Ntu 1: Cov Kab Mob plawv thiab raum Pom Zoo Nrog Finerenone hauv Cov Neeg Mob Nrog Hom 2 Ntshav Qab Zib Thiab Kab Mob Raum Ntev: FIDELITY Pooled Analysis

Yog xav paub ntxiv. tiv taujtina.xiang@wecistanche.com

Hom phiaj

Cov kev tshawb fawb ntxiv FIDELIO-DKD thiab FIGARO-DKD hauv cov neeg mob uas muaj ntshav qab zib hom 2 thiab mob raum mob (CKD) tau tshuaj xyuas cov txiaj ntsig ntawm cov hlab plawv thiab lub raum hauv qhov sib txawv, sib tshooj ntawm CKD. Lub hom phiaj ntawm FIDELITY tsom xam yog los ua tus neeg mob-theem prespecified pooled efficiency thiab kev nyab xeeb tsom xam nyob rau hauv ib tug dav spectrum ntawm CKD los muab ntau zog kwv yees ntawm kev nyab xeeb thiab kev ua tau zoo ntawm finerenone piv nrog cov placebo.

Cov txheej txheem thiab cov txiaj ntsig

For this prespecified analysis, two-phase, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained >57% decrease in estimated glomerular filtration rate from baseline over >4 lis. los yog lub raum tuag. Ntawm 13 026 cov neeg mob uas muaj qhov nruab nrab rov qab los ntawm 3.0 xyoo (interquartile range 2.3-3.8 xyoo), cov txiaj ntsig ntawm cov hlab plawv tau tshwm sim hauv 825 (12.7 feem pua) cov neeg mob tau txais finerenone thiab 939 (14.4 feem pua ​​) tau txais placebo Hazard ratio(HR), 0.86: 95 feem pua ​​​​kev ntseeg siab lub sij hawm (C), 0.78-0.95: P {{2{28}}}}{31}018]. Cov txiaj ntsig ntawm lub raum sib xyaw tau tshwm sim hauv 360 (5.5 feem pua) cov neeg mob tau txais finerenone thiab 465 (7.1 feem pua) tau txais cov placebo (HR, 0.77; 95 feem pua ​​​​Cl, 0.67-0.88;P=0.0002) . Tag nrho cov txiaj ntsig kev nyab xeeb feem ntau zoo ib yam ntawm kev kho caj npab. Hyperkalemia ua rau kev txiav tawm mus tas li tau tshwm sim ntau zaus hauv cov neeg mob tau txais finerenone (1.7 feem pua) dua li cov placebo (0.6 feem pua).

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.

Lo lus tseem ceeb

Puas yog finerenone, ib qho kev xaiv tshiab, uas tsis yog steroidal mineralocorticoid receptor antagonist, ntxiv rau qhov siab tshaj plaws tiv thaiv renin-angiotensin system inhibition txo cov kab mob plawv thiab kab mob raum mus rau ntau yam kab mob raum ntev hauv cov neeg mob ntshav qab zib hom 2?

Nrhiav qhov tseem ceeb

In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of>60 mLmin / 1.73m lawv tau txheeb xyuas los ntawm albuminuria.

Take-Home Message

Finerenone txo qhov kev pheej hmoo ntawm kev kho mob plawv thiab mob raum mus rau ntau yam ntawm cov neeg mob uas mob raum thiab mob ntshav qab zib hom 2. Kev tshuaj ntsuam xyuas albuminuria txhawm rau txheeb xyuas cov neeg mob pheej hmoo ntawm cov neeg mob ntshav qab zib hom 2 pab txhawb kev txo qis ntawm cov kab mob plawv thiab lub raum.

