Kev Koom Tes Ntawm Kev Circulating GDF-15 Thiab Cardio-Lub Raum Cov Ntsiab Lus Thiab Cov nyhuv ntawm Canagliflozin: Cov txiaj ntsig los ntawm CANVAS Kev sim
Mar 03, 2022
Kev soj ntsuam ntawm CANVAS (Canagliflozin Cardiovascular Assessment Study) tau tshawb pom tias sodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozin txo qhov kev pheej hmoo ntawm kev mus pw hauv tsev kho mob rau lub plawv tsis ua hauj lwm (HF) thiab ua rau qeeb ntawm kev loj hlob.lub raum ua haujlwmKev poob qis hauv cov neeg mob uas muaj hom 2 mob ntshav qab zib mellitus ntawm kev pheej hmoo siab plawv.1 Lub hauv paus txheej txheem rau cov teebmeem no tsis to taub tag nrho. Muaj ntau lub tswv yim xav tias yuav tsum tau koom nrog, suav nrog kev rov kho dua ntawm tubuloglomerular tawm tswv yim, txo cov ntshav siab, thiab txhim kho cov hlab ntsha ua rau txo qis tom qab, nrog rau kev txo qis hauv plawv thiabraummob thiab fibrosis.2–7
CISTANCHE yuav txhim kho lub raum / raum tsis ua haujlwm
Kev loj hlob sib txawv -15 (GDF-15) yog ib qho kev ntxhov siab vim cytokine tso tawm nyob rau hauv teb rau kev raug mob los yog oxidative kev nyuaj siab nyob rau hauv ntau yam kabmob thiab yog ib tug tswv cuab ntawm lub transforming loj hlob factor- superfamily.8 GDF{{5 }} tso tawm nyob rau hauv cardiomyocytes thiab cov hlwb ntawm cov ducts.8,9 siab dua GDF-15 qib nyob rau hauv lub systemic circulations raug pom nyob rau hauv cov neeg mob uas muaj hom 2 mob ntshav qab zib, mob ntev.kab mob raum,thiab HF lossis lwm yam kab mob plawv.8,10–14 Cov kev tshawb fawb soj ntsuam kuj tau pom tias GDF nce siab -15 cuam tshuam nrog kev pheej hmoo siab ntawm kev tsim HF thiabraum tsis ua haujlwmHauv cov neeg mob ntshav qab zib hom 2 uas muaj lossis tsis muaj mob ntevmob raum.8,15,16 Ib txoj kev tshawb fawb Mendelian randomization qhia tias GDF-15 tej zaum yuav ua rau muaj kev cuam tshuam rau cov kab mob plawv.17 Tsis tas li ntawd, hauv hom 2 mob ntshav qab zib GDF-15 cov nas khob, SGLT2 qhia hauv Cov tubule proximal raug txo qis, qhia txog kev sib cuam tshuam ntawm SGLT2 thiab GDF-15.18 Hauv qhov kev tshuaj ntsuam xyuas no ntawm CANVAS, peb thawj zaug ntsuas seb cov ntshav plasma GDF-15 qib puas cuam tshuam nrog thawj cov hlab plawv, HF , thiabraumqhov tshwm sim. Qhov thib ob, peb tau tshawb xyuas cov txiaj ntsig ntawm kev kho canagliflozin ntawm GDF-15 qib thiab seb lub hauv paus ntshav plasma GDF-15 lossis kev hloov pauv thaum ntxov hauv GDF-15 tau kho qhov pom muaj txiaj ntsig zoo ntawm canagliflozin ntawm cov hlab plawv, HF, thiabraumqhov tshwm sim.
