Thread by @ckd_ce

(1) Welcome to this #accredited #tweetorial, on recent & emerging data on finerenone, a non-steroidal mineralocorticoid receptor antagonist. We’ll discuss what it is, what evidence supports its use, & where it might fit into future #renal guidelines. I am @drkevinfernando.

(2) This program is supported by an educational grant from Bayer and is intended for #healthcare providers. Author disclosures can be found at ckd-ce.com/disclosures/. Prior programs, still available for CE/#CME credit, are at ckd-ce.com.

(3) Let's start with a knowledge check.
The following therapeutic options have demonstrated a significant reduction in the progression of both #CKD and #cardiovascular mortality in people living with #T2D:
1. ACEi's & ARBs
2. Spironolactone
3. SGLT2 inhibitors
4. Finerenone

(4) So that's a bit of a trick question. The answer is actually both 3 (#SGLTi) and 4 (#finerenone).

5) Seminal renal trials such as RENAAL (🔓nejm.org/doi/full/10.10…) & IDNT (🔓nejm.org/doi/full/10.10…) demonstrated significant ⬇️in progression of CKD via RAS blockade with losartan & irbesartan respectively. However, no corresponding⬇️in cardiovascular mortality was reported.

6) #Canagliflozin in the CREDENCE trial (🔓nejm.org/doi/full/10.10…) & #dapagliflozin in the DAPA-CKD trial (🔓nejm.org/doi/full/10.10…) showed significant ⬇️in #CKD progression in people living with T2D, PLUS ⬇️ in both #cardiovascular and #renal mortality.

7) Notably DAPA-CKD also demonstrated these benefits in people without type 2 diabetes

8) So, what on earth is #finerenone?! Finerenone is a non-steroidal mineralocorticoid receptor antagonist (#MRA) which has quite different pharmacokinetics and clinical effects to #spironolactone, which is a #steroidal MRA. Adverse effects of spironolactone include:

9) So the answer is ALL of the above. There's room for improvement!
Finerenone does not significantly⬇️#bloodpressure like spironolactone & has fewer steroid-induced adverse effects such as gynaecomastia, impotence, & low libido.

10) Interestingly, and perhaps contributing to its beneficial effects, finerenone has established anti-inflammatory and anti-fibrotic properties. For example, see 🔓karger.com/Article/FullTe….

11) Finerenone has recently been approved by the 🇺🇸FDA to⬇️risk of kidney function decline, #kidneyfailure, CV death, non-fatal heart attacks & hospitalisation for #heartfailure in adults living with #CKD associated with #T2D.

12) During December 2021, finerenone was given a positive opinion by the 🇪🇺European Medicines Agency for the treatment of #CKD (stage 3 & 4 with #albuminuria) associated with #T2D in adults.

13) These approvals were based on results of the FIDELIO-DKD study (🔓nejm.org/doi/full/10.10…). The primary endpoint was a composite of renal failure, a sustained⬇️of at least 40% in eGFR from baseline, or death from renal causes.

14) The 🗝️secondary endpoint was a composite of CV death, non-fatal MI, nonfatal stroke, or hospitalisation for HF #HHF.

15) The primary composite endpoint was significantly ⬇️by 18% (absolute risk ⬇️3.3%) with finerenone compared to placebo, and the secondary endpoint by 14% (ARR 1.8%). There was no imbalance in adverse effects such as acute kidney injury or hypotension.

16) However, hyperkalaemia was more frequent with finerenone than with placebo, but only 2.3% of the finerenone group discontinued therapy due to hyperkalaemia.

17) Notably, finerenone⬇️albuminuria to a similar extent as #SGLT2i, but the magnitude of benefit in the primary composite outcome was less than in CREDENCE & DPA-CKD (18% v 30% & 39% respectively). BUT--only 5% of trial participants in FIDELIO-DKD were also treated with SGLT2i.

18) Interestingly, further data from FIDELIO-DKD presented at @ISNkidneycare 2021 by @P_Rossing looking at combinations of finerenone & SGLT2 inhibitor demonstrated a lower incidence of hyperkalaemia in SGLT2 inhibitor treated individuals with no episodes of K>6.0mmol/l.

19) Such comparison, of course, is only for discussion as these are not head-to-head trials; the trials have different recruited populations and designs, and the trial drugs have different mechanisms of action.

