Ntu 2: Cov Kab Mob Ntshav Qab Zib Thiab Lub raum Pom Zoo Nrog Finerenone hauv Cov Neeg Mob Nrog Hom 2 Ntshav Qab Zib Thiab Kab Mob Raum Ntev: FIDELITY Pooled Analysis
May 26, 2022
Yog xav paub ntxiv. tiv taujtina.xiang@wecistanche.com
Cov txiaj ntsig
Txij lub Cuaj Hlis 2015 txog Lub Kaum Hli 2018, 33 292 cov neeg mob los ntawm 48 lub teb chaws tau raug tshuaj xyuas thiab 13 171 cov neeg mob tau randomized (Cov khoom siv ntxiv hauv online, Daim duab S3). Kev ua txhaum GCP tseem ceeb cuam tshuam nrog lub xaib lossis tus neeg mob ua tsis zoo ua rau muaj kev cuam tshuam yav tom ntej ntawm 145 tus neeg mob (saib cov khoom siv ntxiv hauv online, Cov Ntawv Ntxiv), tawm hauv cov pej xeem ntawm 13026 cov neeg mob uas tau txheeb xyuas cov ntaub ntawv.
Cov yam ntxwv ntawm tus neeg mob, cov tshuaj, thiab cov pej xeem ntawm lub hauv paus tau sib npaug ntawm cov neeg mob randomized rau finerenone thiab placebo (Table2 thiab cov khoom siv ntxiv hauv online, Table S1; luam tawm yav dhau los). . Zuag qhia tag nrho,10.2 feem pua ,41.0 feem pua , thiab 48.3 feem pua ntawm cov neeg mob muaj nruab nrab, siab, thiab siab heevKab mob raumTxhim kho Cov txiaj ntsig thoob ntiaj teb kev pheej hmoo, raws li (cov khoom siv ntxiv hauv online, daim duab S4). Keeb kwm ntawm kab mob plawv tau tshaj tawm hauv 45.6 feem pua ntawm cov neeg mob. Ntshav qabzib (txhais tau tias glycated hemoglobin 7.7 feem pua) thiab ntshav siab (txhais tau tias ntshav siab systolic 136.7 ± 14.2) tau tswj tau zoo. Cov tshuaj hauv plawv plawv suav nrog statins, tshuaj tiv thaiv platelets, thiab diuretics hauv 72.2 feem pua, 56.0 feem pua, thiab 51.5 feem pua ntawm cov neeg mob, raws li, thiab renin-angiotensin system inhibition hauv 99.8 feem pua ntawm cov neeg mob. Glucagon-zoo li peptide{{20}} receptor agonists (GLP-1RAs) thiab sodium-glucose co-transporter-2(SGLT-2) inhibitors tau siv los ntawm 7.2 feem pua thiab 6.7 feem pua ntawm cov neeg mob, feem. Cov tshuaj tau pib tom qab kawm cov tshuaj pib tau sau tseg hauv Cov Khoom Siv Ntxiv hauv online, Table S2. Lub sijhawm nruab nrab ntawm kev soj ntsuam yog 3.0years [interquartile range (IQR) 2.3-3.8 xyoo].
Nyem qhov no kom paub seb cistanche siv rau dab tsi
Qhov sib xyawcardiovascular tshwm sim(lub sij hawm rau cov hlab plawv tuag, tsis tuag M, tsis mob stroke, lossis HHF) tshwm sim hauv 825 (12.7 feem pua) cov neeg mob tau txais finerenone thiab 939 (14.4 feem pua) cov neeg mob tau txais cov placebo (HR, 0.{{9 }};95 feem pua Cl,0.78-0.95;P=0.0018; Daim duab 1 thiab 2). Qhov tshwm sim tsawg dua ntawm HHF tshwm sim nrog finer-tsis muaj vs.placebo(HR,0.78;95 feem pua Cl,0.66-0.92[P=0.0030], Figures2 thiab 3).Cardiovascular tuag thiab Cov xwm txheej uas tsis yog Ml tuag tau taw qhia raws li cov txiaj ntsig ntawm cov hlab plawv; mob stroke tsis tuag zoo ib yam nrog finerenone thiab placebo (Daim duab 2 thiab 3). Raws li qhov sib txawv ntawm pawg neeg muaj kev pheej hmoo sib txawv ntawm 2.2 feem pua tom qab 3 xyoos, 46 (95 feem pua Cl, 29-109) cov neeg mob yuav tsum tau kho nrog finerenone los tiv thaiv ib qho kev tshwm sim ntawm cov hlab plawv. Cov txiaj ntsig zoo ib yam tau pom nyob rau hauv cov pab pawg ua ntej (xws li cov neeg uas muaj SGLT-2 inhibitor lossis GLP-1 RA hauv paus siv; Cov khoom siv ntxiv hauv online, Daim duab S5), thiab ib qho prespecified 'on-treatment rhiab heev tsom xam (nrog rau tag nrho cov xwm txheej los ntawm randomization mus txog 30 hnub tom qab kev noj tshuaj zaum kawg) tau lees paub cov txiaj ntsig ntawm kev tsom xam (cov khoom siv ntxiv hauv online, Table S3). Cov txiaj ntsig rau txhua qhov ntawm cov hlab plawv thiab lub raum kawg los ntawm ib tus neeg sim hauv FIDELITY, suav nrog P kev cuam tshuam qhov tseem ceeb, tau nthuav tawm hauv Cov Khoom Siv Ntxiv hauv online, Daim duab S6.