lo lus tseem ceeb:canagliflozin; GDF-15; cov txiaj ntsig ntawm lub raum thiab cov hlab plawv; SGLT2 inhibitor; lub raum ua haujlwm;
Txoj kev
Tus Neeg Mob thiab Kawm TsimRau qhov kev tshuaj ntsuam xyuas no, peb tau siv cov qauv plasma khaws cia thaum lub sijhawm CANVAS sim. Cov qauv tsim, cov txiaj ntsig, thiab cov txiaj ntsig ntawm qhov kev sim no tau tshaj tawm yav dhau los.1 Hauv luv luv, CANVAS sim yog ib qho randomized, placebo-tswj, ob-dig muag, multicenter txoj kev tshawb fawb uas soj ntsuam cov txiaj ntsig ntawm canagliflozin ntawm cov hlab plawv,lub raum,Kev nyab xeeb, thiab kev ua tau zoo ntawm cov neeg mob ntshav qab zib hom 2 uas muaj keeb kwm ntawm cov kab mob plawv lossis ntau yam kab mob plawv. Thaum lub sijhawm sim, kuaj ntshav thiab zis tau muab khaws cia rau kev tshawb nrhiav biomarker. Cov neeg koom nrog tsim nyog suav nrog tau muab tso rau hauv qhov piv ntawm 1: 1: 1 rau kev kho mob nrog 100 mg canagliflozin, 300 mg canagliflozin, lossis placebo. Nyob rau hauv tag nrho, 4330 tus neeg koom los ntawm 24 lub teb chaws uas muaj ntshav qab zib hom 2 tau cuv npe. Qhov kev sim no tau ua raws li cov hauv paus ntsiab lus ntawm Kev Tshaj Tawm ntawm Helsinki thiab tau pom zoo los ntawm cov cai tswj hwm tsim nyog thiab pawg tswj hwm kev coj ncaj ncees. Txhua tus neeg koom nrog tau sau ntawv tso cai. Qhov kev sim no tau sau npe nrog ClinicalTr ials.gov (tus ID NCT01032629).
Eligible participants had type 2 diabetes with a hemoglobin A1c level of ≥58 mmol/mol (7.0%) and ≤91 mmol/mol (10.5%) and were either ≥30 years of age with a history of symptomatic atherosclerotic cardiovascular disease or ≥50 years of age with ≥2 risk factors for cardiovascular disease. Risk factors for cardiovascular disease were defined as a duration of diabetes of ≥10 years, systolic blood pressure >140 mm Hg receiving >1 antihypertensive agent, tam sim no haus luam yeeb, micro- los yog macroalbuminuria, los yog high-density lipoprotein cholesterol theem.<1 mmol .="" at="" inclusion,="" participants="" also="" needed="" to="" have="" an="" estimated="" glomerular="" filtration="" rate="" (egfr)="" of="">30 mL / min rau 1.73 m² thiab ua tau raws li lwm yam kev suav nrog.
Kev ntsuam xyuas BiomarkerKhaws cov ntshav plasma cov qauv tau txais thaum lub sij hawm CANVAS sim ntawm lub hauv paus thiab lub lis piam 52, 156, thiab 312, tau siv los ntsuas GDF-15 siv Eecsys GDF-15 electrochemiluminescence immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Tag nrho GDF-15 kev ntsuas tau tshwm sim thaum Lub Ob Hlis 27, 2019 thiab Lub Yim Hli 8, 2019. Tag nrho ntawm 405 tus qauv raug ntsuas sib npaug los ntsuas qhov ntsuas qhov sib txawv. Lub coefficient ntawm variation ntawm duplicates no yog<8.2%. we="" also="" assessed="" day-to-day="" laboratory="" variability="" in="" the="" gdf-15="" measurements="" by="" analyzing="" samples="" with="" predefined="" gdf-="" 15="" concentrations="" at="" multiple="" time="" points,="" together="" with="" the="" canvas="" trial="" samples.="" the="" coefficient="" of="" variation="" of="" these="" duplicate="" control="" measurements="" was=""><>
Cov txiaj ntsigCov txiaj ntsig ntawm cov hlab plawv tau txhais tau tias yog qhov sib xyaw ntawm cov uas tsis yog-faus myocardial infarction, tsis mob stroke lossis tuag vim yog mob plawv. Qhov txiaj ntsig ntawm HF tau txhais tias yog kev mus pw hauv tsev kho mob rau HF, suav nrog cov ncauj lus nrog HF ntawm qhov pib. Qhov sib xyawraumCov txiaj ntsig tau txhais tau tias yog qhov txo qis ntawm 40 feem pua ntawm eGFR, theem kawgmob raum(txhais tias yog eGFR<15 ml in="" per="" 1.73 m²="" or="" need="" for="" dialysis="">hloov raum) lublub raumkev tuag. Cov ntsiab lus kawg no tau raug txiav txim los ntawm pawg neeg txiav txim siab ywj pheej uas siv cov lus txhais ua ntej thiab nruj kawg nkaus.