20) On that cautionary academic note, let's take a break. Return here TOMORROW for more education and a link to your FREE CE/#CME! Nods to @AmarPut @drpatrickholmes @HannahBeba @edgarvlermamd @scoca1 @kdjhaveri @JavedButler1 @rkramann @ayanlinaa @gabolino43 @jorgericof

21) Welcome back! We are earning CE/#CME as we talk about a newly available nonsteroidal mineralocorticoid antagonist, #finerenone. I am @drkevinfernando of @GoggleDocs. Tip o' the hat to @nephondemand @NephUCommunity @NephUCommunity @MedTweetorials
#nephtwitter #FOAMed

22) FIGARO-DKD explored impact of finerenone in pts with #T2D & a wider range of #CKD. Unlike FIDELIO-DKD, FIGARO-DKD (nejm.org/doi/full/10.10…) had a primary CV endpoint & a secondary renal endpoint but less advanced CKD. Nearly half had #microalbuminuria; mean eGFR was 68ml/min

23) The primary endpoint of FIGARO-DKD was a composite of time to #CV death, non-fatal MI, nonfatal #stroke, or hospitalisation for #HeartFailure (#HHF). The key secondary endpoint was a composite of kidney failure, sustained ⬇️in eGFR by ≥40% from baseline, or renal death 🪦.

24) The primary composite endpoint was significantly ⬇️by 13% (absolute risk reduction 1.8%) with finerenone compared to placebo, mainly driven by a 29% RRR in #HHF. There was also a⬇️in ESRD.
Other components of the primary endpoint were not significantly reduced.

25) CV benefits were seen in all categories of UACR and eGFR benefits were also independent of #SGLT2i & #GLP1RA use.
The secondary composite endpoint of FIGARO-DKD was numerically lower but did not reach statistical significance.

26) There was no significant difference in AEs (inc #AKI & gynaecomastia) between groups, but the incidence of hyperkalaemia-related discontinuation was⬆️with finerenone (1.2%) vs placebo (0.4%)--still < expected hyperkalaemia seen w/steroidal MRAs in a similar population

27) 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 individuals of a Black ethnic background are at increased risk of developing end-stage renal disease #ESRD.

28) Notably, a recently published pre-specified analyses from FIGARO-DKD (🔓ahajournals.org/doi/10.1161/CI…) showed that #finerenone reduced new-onset #HF and improved other clinically important HF outcomes in patients with #CKD and #T2D irrespective of a background of HF

29) Specifically, new-onset HF was significantly ⬇️with finerenone vs placebo by 32% (absolute risk reduction 0.9%). Incidence of AEs was balanced between the treatment groups. This suggests a future role for finerenone as a HF therapy and perhaps a new pillar of HF treatment?

30) But wait, there's more! FIDELITY was a pre-specified meta-analysis of individual patient data from FIDELIO-DKD & FIGARO-DKD and was presented at the virtual @escardio Congress 2021.

31) FIDELITY had 13171 participants, of which around 40% had albuminuric #CKD with relatively preserved kidney function (mean #eGFR = 58ml/min)

32) FIDELITY showed that finerenone significantly ⬇️risk of a composite CV outcome (time to CV death, nonfatal MI, nonfatal stroke or HHF) by 14% ... AND also significantly ⬇️ risk of a composite renal outcome (≥57% decline eGFR, time to kidney failure or renal death) by 23%

33) The FIDELITY pooled analysis concluded that finerenone reduced the risk of CV & renal outcomes compared to placebo in patients with T2D and all stages of CKD.
But ... what about use of finerenone in people WITHOUT type 2 diabetes and CKD?

34) Well, the FIND-CKD trial is underway. Its primary outcome is the impact of finerenone on annual mean rate of change in eGFR measured by the total slope of eGFR from baseline, in ~1580 individuals with CKD but without diabetes.

35) So, in summary we have a new therapeutic option for the management of DKD: finerenone lowers the risk of both CKD progression and cardiovascular events with no imbalance of serious adverse events.

36) Where might finerenone slot into future treatment paradigms for #DKD?
The updated @goKDIGO Oct 2020 guidelines (great reference doc at 🔓kidney-international.org/article/S0085-…) on #T2D management in #CKD already positions #SGLT2i as a pivotal part of the pyramid of treatment.

37) Based on the above results, finerenone also appears to deserve its own place alongside RAS blockade and SGLT2 inhibition and we await to see how renal guidelines will evolve to take into account new and emerging data for finerenone.

38) And that's it! You made it! FREE CE/#CME #physicians #physicianassociate #nurses #nursepractitioner #Pharmacist go to ckd-ce.com/MRA1 to claim your credit, and FOLLOW US for the latest education on #CKD. I am @drkevinfernando, part of the @GoggleDocs team!