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Diabetes Distilled: Finerenone significantly reduces renal and cardiovascular outcomes in people with CKD and type 2 diabetes

The large randomised controlled FIDELIO-DKD trial explored the long-term effects of finerenone, a non-steroidal selective mineralocorticoid receptor antagonist (MRA), on renal and cardiovascular outcomes in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). Compared to placebo, the addition of finerenone to standard care (including renin–angiotensin system [RAS] blockade at maximal tolerated dose) significantly reduced the risk of CKD progression and cardiovascular events. These findings, alongside other recent landmark sodium–glucose cotransporter 2 (SGLT2) inhibitor renal trials such as CREDENCE and DAPA-CKD, have significant implications for the future management of T2D with co-existing CKD.

Diabetic kidney disease (DKD) is the single most common cause of renal failure in adults starting renal replacement therapy in the UK (UK Renal Registry, 2020). A recent UK national diabetes audit reported that 42.3% of people living with T2D and 32.4% with type 1 diabetes also had a diagnosis of renal disease (Hill et al, 2014). Moreover, the presence of diabetes worsens all CKD outcomes. The leading cause of death in individuals with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 remains cardiovascular disease, regardless of the presence of T2D (Thompson et al, 2015).
 
Seminal renal trials such as RENAAL (Brenner et al, 2001) and IDNT (Lewis et al, 2001) have demonstrated significant reductions in the progression of CKD with RAS blockade with losartan and irbesartan, respectively. However, no corresponding reduction in cardiovascular mortality has been reported.
 
The recent SGLT2 inhibitor studies CREDENCE (Perkovic et al, 2019) and DAPA-CKD (Heerspink et al, 2020) showed significant reductions in CKD progression in people living with T2D as well as reductions in both cardiovascular and renal mortality. Notably, DAPA-CKD also demonstrated these benefits in people without T2D.
 
Finerenone is a non-steroidal MRA and as such has quite different pharmacokinetics and clinical effects to spironolactone and eplerenone, which are steroidal MRAs. Specifically, finerenone does not significantly lower blood pressure and has fewer steroid-induced adverse effects such as gynaecomastia, impotence and low libido. Interestingly, and perhaps contributing to its beneficial effects, finerenone has established anti-inflammatory and antifibrotic properties. Finerenone is not yet commercially available.
 
Two large phase III randomised controlled trials are aiming to elucidate the cardiac and renal benefits of finerenone in the context of DKD. FIDELIO-DKD has a primary renal endpoint with secondary cardiac endpoints; whereas FIGARO-DKD has a primary cardiac endpoint and secondary renal endpoints with less advanced CKD (mean eGFR 68 mL/min/1.73 m2; nearly half of participants have microalbuminuria). FIGARO-DKD is due to complete during 2021.
 
FIDELIO-DKD recruited 5734 individuals living with T2D and CKD to receive finerenone or placebo. Finerenone was given at a dose of 10 or 20 mg daily, according to participants’ eGFR and serum potassium levels, and could be discontinued if potassium exceeded 5.5 mmol/L.
 
Trial participants had a urinary albumin to creatinine ratio (ACR) of 30–300 mg/mmol, eGFR of 25–75 mL/min/1.73 m2 (median eGFR 44 mL/min/1.73 m2) and diabetic retinopathy, or urinary ACR 300–5000 mg/mmol and eGFR of 25–75 mL/min/1.73 m2. Importantly, all individuals were on a maximally tolerated dose of RAS blockade before randomisation and also had well-controlled HbA1c (mean HbA1c 60 mmol/mol; 7.7%) and blood pressure (mean systolic pressure 138 mmHg). Notably, individuals with heart failure with reduced ejection fraction were excluded.
 
The primary endpoint of FIDELIO-DKD was a composite of renal failure, a sustained decrease of at least 40% in eGFR from baseline or death from renal causes. The key secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, nonfatal stroke or hospitalisation for heart failure.
 
After a median follow-up of 2.6 years, the primary composite endpoint was significantly reduced by 18% (absolute risk reduction [ARR], 3.3%) and the secondary composite endpoint by 14% (ARR, 1.8%). There was no imbalance in adverse events such as acute kidney injury (4.6% and 4.8% in the finerenone and placebo groups, respectively) or hypotension. Predictably, hyperkalaemia was more frequent with finerenone than with placebo, but only 2.3% of the finerenone group discontinued therapy due to hyperkalaemia.
 
Finerenone reduced albuminuria to the same extent as SGLT2 inhibitors; however, the magnitude of benefit seen in the primary composite outcome in FIDELIO-DKD was less than CREDENCE and DAPA-CKD (18% versus 30% and 39%, respectively). The authors believe this difference may be related to differing trial populations and designs (e.g. CREDENCE excluded individuals treated with MRAs, whereas FIDELIO-DKD allowed SGLT2 inhibitor treatment in around 5% of trial participants) and, of course, different mechanisms of action between drug classes. The authors highlight that the compelling benefits of FIDELIO-DKD were achieved in the absence of any significant blood pressure reduction in comparison to the modest but statistically significant decrease seen with SGLT2 inhibitors.
 
The main limitations of FIDELIO-DKD were exclusion of those with non-albuminuria CKD and CKD not due to T2D, and only around 5% of trial participants being of a Black ethnic origin.
 
In summary, finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo in people living with T2D and advanced CKD, with no imbalance in adverse events. As with all good research, FIDELIO-DKD raises many more questions than answers, including where finerenone might be placed in future DKD treatment paradigms alongside SGLT2 inhibitors and what the additive or synergistic effects might be. We await the results of FIGARO-DKD to help answer these questions.
 
Click here for the full FIDELIO-DKD results:
https://www.nejm.org/doi/full/10.1056/NEJMoa2025845

Brenner BM, Cooper ME, de Zeeuw D et al; RENAAL Study Investigators (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–9
Heerspink HJL, Stefansson BV, Correa-Rotter R et al (2020) Dapagliflozin in patients with chronic kidney disease. N Engl J Med 383: 1436–46
Hill CJ, Cardwell CR, Patterson CC et al (2014) Chronic kidney disease and diabetes in the National Health Service: a cross-sectional survey of the U.K. National Diabetes Audit. Diabet Med 31: 448–54
Lewis EJ, Hunsicker LG, Clarke WR et al; Collaborative Study Group (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–60
Perkovic V, Jardine MJ, Neal B et al; CREDENCE Trial Investigators (2019) Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380: 2295–306
Thompson S, James M, Wiebe N et al (2015) Cause of death in patients with reduced kidney function. JASN 26: 2504–11
UK Renal Registry (2020) UK Renal Registry 22nd Annual Report – data to 31/12/2018. UK Renal Registry, Bristol. Available at: https://renal.org/sites/renal.org/files/publication/fileattachments/22nd_UKRR_ANNUAL_REPORT_FULL.pdf (accessed 19.11.20)

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