@drkevinfernando @kidney_boy @KateIsabelle24 @SantosGallegoMD @aayshacader @VietHeartPA @Lross246 @SeguraCardio @ValleAlfonso @edgarvlermamd @nephondemand @DrRaniKhatib @HanCardiomd @SABOURETCardio @ChristosArgyrop @JavedButler1 @Steph_Achenbach @mvaduganathan #cardiotwitter pic.twitter.com/Kj1Um72Nv3
— cardio-met (@cardiomet_CE) November 1, 2021
2) This series is supported by educational grants from AstraZeneca, Bayer, and Chiesi, and is intended for healthcare professionals. Faculty disclosures are listed at https://t.co/gvXca4G9Xm and earlier programs, still available for credit, are at https://t.co/U6Mo1oSwIh.
— cardio-met (@cardiomet_CE) November 2, 2021
4) … in response to #hyperkalemia or sodium depletion, aldosterone is the culmination of activation of the renin-angiotensin system. It is key to controlling both #bloodpressure and extracellular volume homeostasis by ⬆️ renal sodium reabsorption & ⬆️potassium excretion.
— cardio-met (@cardiomet_CE) November 2, 2021
6) The history of recognizing these diverse impacts is nicely recounted by Epstein in 🔓https://t.co/A4pT69Aq4X. In its “nonepithelial role”, aldosterone in promotes inflammation, collagen formation, fibrosis, and necrosis. Chronically elevated aldosterone, especially …
— cardio-met (@cardiomet_CE) November 2, 2021
8) … might be mediated by MR activity. Similarly, data suggests that blockade of the MR receptor might slow progression of #CKD because its activation by aldosterone promote inflammations and fibrosis and manifests as proteinuria and nephrosclerosis.
— cardio-met (@cardiomet_CE) November 2, 2021
10) … mortality and hospitalization when treating #heartfailure. For example, #HFrEF guidelines from @ACCinTouch updated this year state that “aldosterone antagonists are added in as part of the therapy for patients with symptomatic chronic HFrEF who are already receiving …
— cardio-met (@cardiomet_CE) November 2, 2021
12) And also in 2021, new @escardio #HF guidelines state, “MRAs (spironolactone or eplerenone) are recommended, in addition to an ACE-I &a beta-blocker, in all patients with #HFrEF to reduce mortality and the risk of HF hospitalization. They also improve symptoms.
— cardio-met (@cardiomet_CE) November 2, 2021
14) How does this happen? Again, it’s a steroid effect and it’s off target when one thinks of aldosterone simply ⬆️potassium retention. Spironolactone induces gynecomastia by decreasing testosterone production, by …
— cardio-met (@cardiomet_CE) November 2, 2021
16) And aye, there’s the rub. The problem with steroidal MRAs? Side-effects! Primary? #hyperkalemia Others? #gynecomastia #erectiledysfunction #menstruation irregularities. BTW, “aye there’s the rub” were #Hamlet‘s words when he discovered #uremic #pericarditis. pic.twitter.com/vpJg5FInMs
— cardio-met (@cardiomet_CE) November 2, 2021
18) Return tomorrow and check your answer, then buckle up for more learning. @MedTweetorials @goKDIGO @DLBHATTMD @CMichaelGibson @cpcannon @gcfmd @hvanspall @ShelleyZieroth @renaltubules @DrMarthaGulati @JonathanNefro @edurontoFF pic.twitter.com/aTL1jhKbc9
— cardio-met (@cardiomet_CE) November 2, 2021
20) Yesterday’s poll? All but an effect on cardiac conduction. Per @AgarwalRajivMD (https://t.co/Pv5YFACP6J), the MR has the same binding affinity for aldosterone and cortisol, & mediates fluid, electrolyte, & hemodynamic homeostasis, as well as tissue repair.
— cardio-met (@cardiomet_CE) November 3, 2021
22) These data still carry into contemporary guidelines as cited above. Limitations were ⬆️rates of breast pain & gynecomastia & risk of #hyperkalemia. In fact, a 2004 pharmacoepidemiological study showed . . .
— cardio-met (@cardiomet_CE) November 3, 2021
24) … sodium and importantly potassium, but has fewer progestational and antiandrogenic adverse effects and therefore less painful breast/#gynecomastia risk. The risk of #hyperkalemia however remains a significant limitation of #MRA use and has been shown to limit . . .
— cardio-met (@cardiomet_CE) November 3, 2021
26) But could there be a way to provide a therapeutic MR blockade without the baggage of a steroid? No off-target antiandrogen effects and maybe less hyperkalemia? Enter the #nonsteroidal MRAs! Recently approved 🇺🇸🇪🇺, #finerenone is a novel, selective, nonsteroidal MRA.