The incidence of the composite kidney outcome(time to the first onset of kidney failure, sustained>57 feem pua txo qis hauv eGFR los ntawm lub hauv paus-kab dhau Ntau dua lossis sib npaug rau 4 lub lis piam, lossis lub raum tuag) tau qis dua nrog finer-enone vs. placebo (Figures 1 thiab 2), tshwm sim hauv 360(5.5 feem pua ) cov neeg mob tau txais finerenone thiab 465 (7.1 feem pua) cov neeg mob tau txais cov placebo (HR,0.77; 95 feem pua Cl,0.67-0.88; P=0. {32}}002); tus naj npawb xav tau los kho raws li qhov sib txawv ntawm pab pawg muaj kev pheej hmoo sib txawv ntawm 1.7 feem pua ntawm 3 xyoos yog 60 (95 feem pua Cl, 38-142). Kev tshuaj xyuas ntawm cov kev txhawb nqa siab dua lossis sib npaug li 57 feem pua ntawm eGFR cov khoom pov thawj pom tias 30 feem pua kev pheej hmoo txo (HR, 0.70; 95 feem pua Cl, 0.60-0.83;P<0.0001) and="" the="" eskd="" component="" a="" 20%="" risk="" reduction="" with="" finerenone="" vs.placebo(hr,0.80;95%="" cl,0.64-0.99;p="0.040)." the="" prespecified="" 'on-treatment="" sensitivity="" analysis="" confirmed="" the="" results="" of="" the="" primary="" analysis="" (supplementary="" material="" online,="" table="">
Cov txiaj ntsig ntawm lub raum sib xyaw ua ke ntawm lub raum tsis ua haujlwm, txhawb nqa ntau dua lossis sib npaug li 40 feem pua eGFR txo qis, lossislub raum tuagtshwm sim nyob rau hauv 854 (13.1 feem pua) thiab 995 (15.3 feem pua) cov neeg mob tau txais finerenone thiab placebo, feem (HR, 0.85; 95 feem pua Cl,0.{{10} }.93; P=0.0004; Figures1and 2). Cov xwm txheej ntawm txhua qhov ua rau tuag taus (Daim duab 1 thiab 2) thiab pw hauv tsev kho mob rau ib qho laj thawj (Daim duab 2) nrog finerenone tsis txawv ntawm cov placebo (P=0.051 thiab P=0.087, raws li) . Qhov kev hloov pauv hauv UACR los ntawm lub hauv paus mus rau 4 lub hlis yog 32 feem pua qis nrog finerenone vs. placebo (qhov piv txwv ntawm qhov tsawg tshaj plaws-squares txhais tau tias hloov pauv los ntawm cov hauv paus, 0.68; 95 feem pua Cl, 0.66-0.70), cov nyhuv tswj thoob plaws kev sim (Cov khoom siv ntxiv hauv online, daim duab S7A).