Ntsiab lus

Cardiorenal outcomes · Mob raum mob · Finerenone · Mus pw kho mob rau lub plawv tsis ua hauj lwm ●Hyperkalemia · Hom 2 mob ntshav qab zib

Nyem qhov no kom paub txog cistanche tubulosa extract cov txiaj ntsig

Taw qhia

Cov neeg mob nrogmob raum mob(CKD) thiabmob ntshav qab zib hom 2muaj siab residualcardiorenalmorbidity thiab tuag, txawm tias tam sim no cov kev kho mob, thiab cov kev pheej hmoo ntawm kev loj hlob ntawm lub raum tsis ua hauj lwm thiab cov hlab plawv cov xwm txheej nce nrog rau qhov hnyav thiab theem ntawm CKD. Piv nrog rau cov neeg mob uas muaj kab mob hauv lub raum, uas muaj feem yuav ua rau kev lim ntshav ntau dua, cov neeg mob uas muaj kev tiv thaiv zoo dua qhov ntsuas glomerular filtration rate (eGFR) muaj kev pheej hmoo ntau dua ntawm kev mob plawv xws li plawv tsis ua hauj lwm, myocardial infarction (M), stroke, lossis tuag los ntawm kev mob plawv.

Cov pov thawj qhia tias overactivation ntawm mineralocorticoid receptor (MR) ua raumobthiab fibrosis nyob rau hauv lub plawv, ob lub raum, thiab vasculature qhov twg MR yog nthuav qhia uas yuav tsav CKD thiabkab mob plawvkev vam meej. Finerenone yog ib qho tshiab, xaiv, nonsteroidal MR antagonist (MRA) uas thaiv MR-mediated sodium reabsorption thiab MR overactivation thiab tau pom tias muaj kev cuam tshuam los tiv thaiv thiab tiv thaiv fibrotic hauv lub raum preclinical thiab kab mob plawv.89 Lub FInerenone hauv kev txo qis kiDnEy tsis ua haujlwm. thiab kab mob prOgression nyob rau hauv Diabetic raum Kab Mob (FIDELIO-DKD) thiab FInerenone nyob rau hauv reducinG cArdiovascular moRtality thiab mOrbidity nyob rau hauv Diabetic raum Kab Mob (FIGARO-DKD) theem ll trials yog complementary vim cov yam ntxwv xws li lawv zoo sib xws designs thiab endpoints. Ua ke, lawv tsim qhov kev pab cuam cardiorenal loj tshaj plaws hauv CKD hauv hom 2 mob ntshav qab zib rau hnub tim. Lawv tau tshawb xyuas qhov ua tau zoo thiab kev nyab xeeb ntawm finerenone, nyob rau sab saum toj ntawm qhov siab tshaj plaws renin-angiotensin system inhibition, ntawm cov menyuam yaus thiab cov hlab plawv cov txiaj ntsig hauv cov neeg mob uas mob me-rau- mob CKD hauv hom 2 mob ntshav qab zib (Cov khoom siv ntxiv hauv online, Daim duab S1). Hauv FIDELIO-DKD, finerenone txo qis qhov kev pheej hmoo ntawm thawj lub raum sib xyaw cov txiaj ntsig thiab cov txiaj ntsig tseem ceeb thib ob ntawm cov hlab plawv hauv cov neeg mob uas feem ntau theem 3-4 CKD nrog mob hnyav ntxiv albuminuria thiab ntshav qab zib hom 2. Hauv FIGARO-DKD, finerenone txo qis qhov tshwm sim ntawm cov kab mob plawv hauv cov neeg mob thoob plaws ntau dua li tau kawm hauv FIDELIO-DKD (cov neeg mob uas muaj theem 2-4 CKD thiab qis qis dua albuminuria los yog theem 1-2 CKD nrog hnyav nce. albuminuria), 710

Qhov kev sim FIDELIO-DKD tau tsim los txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txiav Cov txiaj ntsig tsis ua haujlwm, cov neeg mob uas muaj cov zis ntau dua albumin-to-creatinine piv (UACR) tau raug xaiv los ntawm FIDELIO-DKD sim. Txhawm rau muab lub raum tsis ua haujlwm ntau dua-dawb lub sijhawm txhawm rau txheeb xyuas qhov kev kho mob ntawm cov kab mob plawv, hauv FIGARO-DKD, cov pejxeem uas muaj UACR nruab nrab thiab ntau dua eGFR tau xaiv. Yog li, ob qhov kev sim ua tiav ib leeg nrog me ntsis sib tshooj hauv cov neeg kawm, thiab lawv cov qauv zoo sib xws thiab cov chaw tshawb fawb sib tshooj tso cai rau kev sib piv thiab sib sau ua ke ntawm lawv cov txiaj ntsig.

