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Effect of MRAs on Chronic Kidney Disease Outcomes in Type 2 Diabetes

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Meet our Panelists

Dr. David Cherney
David Cherney, MD CM PhD FRCPC Professor of Medicine, University of Toronto Clinician Scientist, Division of Nephrology, University Health Network Senior Scientist, Toronto General Hospital Research Institute Director, Renal Physiology Laboratory, University Health Network Toronto, ON
Dr. Adeera Levin
Adeera Levin, MD FRCPC FCAHS CM Professor of Medicine, University of British Columbia Head Division of Nephrology Executive Director BC Renal Consulting Nephrologist St Paul’s Hospital Vancouver, BC
Dr. George Bakris
George L. Bakris, MD F.A.S.N. F.A.H.A. Professor of Medicine
Director, Am. Heart Assoc Comprehensive Hypertension Center
Chicago, IL
Dr. Rajiv Agarwal
Rajiv Agarwal, MD MS FASN Professor of Medicine,
Indiana University School of Medicine
Indianapolis, IN
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Hint: Click this icon to see some chapters in this video for easy navigation

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Questions & Answers

Our panelists addressed visitor questions below. Do you have a question not answered already? Please ask our panelists here.

Is there a reason why patients with HFrEF were excluded from the FIDELIO-DKD trial?

When the FIDELIO-DKD trial was designed, there was the intent to conduct a separate trial on heart failure, therefore these patients were excluded. Moreover, randomizing patients to finerenone when spironolactone is indicated in patients with HFrEF may be ethically questionable.

Which patient populations enrolled in FIDELIO-DKD did not respond to finerenone?

This has not yet been formally analyzed. However, biomarker data was only collected in a subset of patients.

For patients who cannot take finerenone for financial reasons or because of lack of availability, is there any data to support use of aldactone as an alternative?

There is data in patients with resistant hypertension. It may also be reasonable to consider patients with HFrEF who have a reasonable GFR. However, in patients with advanced CKD and serum potassium ~5.0 mmol/L, increased hyperkalemia leading to discontinuation may be observed (as was seen in the AMBER trial). There is also no data other than on blood pressure and albuminuria on hard outcomes in these patients.

We spent many years thinking about the anti-inflammatory effect of Ang II blockade (ACEi or ARB). Why might we need additional anti-inflammatory effect from finerenone?

Despite those advances, there remains a high level of residual risk of CKD progression with current therapies. This would suggest that while these therapies alone are insufficient.

There is currently a renaissance in nephrology with many new targeted therapies. Finerenone very different from spironolactone, it is a novel non-steroidal MRA specially designed to target inflammation and fibrosis while minimally affect potassium and blood pressure levels. While biopsies of patients from the FIDELIO-DKD trial were not done to assess inflammation, a vast amount of non-clinical research suggests that finerenone acts to reduce inflammation and fibrosis.

Does finerenone have a diuretic/filtration effect in addition to the anti-inflammatory effects? Can it potentiate diuretic effects of other diuretics?

Yes, finerenone was discovered using the Kanagawa Model in which an agent is administered and the urine Na+:K+ ratio monitored. A change in the Na+:K+ ratio implies that there is a mineralocorticoid effect in the kidney, as was the case with finerenone. However, this data was obtained in the context of normal kidney function and may not necessarily be extrapolated to patients with CKD stages 4 and 5.

How can finerenone have a long-lasting effect with such a short half-life (~2 hours)?

Finerenone has very short half-life and no known active metabolites. It acts on a nuclear receptor and animal models suggest that finerenone blocks transcription factors. At the end of the finerenone dosing interval, 12 half-lives have elapsed. One important implication is that there is less hyperkalemia than with spironolactone (whose metabolites have a half-life of 168 hours).

Finerenone is associated less hyperkalemia than the steroidal MRAs. Does this give us any insight on the MOA?

Hyperkalemia is a manageable condition for which new therapies are available. But, like the RALES trial, it is possible that in the clinical setting, the rate of hyperkalemia observed with finerenone will be greater than what was observed in clinical trials. However, because of their different pharmacologic properties, the rate of hyperkalemia with finerenone will be lower than with spironolactone. This can partially be attributed to the fact that spironolactone has 2 metabolites – canrenone and 7α-thiomethylspironolactone (7α-TMS). These metabolites were shown to be present in the urine of 3/8 of patients from the AMBER trial 3 weeks after having discontinued treatment. In addition, 2 weeks after discontinuing spironolactone, blood pressure effects persisted. In contrast, the half-life of finerenone is only 2 hours.