CISTANCHE yuav txhim kho lub raum / raum kab mob
Kev txheeb caisCov kev hloov pauv tsis tu ncua nrog cov kev faib tawm ib txwm raug tshaj tawm raws li txhais tau tias nrog SDs. Lub hauv paus hloov pauv nrog skewed distributions tau tshaj tawm raws li qhov nruab nrab nrog qhov sib txawv. Qhov sib txawv nrog skewed distributions yog ntuj logarithmic hloov ua ntej kev soj ntsuam. Cov kev hloov pauv hauv categorical xaj tau tshaj tawm raws li feem pua. Kev phom sij txaus ntshai ib ob npaug hauv GDF hauv paus -15 tau kwv yees siv ntau qhov sib txawv Cox feem cuam tshuam txog kev phom sij. Tsis tas li ntawd, lub hauv paus GDF-15 theem tau muab faib ua quartiles, thiab qhov kev phom sij txaus ntshai (HR) hauv txhua lub quartile tau kwv yees siv thawj quartile raws li kev siv ntau. Plaub tus qauv sib law liag tau tsim, txhua qhov ntxiv cov sib txawv sib txawv los ntsuam xyuas cov txiaj ntsig ntawm cov kauj ruam ntxiv ntawm covariates ntawm kev koom tes ntawm GDF-15 thiab cov txiaj ntsig. Hauv thawj tus qauv, hnub nyoog, poj niam txiv neej, haiv neeg, thiab kev kho mob randomized (canagliflozin lossis placebo) tau suav nrog. Hauv tus qauv thib ob, keeb kwm ntawm cov kab mob plawv (yog lossis tsis yog), hemoglobin A1c, systolic thiab diastolic ntshav siab, lub cev qhov hnyav, thiab qis lipoprotein cholesterol tau ntxiv. Tus qauv thib peb tau qhia txog eGFR (xam nrog Kev Hloov Kho Kev Noj Qab Haus Huv hauvMob raumformula) thiab, nyob rau hauv tus qauv kawg, lub ntuj log-transformed zis albumin-to-creatinine ratio (UACR) tau ntxiv rau cov lus hais saum toj no. Tus qauv hloov kho tag nrho kuj tau siv los kwv yees HRs ntawm lub koom haum ntawm GDF 15 thiab cov txiaj ntsig hauv pawg pawg uas tau teev tseg los ntawm kev kho mob randomized, lub hnub nyoog hauv paus, poj niam txiv neej, eGFR, UACR, thiab keeb kwm kab mob plawv. Peb tau soj ntsuam C-statistics los ntsuas qhov muaj peev xwm ntawm kev ntxub ntxaug ntawm GDF-15.
Qee tus neeg mob (<0.5%) had="" missing="" values.="" these="" few="" missing="" values="" in="" continuous="" normally="" distributed="" covariates="" were="" imputed="" as="" means="" of="" the="" respective="" covariate,="" and="" missing="" values="" in="" continuous="" not="" normally="" distributed="" covariates="" were="" imputed="" as="" medians.="" the="" modification="" of="" treatment="" effect="" of="" canagliflozin="" versus="" placebo="" on="" cardiovascular,="" hf,="">raumCov txiaj ntsig tau los ntawm cov kab hauv qab GFD-15 tau tshawb pom hauv Cox cov qauv kev pheej hmoo rov qab los. Cov ntsiab lus sib cuam tshuam ntawm plasma GDF-15 pawg tertile thiab randomized kev kho mob tau muab tso rau hauv cov qauv Cox uas cuam tshuam rau kev sim rau heterogeneity. Cov txiaj ntsig ntawm canagliflozin piv rau cov placebo ntawm GDF-15 ntau npaum li lub sijhawm tau soj ntsuam los ntawm kev suav qhov sib txawv ntawm pawg hauv kev hloov pauv los ntawm cov hauv paus hauv GDF-15 siv cov qauv sib xyaw ua ke. Cov qauv suav nrog kev faib cov kev kho mob thiab lub sijhawm raws li qhov tseem ceeb, lub sijhawm sib cuam tshuam ntawm kev faib nyiaj kho mob thiab sijhawm, thiab tau hloov kho rau lub hauv paus GDF-15 tus nqi thiab lub sijhawm sib cuam tshuam ntawm lub sijhawm thiab lub hauv paus GDF-15 tus nqi. Lub variance-covariance matrix tau xav tias tsis muaj qauv (piv txwv li, cov ntaub ntawv nkaus xwb-raws li). Kev txheeb xyuas pawg sub los ntawm cov hauv paus (<30 and="" ≥30 mg/g)="" and="" egfr=""><60 and="" ≥60 ml/min="" per="" 1.73 ="" m²)="" were="" performed="" to="" explore="" the="" consistency="" of="" the="" treatment="" effect="" of="">
Rau txhua qhov tshwm sim, peb kuj tau muab cov lus piav qhia txog qhov feem pua ntawm cov txiaj ntsig kev kho mob randomized tshem tawm nrog kev hloov pauv hauv cov qib ntshav biomarker, raws li tau ua dhau los hauv CANVAS trial.19 Rau txhua qhov tshwm sim, feem pua ntawm cov txiaj ntsig kho tau piav qhia yog qhia siv qhov sib npaug: 100 feem pua ×([HR−HRadjusted]/[HR−1]). Txhua qhov kev txheeb xyuas tau ua tiav hauv SAS, version 9.4 (SAS Institute, Cary, NC, USA), thiab Stata, version 16.1 (StataCorp College Station, TX, USA).