Kev ua tau zoo thiab kev nyab xeeb ntawm finerenone, txawm li cas los xij, tsis tau soj ntsuam tag nrho thoob plaws spectrum ntawm CKD hauv hom 2 mob ntshav qab zib. Fnerenone nyob rau hauv mob raum mob thiab mob ntshav qab zib hom 2: Ua ke FIDELIO-DKD thiab FIGARO-DKD Kev sim tshuaj ntsuam xyuasYsis (FIDELITY) suav nrog cov kev tshawb fawb ntxiv nrog cov qauv zoo sib xws, kev ntsuam xyuas, thiab kev coj ua. FIDELITY prespecified pooled tsom xam los muab kev kwv yees muaj zog ntau dua ntawm finerenone kev ua tau zoo thiab kev nyab xeeb thoob plaws spectrum ntawm cov neeg mob CKD thiab hom 2 mob ntshav qab zib, los muab kev lees paub txog qhov tshwm sim hauv ntau tus neeg mob nrog rau qib ntawm qhov tseeb uas tsis tuaj yeem tau txais. los ntawm kev txiav txim siab ob qho kev sim sib cais.

Cov txheej txheem

Kawm tsim qauv

Qhov no prespecified pooled efficiency thiab kev nyab xeeb tsom xam, uas yog prespecified nyob rau hauv ib tug formal statistical tsom xam txoj kev npaj, combines cov ntaub ntawv los ntawm FIDELIO-DKD (NCT02540993) thiab FIGARO-DKD (NCTO2545049), ob-theem III, randomized, ob-dig muag, placebo Kev sim ntau qhov chaw kho mob (Table 1 thiab cov khoom siv ntxiv hauv online, daim duab S2). Kev sim tsim thiab kev kawm raws tu qauv tau tshaj tawm yav dhau los.11 Cov neeg mob

Cov neeg mob tsim nyog yog cov neeg laus (hnub nyoog siab dua lossis sib npaug li 18 xyoo) nrog hom 2 mob ntshav qab zib thiab CKD kho nrog qhov siab tshaj plaws uas tau sau npe koob tshuaj ntawm angiotensin-hloov enzyme inhibitor (ACEi) lossis angiotensin receptor blocker (ARB).

Mob raum mob hauv FIDELIO-DKD

CKD hauv FIDELIO-DKD tau txhais tias yog: (i) tsis tu ncua (tso tawm ntawm ob qhov kev mus ntsib thiab tshuaj ntsuam xyuas, uas tau tshwm sim ntawm qhov tsawg kawg ntawm 4 mus rau qhov siab tshaj plaws ntawm 16 lub lis piam sib nrug), nce qib albuminuria (UACR Ntau dua. los yog sib npaug rau 30-<300mg )="" with="" an="" egfr="" of=""><60ml in/1.73="" m²="" and="" the="" presence="" of="" diabetic="" retinopathy,="" or（i）="" persistent,="" severely="" increased=""><5000mg )and="" an="" egfr="" of=""><75ml in/1.73="">

Mob raum mob hauv FIGARO-DKD

CKD in FIGARO-DKD was defined as either:(i) persistent, moderately increased albuminuria (UACR >30-<300mg )="" with="" an="" egfr="" of=""><90ml in/1.73="" m²,="" or="" （i）="" persistent,="" severely="" increased="" albuminuria="" （uacr=""><5000mg ）and="" an="" egfr="" ≥60ml/min/1.73="" m².="" patients="" in="" both="" trials="" had="" to="" have="" serum="" potassium≤4.8mmol/l="" at="" both="" the="" run-in="" and="" screening="" visits.="" other="" key="" exclusion="" criteria="" included="" a="" clinical="" diagnosis="" of="" symptomatic="" chronic="" heart="" failure="" with="" reduced="" ejection="" fraction="" (ie.,="" a="" class="" ia="" recommendation="" for="" mra="" treatment).="" inclusion="" and="" exclusion="" criteria="" are="" listed="" in="" the="" supplementary="" material="" online,="">