— cardio-met (@cardiomet_CE) November 3, 2021
28) Finerenone blocks the MR as a bulky, passive antagonist, is more selective than spironolactone, & is at least as potent. Again per @AgarwalRajivMD, finerenone’s physicochemical properties–lipophilicity & polarity–determine tissue penetration & distribution, allowing …
— cardio-met (@cardiomet_CE) November 3, 2021
30) Other differences include a more balanced kidneys-heart distribution for finerenone, improved #pharmacokinetics that may ⬇️hyperkalemia, and thru various mechanisms finerenone likely offers greater protection from cardiac & renal injury/remodelling & stronger inhibition . . .
— cardio-met (@cardiomet_CE) November 3, 2021
32) Mark your response and return tomorrow for the answer, a wrap-up of this program, and your link to FREE CE/#CME—#physicians #nurses #Pharmacists #PAs #NPs. Nod to @GoggleDocs @CardioNerds @DrRaniKhatib @Drroxmehran @BiykemB @Steph_Achenbach @KateIsabelle24 @HanCardiomd
— cardio-met (@cardiomet_CE) November 3, 2021
34) So yesterday we were talking about finerenone, the prototypical nonsteroidal #MRA. The poll? #Finerenone has a short half-life. It inhibits cardiorenal fibrosis and it isn't a great #antihypertensive. There have been lots of new data coming out in 2021.
— cardio-met (@cardiomet_CE) November 4, 2021
36) Approval was largely on the basis of FIDELIO-DKD which had 1º renal & 2º CV endpoints. It explored the use of finerenone in people with CKD stage 3 or 4 & severely elevated albuminuria & T2D. (Thanks, @GoggleDocs) pic.twitter.com/ThrXIWMQwu
— cardio-met (@cardiomet_CE) November 4, 2021
38) So, who was studied?
— cardio-met (@cardiomet_CE) November 4, 2021
✅7437 participants T2D & CKD
✅ACR 30-300mg/g (microalbuminuria) & eGFR 25-90ml/min (CKD 2-4)
✅ACE 300-5000 (macroalbuminuria) & eGFR at least 60ml/min (CKD stage 1-2), a group not extensively studied in the past
✅ Max tolerated #RAAS inhibitor
40) Individuals like those recruited to FIDELIO-DKD i.e., advanced #CKD were excluded from FIGARO-DKD Additionally, individuals with symptomatic #HFrEF were also excluded as MRAs are a key pillar of HFrEF management with prognostic and symptomatic benefit. pic.twitter.com/NdLwAVOOCA
— cardio-met (@cardiomet_CE) November 4, 2021
42) The 1º composite endpoint was significantly ⬇️by 13% (ARR 1.8%) mainly driven by a 29% RRR in HHF. Other components of 1º endpoint were not significantly reduced. CV benefits were seen in all categories of UACR & eGFR. Benefits were also independent of SGLT2i & GLP1RA use. pic.twitter.com/ClbXx04WzQ
— cardio-met (@cardiomet_CE) November 4, 2021
44) Incidence of #hyperkalemia-related discontinuation was not high, but was ⬆️ with finerenone (1.2%) compared w/placebo (0.4%). This is less than the expected hyperK+ with steroidal MRAs in a similar population.
— cardio-met (@cardiomet_CE) November 4, 2021
46) FIDELIO-DKD was published in https://t.co/fQfRwb3UfE. FIDELITY, a pre-specified meta-analysis of individual pt data from FIDELIO-DKD & FIGARO-DKD, was presented at the virtual #ESCCongress2021. Again cited @AgarwalRajivMD discusses FIDELITY here: https://t.co/Vs1rJtpDa9
— cardio-met (@cardiomet_CE) November 4, 2021
48) Such data clearly suggest that a nonsteroidal #MRA has benefits, especially in patients with CKD/DKD who might benefit from aldosterone inhibition but are at particularly high risk for hyperkalemia. Data on combo finerenone and #SGLT2i are eagerly awaited in such pts.
— cardio-met (@cardiomet_CE) November 4, 2021
49) That's it! You made it! Claim your 0.5h CE/#CME at https://t.co/FUpSqF9ByG now, and then FOLLOW US for more of the ONLY accredited serialized #tweetorials in #cardiometabolic medicine! I am @md_pollack. Also JOIN US at @ckd_ce for more credit focused on–you guessed it–#CKD!
— cardio-met (@cardiomet_CE) November 4, 2021