TSEEM CEEB
Kawm Pej XeemNyob rau hauv tag nrho, 3549 (82. Cov yam ntxwv hauv paus ntsiab lus ntawm cov neeg koom nrog no muaj nyob rau hauv Table 1. Cov yam ntxwv hauv paus tau zoo sib xws ntawm cov pab pawg sib txawv thiab yog tus sawv cev ntawm tag nrho cov neeg sim. Zuag qhia tag nrho, lub hnub nyoog nruab nrab ntawm cov pej xeem yog 62.8 xyoo, 33.1 feem pua yog poj niam, 13.3 feem pua tau muaj keeb kwm HF, 59.5 feem pua tau muaj keeb kwm mob plawv, lub cev qhov hnyav yog 32.7, txhais tau tias hemoglobin A1c yog 65.7 mmol / mol ( 8.2 feem pua), txhais tau tias mob ntshav qab zib ntev yog 13.5 xyoo, txhais tau tias eGFR yog 77.0 mL/min ib 1.73 m², thiab nruab nrab GDF{26}} qib yog 1774 pg/mL ntawm lub hauv paus. Pearson correlation coefficients pom tau tias feem ntau tsis muaj kev sib raug zoo ntawm cov hauv paus GDF-15 qhov tseem ceeb thiab cov kab mob plawv, tshwj tsis yog rau hauv paus eGFR, UACR, thiab hnub nyoog (Daim duab S1).
Association of Baseline GDF-15 Nrog Kev Mob plawv, HF, Lub raum, thiab Txhua Yam Ua Rau Tuag Tau LosCov neeg koom nrog tau ua raws li qhov nruab nrab ntawm 6.1 (interquartile range, 5.8 txog 6.3) xyoo. Thaum ua raws li, 555 (15.6 feem pua), 129 (3.6 feem pua), thiab 137 (3.9 feem pua) cov neeg koom nrog kev mob plawv, HF, thiabraumqhov tshwm sim, feem. Cox proportional hazard regression nrog kev hloov kho rau cov neeg mob pej xeem thiab kev kho mob randomized pom tias txhua qhov kev ua ob npaug hauv GDF-15 tau cuam tshuam nrog cov hlab plawv, HF, thiabraumcov txiaj ntsig (Table 2). Cov koom haum no tseem muaj txiaj ntsig zoo tom qab kev hloov kho ntxiv rau cov cim kev pheej hmoo, suav nrog eGFR thiab UACR, nrog rau HRs sib raug rau ib ob npaug ntawm cov hauv paus GDF-15 hauv cov qauv hloov kho tag nrho ntawm 1.2 (95 feem pua CI, 1.0‒ 1.3; P=0 01), 1.5 (95% CI, 1.2‒2.0; P<0.01), and="" 1.5="" (95%="" ci,="" 1.2‒2.0;=""><0.01) for="" the="" cardiovascular,="" hf,="">raumcov txiaj ntsig, ntsig txog (Table 2). Cov txiaj ntsig zoo sib xws tau txais nyob rau hauv pawg kev tshuaj ntsuam xyuas los ntawm kev kho mob, hnub nyoog, poj niam txiv neej, UACR, eGFR, thiab keeb kwm kab mob plawv rau cov hlab plawv, HF, thiabraumcov txiaj ntsig (Daim duab 1). Thaum lub hauv paus GDF-15 tau txheeb xyuas raws li qhov sib txawv ntawm qhov sib txawv, qhov siab tshaj plaws quartile ntawm GDF-15 tau cuam tshuam nrog 2- thiab 3-fold nce kev pheej hmoo ntawm HF thiabraumCov txiaj ntsig, ntsig txog, hauv cov qauv hloov kho tag nrho (Table 2). Hauv kev tshuaj ntsuam ntxiv, peb tau pom tias txhua qhov ob npaug ntawm qhov hauv paus GDF-15 tau cuam tshuam nrog txhua qhov kev tuag vim muaj kev sib raug zoo HR ntawm 1.3 (95 feem pua CI, 1.1‒1.5) hauv cov qauv hloov kho tag nrho nrog cov txiaj ntsig zoo sib xws rau cov pab pawg. (Table S1 thiab Figure S2). Kev soj ntsuam ntawm C-statistics ntawm cov qauv rau txhua qhov kev tshwm sim pom tau hais tias qhov nruab nrab mus rau qhov ua tau zoo prognostic (Table S2).
