if we can introduce some of these drugs very early on, especially in a primary care setting, that would be amazing.

This wraps up our discussion of SCORED and FIDELIO-DKD. Thank you very much for tuning in, and we hope that you found our discussion informative.

Wilcox: Thanks so much.

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