Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes

Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes

• Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. N Engl J Med. 2020;383(23):2219–2229.

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Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD).¹

For CKD in people with T2D, international guidelines, such as the Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group guideline, recommend management of hypertension and hyperglycaemia, use of a renin-angiotensin system (RAS) blocker and a sodium-glucose cotransporter 2 (SGLT2) inhibitor.^1,2 

CKD is progressive and irreversible, and slowing progression remains a clinical challenge³.

The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial evaluated the hypothesis that finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist with anti-inflammatory and antifibrotic effects^4–6, slows CKD progression and reduces cardiovascular morbidity and mortality in people with advanced CKD and T2D⁷.

What did the FIDELIO-DKD investigators do?

• FIDELIO-DKD was a phase 3, randomised, double-blind, placebo-controlled multicentre clinical trial
• The trial consisted of run-in (4–16 weeks), screening (≤2 weeks) and double-blind treatment periods (conducted at Month 1, Month 4, then every 4 months until trial completion)
• Following the run-in period, eligible patients ≥18 years of age with type 2 diabetes and CKD were randomly assigned in a 1:1 ratio to receive oral finerenone or placebo; patients with an estimated glomerular filtration rate (eGFR) of 25 to <60 ml/min/1.73m² of body-surface area (screening visit) received an initial dose of 10 mg once daily; those with an eGFR of ≥60 ml/min/1.73m² (screening visit) received an initial dose of 20 mg once daily

FIDELIO-DKD outcomes

Primary outcome: a composite of kidney failure, a sustained decrease of at least 40% in eGFR from baseline over a period of at least 4 weeks or death from renal causes.

Key secondary outcome: a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure.

What did the investigators find?

Between 2015–2018, 13,911 patients in 48 countries were screened; 5,734 patients were randomised.

Baseline characteristics and concomitant medications were balanced between the finerenone and placebo groups.

Primary outcome

The incidence of the primary composite outcome was significantly lower in the finerenone group than in the placebo group, occurring in 504 of 2,833 patients (17.8%) and 600 of 2,841 patients (21.1%), respectively (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.73–0.93; P=0.001) (Figure 1).

Figure 1. Incidence of primary composite outcome in the finerenone and placebo groups (Adapted⁷). Outcomes were assessed in time-to-event analyses. The primary composite outcome consisted of kidney failure, a sustained decrease of at least 40% in eGFR from baseline or death from renal causes.

Based on an absolute between-group difference of 3.4% points (95% CI, 0.6–6.2) after 3 years, 29 patients needed to be treated with finerenone to prevent one primary outcome event (95% CI, 16–166)

Key secondary outcome

Patients in the finerenone group had a significantly lower risk of a key secondary outcome event, which occurred in 367 patients (13.0%) in the finerenone group and 420 patients (14.8%) in the placebo group (HR 0.86; 95% CI, 0.75–0.99; P=0.03). The incidences of the components were lower with finerenone than with placebo, except for non-fatal stroke, which had a similar incidence in the two groups.

After 3 years, based on an absolute between-group difference of 2.4% points (95% CI, 0.3–4.5), 42 patients needed to be treated with finerenone to prevent one key secondary outcome event (95% CI, 22–397)

Safety outcomes

The incidence of adverse events that occurred during the treatment period was similar in both groups; 31.9% of serious adverse events occurred with finerenone; 34.3% with placebo.

Finerenone had modest effects on blood pressure: changes in mean systolic blood pressure from baseline to Month 1 and to Month 12 were −3.0 and −2.1 mm Hg, respectively, with finerenone and −0.1 and 0.9 mm Hg, respectively, with placebo. Glycated haemoglobin levels were similar in the two groups.

Key learnings from FIDELIO-DKD

In the FIDELIO-DKD trial, people with CKD and T2D who received finerenone had a lower risk of a primary outcome event, and a lower risk of a key secondary outcome event, than placebo.

The delayed separation of the Kaplan-Meier curves for the primary outcome is evidence that finerenone may slow CKD progression by influencing tissue remodelling.

Three factors that may limit the generalisability of the FIDELIO-DKD trial included the exclusion of patients with non-albuminuric CKD and CKD not due to T2D, only 4.7% of the participating patients identified themselves as Black, and most patients had advanced CKD.

In summary, based on the findings of the FIDELIO-DKD trial, in people with CKD and T2D, finerenone may be an effective treatment for kidney and cardiovascular protection.

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References

1. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(4):S1–S115.
2. Cheung AK, Chang TI, Cushman WC, Furth SL, Hou FF, Ix JH, et al. Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021;99(3):559–569.
3. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295–2306.
4. Agarwal R, Kolkhof P, Bakris G, Bauersachs J, Haller H, Wada T, et al. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J. 2021;42(2):152–161.
5. Grune J, Beyhoff N, Smeir E, Chudek R, Blumrich A, Ban Z, et al. Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone’s antifbrotic activity. Hypertension. 2018;71(4):599–608.
6. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA. 2015;314(9):884–894.
7. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219–2229.