Cov txiaj ntsig ntawm Canagliflozin ntawm Cardiovascular, HF, thiab raum Cov txiaj ntsig los ntawm Baseline Plasma GDF-15 QibHauv cov pab pawg neeg no ntawm CANVAS cov neeg koom nrog GDF -15 cov concentrations, canagliflozin txo qhov kev pheej hmoo ntawmraumCov txiaj ntsig tau los ntawm 44 feem pua (HR, 0.56 [95 feem pua CI, 0.40‒0.79; P<0.01]) compared="" with="" placebo.="" the="" hrs="" for="" the="" cardiovascular="" and="" hf="" outcomes="" were="" 0.91="" (95%="" ci,="" 0.76‒1.08;="" p="0.28)" and="" 0.82="" (95%="" ci,="" 0.58‒="" 1.17;="" p="0.28)," respectively.="" there="" was="" no="" evidence="" that="" the="" effect="" size="" of="" canagliflozin="" for="" cardiovascular,="" hf,="">raum outcomes varied by the baseline level of GDF-15 (all P values for heterogeneity >0.07; Daim duab 2).
Cov nyhuv ntawm Canagliflozin ntawm Plasma GDF-15 Hauv pawg placebo, GDF-15Cov concentrations nce ntxiv raws sijhawm (Daim duab 3). Canagliflozin txo qis qhov nce no, ua rau muaj qhov tsawg kawg nkaus-squares txhais tau tias sib txawv hauv GDF-15 ntawm −3.4 feem pua (95 feem pua CI, −6.5 feem pua rau −0.3 feem pua ; P{{1{{ 32}}}}.032) ntawm 3 xyoos thiab −7.1 feem pua (95 feem pua CI, −11.6 feem pua rau −2.4 feem pua; P=0.004) ntawm 6 xyoo (Daim duab 3). Qhov tsawg tshaj plaws-squares txhais tau hais tias qhov sib txawv thaum rov qab los ntawm canagliflozin thiab placebo, xav txog txhua qhov kev ntsuas, yog −3.7 feem pua (95 feem pua CI, −6.3 feem pua rau −1.0 feem pua ; P=0.007). Cov txiaj ntsig ntawm canagliflozin piv nrog cov placebo ntawm qhov sib txawv hauv GDF-15 ua haujlwm dhau sijhawm tau zoo ib yam hauv cov pab pawg uas tau teev tseg los ntawm lub hauv paus UACR<30 or="" ≥30 mg/g="" or="" egfr=""><60 or="" ≥60 ml/min="" per="" 1.73 m2="">
Qhov kev faib ua feem ntawm Kev Kho Mob Piav Qhia los ntawm Kev Hloov hauv GDF-15Kev soj ntsuam ntawm qhov kev faib ua feem ntawm kev kho mob ntawm cov hlab plawv, HF, thiabraumCov txiaj ntsig tau piav qhia los ntawm kev hloov pauv hauv cov ntshav plasma biomarkers, pom tau tias kev hloov pauv hauv GDF{{{0}}} tsis tau piav qhia txog cov txiaj ntsig ntawm canagliflozin ntawm cov txiaj ntsig no (qhov feem cuam tshuam tau piav qhia 0.1 feem pua , 2.3 feem pua , thiab 2.3 feem pua rau mob plawv, HF, thiabraumcov txiaj ntsig, ntsig txog).