Cov txheej txheem

Cov txheej txheem rau kev tshawb fawb FIDELIO-DKD thiab FIGARO-DKD tau piav qhia yav dhau los. Luv luv, cov neeg mob tsim nyog tau txais kev pom zoo 1: 1 kom tau txais qhov ncauj finerenone (10 lossis 20mg) lossis cov placebo. Ob qho kev tshawb fawb muaj xws li khiav-hauv, tshuaj ntsuam xyuas, kho ob qhov muag tsis pom kev, thiab lub sijhawm taug qab kev nyab xeeb (Cov khoom siv ntxiv hauv online, Daim duab S2).10 Lub sijhawm khiav-hauv yuav tsum tau kho ACEi lossis ARB kev kho kom raug kho kom haum rau qhov siab tshaj plaws uas tau sau npe koob tshuaj. uas tsis tau ua rau cov kev mob tshwm sim tsis txaus ntseeg. Kev tshawb fawb tshuaj raug txwv yog tias cov poov tshuaj ntau dua 5.5 mmol / L thiab rov pib dua thaum cov qib poov tshuaj poob mus rau<5.0mmol .="" further="" details="" are="" found="" in="" the="" supplementary="" material="" online,="">

Cov txiaj ntsig

The outcome definitions for FIDELIO-DKD and FIGARO-DKD have been described previously.10 The efficacy outcomes selected for this analysis were either a primary or a secondary outcome or those prespecified in the hierarchical outcomes in the complementary studies. The eff-cacy outcomes of interest for this pooled analysis were a composite cardiovascular outcome of time to cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure(HHF), and a composite kidney outcome of time to the first onset of kidney failure, sustained >57 feem pua ​​​​txo qis hauv eGFR los ntawm cov hauv paus hauv qab ntau dua lossis sib npaug rau 4 lub lis piam, lossis lub raum tuag. Hauv

Cov txiaj ntsig ntawm lub raum sib xyaw, lub raum tsis ua haujlwm tau txhais tau tias yog kab mob raum kawg (ESKD) lossis kev txo qis hauv eGFR mus rau<15 ml/min/1.73="" m2,="" and="" eskd="" was="" defined="" as="" the="" initiation="" of="" chronic="" dialysis(for="">90days) or kidney transplantation. Other prespecified outcomes included: a second composite kidney outcome of time to the first occurrence of kidney failure, sustained >40% decrease in eGFR from baseline over >4 lub lis piam, lossis raum tuag; lub sij hawm rau tag nrho-ua rau tuag; sij hawm mus pw hauv tsev kho mob tag nrho; thiab hloov hauv UACR los ntawm lub hauv paus mus rau Lub Hlis 4.

The eGFR ≥40% composite kidney outcome was the primary or secondary outcome in the complimentary trials.10 However, a sustained >57% decrease in eGFR(equivalent to doubling of serum creatinine)was selected in FIDELITY because it is a classic outcome in diabetic nephropathy studies.12-14and is a more robust kidney failure surrogate outcome than a ≥40% decrease in eGFR, particularly when initial changes in eGFR occur.415 This outcome was selected before data pooling and analysis. Furthermore, the eGFR>57 feem pua ​​​​ntawm cov txiaj ntsig yog qhov tshwm sim ua ntej hauv qhov kev sim pub dawb.

Hauv kev tshuaj ntsuam xyuas kev nyab xeeb, cov xwm txheej tsis zoo raug suav hais tias yog kev kho mob-ceem mob yog tias lawv pib lossis mob hnyav dua thaum kawm txog kev noj tshuaj lossis txog li 3 hnub tom qab muaj kev cuam tshuam ib ntus lossis mus tas li. Txoj kev tswj hwm hyperkalemia tau piav qhia yav dhau los.

Kev txheeb cais

Kev txheeb xyuas kev txheeb xyuas tau raug txheeb xyuas qhov kev tshuaj ntsuam xyuas es tsis yog qhov kev xav pom tseeb. Kev ntsuam xyuas txheeb cais qhov twg P-tus nqi muab yog kev tshawb nrhiav; yog li ntawd, tsis muaj kev hloov kho rau ntau qhov ntau tau ua.