In addition, the distribution of finerenone and spironolactone differ. The concentration of spironolactone is 6-fold increased in the kidney as compared to the heart, whereas the distribution of finerenone in the kidneys and heart is comparable. Therefore, finerenone is only a “distant relation” to spironolactone.

Nonetheless, like spironolactone, it is important to prescribe finerenone and monitor serum potassium levels as indicated in product monographs and as done in the clinical trial setting to help mitigate the risk of hyperkalemia.

Do you think the benefits observed with finerenone in the FIDELIO-DKD trial will be additive to the effect of SGLT2i?

There were an insufficient number of patients on an SGLT2i enrolled in the FIDELIO-DKD trial to conduct a statistically meaningful analysis. However, other data suggests that low doses of finerenone and SGLT2i combined have an additive effect on markers of inflammation, fibrosis, and albuminuria.

The breadth of evidence with SGLT2i is substantial and positive, resulting in their recent inclusion in several clinical practice guidelines. Should the same be anticipated for finerenone based on the FIDELIO-DKD trial?

The results of the FIDELIO-DKD alone may not justify inclusion and recommendation to use finerenone in clinical practice guidelines. However, if the FIGARO trial, which enrolled more patients than FIDELIO-DKD, demonstrates positive outcomes, there may be sufficient evidence to justify inclusion and recommendation of finerenone.

Importantly though, trials such as CREDENCE suggest that there is residual risk in some patients treated with SGLT2i. Finerenone offers another tool to help individualize treatment and should be considered one of the new “pillars” in nephrology along with ACEi/ARBs and SGLT2i.

Might there be benefit with SGLT2i or finerenone in patients with low proteinuria (in the microalbuminuria range)?

Microalbuminuria has been demonstrated to be an inflammatory marker. However, despite guidelines, screening for microalbuminuria remains low.

Approximately half of the patients enrolled in the FIGARO trial, which will examine CV events, have microalbuminuria or A2 albuminuria. In addition, 62% of the patients enrolled have an eGFR of >60 mL/min/1.73 m2. Therefore, the FIGARO trial is powered to assess whether in patients with persevered kidney function and minimal proteinuria, finerenone reduces CV events.

Does the sub-specialization of practitioners limit the uptake of ACEi/ARBs, SGLT2i, and finerenone? Nephrologists may wait for the endocrinologist to prescribe an SGLT2i, whereas endocrinologists are hesitant to add MRAs despite local nephrologists declining to see patients until eGFR is <30 mL/min/1.73 m2 for diabetic nephropathy.

With the approval of new therapies, nephrologists should now focus more on the prevention and mitigation of complications. While present, the risk of hyperkalemia with finerenone is comparable to what was observed in the RENAAL trial. Thus, whoever is the first to see the patient, should offer them the disease modifying drug.

Given these new therapies, what is next?

If the FIGARO trial results are positive, with proper implementation finerenone will offer cardiorenal benefits to patients with microalbuminuria and normal GFR. Whereas the FIDELIO-DKD trial has shown that finerenone offers cardiorenal benefits to patients with more advanced disease. In addition, the FINEARTS-HF study will examine finerenone in diabetic and non-diabetics with HFpEF patients.

Therefore, while speculative, finerenone may become the new aspirin for kidney and heart disease.

Article

Journal link | Visual Abstract

Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes. However, its long-term effects on kidney and cardiovascular outcomes are unknown.

METHODS

In this double-blind trial, we randomly assigned 5734 patients with CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300, an estimated glomerular filtration rate (eGFR) of 25 to less than 60 ml per minute per 1.73 m2 of body-surface area, and diabetic retinopathy, or they had a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of 25 to less than 75 ml per minute per 1.73 m2. All the patients were treated with renin–angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer’s label that did not cause unacceptable side effects. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. The key secondary composite outcome, also assessed in a time-to-event analysis, was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.

RESULTS

During a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P=0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P=0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively).

CONCLUSIONS

In patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo. (Funded by Bayer; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993)

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