Cov xwm txheej zoo sib xws ntawm cov neeg tshawb nrhiav-txhais qhia txog kev kho mob- xwm txheej tsis zoo tshwm sim tau pom ntawm pawg kho mob (Table 3 thiab cov khoom siv ntxiv hauv online, Table S4). Cov xwm txheej tsis zoo tshwm sim hauv 31.6 feem pua ntawm cov neeg mob hauv pawg finerenone thiab 33.7 feem pua ntawm cov neeg mob hauv pawg placebo. Cov xwm txheej tsis zoo rau lub raum, suav nrog mob raum raug mob, tau tshwm sim hauv qhov sib npaug ntawm cov neeg mob ntawm pawg. Hyperkalemia-txog cov xwm txheej tsis zoo tshwm sim ntau zaus nrog finerenone(14.0 feem pua )vs. cov placebo (6.9 feem pua), tab sis tsis muaj cov xwm txheej tsis zoo cuam tshuam txog hyperkalemia tau ua rau tuag taus thiab tsuas yog ib feem me me ua rau kev kho mob mus tas li [1.7 feem pua (qhov tshwm sim 0.66 ib 100}). tus neeg mob-xyoo) thiab 0.6 feem pua (tus nqi tshwm sim 0.22 rau 100 tus neeg mob-xyoo), ntsig txog] lossis tsev kho mob (0 .9 feem pua thiab 0.2 feem pua). Tom qab lub hlis thib plaub ntawm kev kho mob, qhov kev hloov pauv hauv cov ntshav ntawm cov poov tshuaj los ntawm lub hauv paus yog ntxiv rau 0.21mmol / L [tus qauv sib txawv (SD) 0.47mmolL] nrog finerenone thiab ntxiv rau 0.02 mmol L (SD 0.43mmol / L) nrog placebo; Qhov nruab nrab cov poov tshuaj hauv cov ntshav tau ruaj khov nyob rau lub sijhawm tom qab ntawd (Cov khoom siv ntxiv hauv online, daim duab S7B).
Hypokalaemia tshwm sim tsawg zaus nrog finerenone (1.1 feem pua) vs. placebo (2.3 feem pua), thaum gynecomastia zoo sib xws hauv pawg finerenone (0.1 feem pua) thiab cov placebo pawg (0.2 feem pua) . Cov neeg mob tau txais txiaj ntsig zoo-tsis muaj qhov txo qis me me hauv cov ntshav siab systolic piv nrog cov neeg mob tau txais cov placebo [hloov qhov txhais tau tias systolic ntshav siab ntawm 4 hli yog {{10}}.2mmHg (SD 15.0 mmHg) nrog nplua-tsis muaj thiab ntxiv rau 0.5 mmHg (SD 14.6mmHg) nrog cov placebo; Cov khoom siv ntxiv hauv online.
Kev sib tham
Kev txheeb xyuas sib koom ua ke ntawm ob qhov kev sim ua ntxiv suav nrog 13 026 cov neeg mob uas muaj qhov dav dav ntawmCKDthiabmob ntshav qab zib hom 2, txhua yam kho nrog kev kho kom zoo ntawm ACEi lossis ARB, 7.10 muab cov pov thawj muaj zog ntawm ob lub plawv thiab lub raum tiv thaiv nrog finerenone vs. placebo. Raws li cov txiaj ntsig ntawm FIDELIO-DKD sim, finerenone tam sim no tau qhia kom txo qis kev pheej hmoo ntawm eGFR poob qis, ESKD, mob plawv tuag, tsis tuag Ml, thiab HHF hauv cov neeg laus uas muaj CKD cuam tshuam nrog hom 2 mob ntshav qab zib.7·16 Hla. FIDELITY cov pej xeem, qhov kev pheej hmoo txo qis yog 14 feem pua rau cov txiaj ntsig ntawm cov hlab plawv thiab 23 feem pua rau cov txiaj ntsig ntawm lub raum; Cov txiaj ntsig ntawm cov hlab plawv thoob plaws cov pab pawg los ntawm cov pej xeem hauv paus thiab cov yam ntxwv kho mob feem ntau zoo ib yam. Cov txiaj ntsig ntawm no ana-lysis muab kev lees paub txog kev nyab xeeb thiab kev ua tau zoo ntawm finerenone thoob plaws ntau qhov ntawm cov neeg mob CKD thiab hom 2 mob ntshav qab zib mellitus nrog rau qib ntawm qhov tseeb uas yav tas los tsis tuaj yeem tau los ntawm kev txiav txim siab ob qho kev sim sib cais.
