Diabetes Distilled: FIDELIO, FIGARO, MAGNIFICO!

Finerenone is a non-steroidal selective mineralocorticoid receptor antagonist (MRA) with 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. However, like steroidal MRAs, finerenone can result in hyperkalaemia.

Finerenone has not yet been approved for use in the UK, but in the US it has recently been approved by the Food and Drug Administration as Kerendia to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks and hospitalisation for heart failure (HHF) in adults living with chronic kidney disease (CKD) associated with type 2 diabetes.

Two large phase 3 randomised controlled trials explored the cardiovascular and renal benefits of finerenone in the context of CKD in people living with type 2 diabetes. FIDELIO-DKD had a primary renal endpoint with secondary cardiovascular endpoints, while FIGARO-DKD had a primary cardiovascular endpoint and secondary renal endpoints but with less advanced CKD (mean eGFR 68 mL/min/1.73 m²; nearly half of participants had microalbuminuria). I have summarised the key findings of the FIDELIO-DKD study in a previous Diabetes Distilled. Together, these trials explore a wide range of CKD in people living with type 2 diabetes.

FIGARO-DKD recruited 7437 individuals living with type 2 diabetes and CKD to receive finerenone or placebo. Trial participants had either a urinary albumin:creatinine ratio (ACR) of 30–300 mg/g (microalbuminuria range) with eGFR 25–90 mL/min/1.73 m² (CKD stage 2–4), or a urinary ACR of 300–5000 mg/g (macroalbuminuria range) with eGFR of at least 60 mL/min/1.73 m² (CKD stage 1 or 2). This latter group of participants has not been extensively studied in the past.

Mean HbA_1c was 61 mmol/mol (7.7%) and mean systolic blood pressure was 136 mmHg. Overall, 45% of recruited individuals had a history of cardiovascular disease.

Individuals were required to have a potassium level of ≤4.8 mmol/L at screening, and all individuals were on the maximally tolerated dose of renin–angiotensin system blockade before randomisation. Of note, there was an 8.4% background rate of SGLT2 inhibitor use and a 7.5% rate of GLP-1 receptor agonist use. These agents have been recommended to reduce cardiorenal risk in many guidelines across the world for the management of type 2 diabetes.

Individuals like those recruited to the FIDELIO-DKD trial – that is, those with advanced CKD, were excluded from FIGARO-DKD. Additionally, individuals with symptomatic heart failure with reduced ejection fraction (HFrEF) were excluded, as MRA antagonists are a key pillar of HFrEF management, with prognostic and symptomatic benefits.

The primary endpoint of FIGARO-DKD was a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or HHF. The key secondary endpoint was a composite of kidney failure, a sustained decrease from baseline eGFR of at least 40% or death from renal causes.

After a median follow-up of 3.4 years, the primary composite endpoint was significantly reduced by 13% (absolute risk reduction (ARR), 1.8%), mainly driven by a 29% relative risk reduction in HHF. The other components of the primary composite endpoint were not significantly reduced. Cardiovascular benefits were seen across all categories of urinary ACR and eGFR. Importantly, cardiovascular benefits were also observed independent of, and in combination with, the use of SGLT2 inhibitors or GLP-1 receptor agonists. The secondary composite renal outcome was numerically lower but did not reach statistical significance.

There was no significant difference in frequency of adverse events (including acute kidney injury and gynaecomastia) between finerenone and placebo; however, the incidence of hyperkalaemia leading to discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%). Expert opinion suggests this is less than the hyperkalaemia rate that would be expected with a steroidal MRA in a similar population. Moreover, finerenone had only a modest impact on lowering blood pressure (–2.6 mmHg after 24 months) and there were no differences in body weight or HbA_1c throughout the trial.

One of the main limitations of FIGARO-DKD was that only around 3.5% of trial participants were of Black ethnic origin. It is well established that Black individuals are at increased risk of developing end-stage renal disease, so this was a missed opportunity.

Finally, a pre-specified meta-analysis of individual patient data from FIDELIO-DKD and FIGARO-DKD – the FIDELITY study – was presented at the 2021 virtual European Society of Cardiology Congress. Total participants numbered 13 171, of whom around 40% had albuminuric CKD with relatively preserved kidney function (mean eGFR 58 mL/min/1.73 m²). This meta-analysis found that finerenone significantly reduced the risk of a composite cardiovascular outcome (time to cardiovascular death, non-fatal MI, non-fatal stroke or HHF) by 14% and significantly reduced the risk of a composite renal outcome (≥57% decline in eGFR, time to kidney failure or renal death) by 23% compared to placebo.

In summary, FIGARO-DKD demonstrated that finerenone improved cardiovascular outcomes compared with placebo, mainly driven by a reduction in HHF, in people living with type 2 diabetes and less advanced CKD, with no significant imbalance in adverse events. Moreover, the FIDELITY meta-analysis also demonstrated that finerenone is effective for cardiorenal protection across a wide range of CKD alongside type 2 diabetes, and cements the importance of measuring urinary ACR in people living with type 2 diabetes and preserved kidney function.

Click here to read the FIGARO-DKD results in full.