Cov kev soj ntsuam tag nrho suav nrog tag nrho cov neeg mob randomized [tshwj tsis yog cov uas muaj qhov tseem ceeb ntawm Kev Ua Haujlwm Zoo Zoo (GCP) kev ua txhaum cai, uas yog qhov kev cia siab heev-tsis suav nrog txhua qhov kev ntsuam xyuas]. Kev soj ntsuam kev nyab xeeb tau ua nyob rau hauv kev tsom xam kev nyab xeeb, txhais tau tias yog txhua tus neeg mob randomized yam tsis muaj kev ua txhaum GCP tseem ceeb uas tau siv ntau dua lossis sib npaug rau 1 koob tshuaj ntawm kev tshawb fawb tshuaj. Cov txiaj ntsig ntawm kev tshawb fawb tau txheeb xyuas los ntawm cov qauv Cox cov qauv kev phom sij uas haum rau kev siv stratification yam: kev kawm, cheeb tsam (North America, Latin America, Europe, Asia, thiab lwm yam), eGFR qeb ntawm kev tshuaj ntsuam (25-<><60, and="" ≥60mlmin/1.73="" m),="" albuminuria="" category="" (moderately="" increased="" and="" severely="" increased)="" at="" screening,="" and="" a="" history="" of="" cardiovascular="" dis-ease="" (present="" or="" absent;="" see="" supplementary="" material="" online,="" appendix,="" for="" further="" details).p-values="" for="" the="" comparison="" of="" treatment="" groups="" are="" presented="" based="" on="" a="" stratified="" log-rank="" test="" treatment="" effects="" are="" expressed="" as="" hazard="" ratios(hrs)="" with="" corresponding="" 95%="" confidence="" intervals(cls)="" from="" the="" stratified="" cox="" proportional="" hazards="" models.="" events="" were="" counted="" from="" randomization="" up="" to="" the="" end-of-study="" visit="" and="" patients="" without="" an="" event="" were="" censored="" at="" the="" date="" of="" their="" last="" contact="" with="" complete="" information="" on="" all="" components="" of="" the="" respective="" outcome.="" the="" time-to-event="" analysis="" reporting="" included="" first="" events="" only.="" events="" based="" on="" a="" sustained="" decrease="" in="" egfr="" were="" considered="" in="" the="" analysis="" from="" randomization="" up="" until="" 5="" months="" after="" the="" last="" egfr="" was="" recorded="" at="" a="" clinic="" visit.="" for="" subgroup="" analyses,="" hrs="" were="" derived="" from="" stratified="" cox="" proportional="" hazards="" models,="" including="" a="" treatment="" sub-group="" and="" a="" subgroup="" by="" treatment="" interaction="" term="" as="" fixed="">

Cov xwm txheej sib sau ua ke raws li Aalen-Johansen suav txog kev tuag rau kev tuag raws li kev pheej hmoo sib tw thiab cov lej sib txuas uas xav tau los kho tau suav nrog hauv 6- lub hlis ib hlis rau cov txiaj ntsig ntawm cov hlab plawv thiab cov txiaj ntsig tseem ceeb hauv lub raum. Cov xwm txheej sib sau ua ke raws li Kaplan-Meier tau suav rau txhua qhov ua rau tuag. Kev tshuaj xyuas txog kev kho mob rhiab heev tau ua rau cov txiaj ntsig tau txiav txim siab tsuas yog cov xwm txheej tshwm sim txog 30 hnub tom qab kawm txog kev txiav tshuaj yeeb hauv tag nrho cov kev tshuaj ntsuam xyuas.

Tus neeg txhawb nqa, Bayer, tau ua qhov kev txheeb xyuas kev txheeb xyuas, thiab txhua tus kws sau ntawv tau nkag mus rau cov ntaub ntawv thiab koom nrog nws txhais lus. Txhua qhov kev ntsuam xyuas tau ua tiav siv SAS software, version 9.4 (SAS Institute, Cary, NC, USA). Cov txheej txheem txheeb cais ntxiv muaj nyob hauv Cov Khoom Siv Ntxiv hauv online, Cov Ntawv Ntxiv.