MRAs tau qhia rau kev kho mob ntawm cov neeg mob uas mob chronicsymp-automatic lub plawv tsis ua hauj lwm nrog txo ejection fraction18-cov neeg mob no raug tshem tawm los ntawm FIDELIO-DKD thiab FIGARO-DKD cov kev tshawb fawb710-tab sis cov ntaub ntawv txhawb kev siv MRAs los txo cov kev pheej hmoo ntawm lub plawv tsis ua hauj lwm tsim nyob rau hauv Cov neeg mob CKD thiab hom 2 mob ntshav qab zib muaj tsawg. FIDELITY tsom xam muab pov thawj tias kev siv finerenone rau cov neeg mob CKD thiab hom 2 mob ntshav qab zib, cov pej xeem uas muaj kev pheej hmoo siab mob plawv, tiv thaiv HHF. Hauv kev tshuaj xyuas FIDELITY, HHF yog tus tsav tsheb tseem ceeb ntawm cov txiaj ntsig ntawm cov hlab plawv nrog finerenone, nrog rau kev pheej hmoo txo qis ntawm 22 feem pua vs.placebo(P=0.0030), nyob rau hauv cov pej xeem uas tsis suav nrog cov neeg mob uas mob plawv tsis ua hauj lwm. nrog txo qis ejection feem ntawm qhov kev mus ntsib.710Qhov kev tshawb pom no yog qhov tseem ceeb vim tias lub plawv tsis ua haujlwm yog ib qho tseem ceeb ntawm kev mob thiab cov nqi kho mob ntawm cov neeg mob CKD thiab hom 2 mob ntshav qab zib1-21; Yog li ntawd, kev tiv thaiv cov xwm txheej zoo li no tuaj yeem txhim kho cov txiaj ntsig ntawm tus neeg mob thiab tuaj yeem txo cov nqi kho mob. Tsis tas li ntawd, qhov tseeb tias finerenone txo qis HHF kev pheej hmoo thoob plaws CKD spectrum hais txog qhov yuav tsum tau tshuaj xyuas txhua tus neeg mob ntshav qab zib hom 2 rau qhov kev pheej hmoo no.
The FIDELITY analysis shows not only a 30% reduction in the risk of a sustained ≥57% decrease in eGFR on top of optimized ACEi or ARB therapy but also a relative risk reduction of 20% in ESKD with finerenone vs. placebo (P=0.0403). The relative risks of all components of the kidney composite outcome were reduced with finer-none vs. placebo, except for time to renal death (this finding was likely due to low event numbers, although the HR of 0.53 still favoured finerenone over placebo). The relative risk of a sustained>57% de-crease hauv eGFR raug txo los ntawm 30 feem pua, ESKD los ntawm 20 feem pua, sustained de-crease hauv eGFR rau<15mlmin .73="" m²by="" 19%,="" and="" kidney="" failure="" by="" 16%.="" the="" requirement="" for="" dialysis="" is="" one="" of="" the="" most="" dreaded="" complications="" of="" ckd="" progression2;="" it="" is="" associated="" with="" substantial="" morbidity="" and="" costs.23="" reduction="" of="" this="" outcome,="" which="" is="" of="" great="" relevance="" to="" both="" patients="" and="" payers,="" is="" therefore="">
Kev sim ua ntej ntawm dual renin-angiotensin system blockade tau ua tsis tiav los qhia cov hlab plawv lossis lub raum kev tiv thaiv ntawm cov neeg mob CKD thiab type2diabetes, qhia tias yuav ua li cas renin-angiotensin-aldosterone system raug thaiv qhov tseem ceeb.42 FIDELITYanalysis qhia txog qhov muaj zog ntawm MR overactivation hauv pathogenesis. ntawm ob qho tib si kab mob plawv thiab CKD kev loj hlob hauv cov neeg mob CKD thiab hom 2 mob ntshav qab zib.
Cov kev tshawb fawb yav dhau los ntsuas SGLT-2 inhibitors hauv cov neeg mob CKD thiab hom 2 mob ntshav qab zib, xws li CREDENCE lossis DAPA-CKD, suav nrog cov neeg mob sawv cev ib feem me me ntawm CKD spectrum dua li FIDELITYanalysis.27 Vim tias qhov kev sim sib txawv ntawm cov pejxeem , tsim, thiab lwm yam uas tau piav qhia yav dhau los, lawv cov txiaj ntsig tsis tuaj yeem ncaj qha piv nrog FIDELITY tsom xam.1In FIDELITY, 877 tus neeg mob (6.7 feem pua) tau txais SGLT-2 inhibitors thiab 944 tus neeg mob (7.2 feem pua) tau txais GLP{{12} }RAs ntawm lub hauv paus, thiab cov txiaj ntsig ntawm lub plawv thiab lub raum ntawm finerenone tsawg kawg yog loj npaum li cov neeg mob ntawm SGLT-2 inhibitors lossis GLP-1RAs xws li cov tsis muaj cov ntaub ntawv Preclinical ntawm thawj zaug ua ke ntawm finerenone thiab empagliflozin nyob rau hauv tus qauv nas ntawm kev kub siab-vim qhov kawg ntawm lub cev puas tsuaj kuj pom tau hais tias kev sib xyaw ua ke tau txais kev tiv thaiv kev tiv thaiv thoob plaws ntau yam kev mob plawv.28Nws muaj peev xwm hais tias muaj cov nyhuv ntxiv ntawm kev sib xyaw ua ke ntawm f inerenone nyob rau sab saum toj ntawm SGLT{18}} inhibitors lossis GLP{19}}RAs, uas yuav cuam tshuam rau lawv cov txheej txheem ntawm kev ua haujlwm. Txawm li cas los xij, qhov no tsis yog qhov kev sim sim ntawm finerenone thiab SGLT-2 inhibitor lossis GLP-1RA kev sib xyaw ua ke, thiab kev ua tau zoo thiab kev nyab xeeb ntawm cov neeg ua haujlwm sib xyaw ua ke yuav raug txiav txim siab hauv kev sim tshuaj thiab tshuaj ntsuam yav tom ntej.
Raws li nws cov txheej txheem ntawm kev ua, kev kho mob finerenone yuav tsum ua kom cov ntshav cov ntshav ntau ntxiv los ntawm MR antagonism. Hauv FIDELITY, hyperkalemia tau nquag nrog finerenone vs. placebo. Txawm li cas los xij, qhov tshwm sim ntawm hyperkalemia-txog cov xwm txheej tsis zoo uas cuam tshuam nrog kev kho mob tsawg, nrog hyperkalemia cuam tshuam txog kev kho mob mus tas li tsuas yog 1.7 feem pua ntawm cov neeg mob tau txais finerenone vs.0.6 feem pua ntawm cov placebo tshaj qhov nruab nrab ntawm kev soj ntsuam ntawm 3. 0xyoo (IQR 2.3-3.8years). Hypokalaemia tshwm sim tsawg zaus hauv cov neeg mob kho finerenone ntau dua li cov neeg mob uas tau txais cov placebo.
Potassium intake was not restricted during the trials, but finerenone or placebo was withheld in cases where potassium concentrations >5.5 mmol / L tau kuaj pom kom txog thaum cov poov tshuaj concentration poob rau<5.0mmov .="" therefore,="" finerenone="" improves="" cardiorenal="" outcomes="" in="" patients="" with="" ckd="" and="" type="" 2="" diabetes="" with="" a="" manageable="" hyperkalaemia="" risk="" and="" a="" reduction="" in="" hypokalaemia.="" hypokalaemia="" reduction="" is="" notable="" because="" it="" is="" causatively="" associated="" with="" adverse="" outcomes="" in="" heart="">
Txawm hais tias qhov kev tshuaj ntsuam xyuas ua ntej ntawm ob txoj kev tshawb fawb nrog cov kev cai zoo sib xws suav nrog cov neeg mob loj nrog CKD thiab hom 2 mob ntshav qab zib, kev txwv yog tias nws tsis suav nrog cov neeg mob uas tsis yog-albuminuric CKD thiab tsuas yog ib feem me me ntawm cov neeg mob Dub tau suav nrog. Txij li thaum tsim los ntawm FIGARO-DKD thiab FIDELIO-DKD cov kev tshawb fawb, SGLT-2 inhibitors tau tshwm sim los ua cov kev xaiv kho mob rau cov neeg mob uas muaj CKD thiab hom 2 mob ntshav qab zib.30Qee cov neeg mob nyob rau hauv lub finer-tsis muaj ib theem kuv rials kuj tau txais cov tshiab cov neeg sawv cev ntawm kev kawm pib, thiab cov txiaj ntsig ntawm cov hlab plawv zoo ib yam tau pom nyob hauv cov pab pawg no.
Hauv kev xaus, finerenone txo qhov kev pheej hmoo ntawm kev soj ntsuam tseem ceeb ntawm cov hlab plawv thiab lub raum cov txiaj ntsig vs. placebo thoob plaws spectrum ntawm CKD hauv cov neeg mob ntshav qab zib hom 2. Cov txiaj ntsig tau qhia txog qhov tseem ceeb ntawm kev kho mob ntxov ua ntej CKD tau nce qib los txhim kho cov txiaj ntsig hauv cov neeg mob no.