Kev sib thamCirculating GDF-15 yog ib qho cim ntawm o thiab cellular raug mob thiab nce ntxiv rau cov neeg mob ntshav qab zib hom 2, mob ntevmob raum, thiab HF. Hauv qhov kev tshuaj ntsuam xyuas no los ntawm CANVAS kev sim, peb pom tau tias hauv cov neeg mob uas muaj ntshav qab zib hom 2 ntawm kev pheej hmoo plawv plawv, nce qib ntawm GDF-15 cuam tshuam nrog plawv plawv, HF, thiabraumqhov tshwm sim. Peb kuj tau ua pov thawj tias canagliflozin txo qis qhov nce hauv GDF-15 dhau sijhawm, txawm hais tias qhov feem pua ntawm canagliflozin qhov kev tiv thaiv ntawm 3 qhov kev tshwm sim ua ntej tsis tuaj yeem piav qhia los ntawm kev txo qis hauv GDF-15 pom. Cov kev tshawb fawb ua ntej twb tau tshuaj xyuas cov kev sib raug zoo ntawm GDF-15 thiab cov hlab plawv thiabraumCov txiaj ntsig tau tshwm sim hauv cov neeg mob ntshav qab zib hom 2 nrog lossis tsis muajmob raum.8,16 Peb lees paub thiab txuas ntxiv cov kev tshawb pom no mus rau cov pej xeem loj, ntau haiv neeg ntawm cov neeg mob ntawm ntau haiv neeg uas muaj ntshav qab zib hom 2 ntawm kev pheej hmoo siab plawv, uas tau kho raws li cov lus qhia niaj hnub no. Peb kuj tau pom tias cov koom haum no tau sib xws nyob rau ntau pawg neeg mob uas tau teev tseg los ntawm cov pej xeem hauv paus thiab cov chaw soj ntsuam kuaj mob. Qhov sib piv ntawm peb cov txiaj ntsig nrog cov kev tshawb pom yav dhau los hauv cov neeg sib txawv qhia txog tus nqi prognostic ntawm lub hauv paus GDF-15 rau qhov tsis zoo cardio-raumqhov tshwm sim.
Ib txoj kev tshawb fawb yav dhau los hauv GDF-15 tus qauv kho mob ntshav qab zib mellitus tau tshaj tawm tias nce glycosuria vim qhov txo qis ntawm tubular SGLT2 qhia, qhia tias, qis GDF-15 qib, SGLT2 kev ua haujlwm yuav raug txo qis.18 Los ntsuas Txawm hais tias qhov kev tshawb pom no muaj qhov cuam tshuam rau kev kho mob, peb tau soj ntsuam cov txiaj ntsig ntawm canagliflozin raws li cov hauv paus GDF-15 qib thiab pom cov txiaj ntsig zoo ib yam ntawm canagliflozin ntawm cov hlab plawv, HF, thiabraumCov txiaj ntsig tau, tsis hais qhov pib GDF-15 qib. Txawm hais tias kev txo qis ntawm cov txheeb ze tau zoo ib yam, cov txiaj ntsig zoo ntawm canagliflozin hauv kev tiv thaiv kab mob plawv, HF, thiabraumCov txiaj ntsig tau ntau dua nyob rau hauv qhov siab tshaj plaws tertile ntawm lub hauv paus GDF-15 qib vim tias muaj kev pheej hmoo siab dua ntawm cov neeg koom no.
Cov txheej txheem piav qhia yuav ua li cas SGLT2 inhibitors txo cov hlab plawv thiabraumcov xwm txheej yog thaj chaw ntawm kev tshawb fawb zoo heev. Raws li ib qho kev mob thiab cov ntaub so ntswg raug mob kev ntxhov siab, nws yog qhov nthuav tias GDF-15 qib tau txo qis los ntawm canagliflozin. Cov teebmeem no tau tshwm sim tom qab 3 xyoos ntawm kev kho mob thiab tau zoo ib yam hauv cov neeg mob uas tau khaws cia thiab tsis zoolub raum ua haujlwm. Cov txiaj ntsig no sib piv rau kev kawm ua ntej ntawm empagliflozin, uas tau tshaj tawm tias empagliflozin nce GDF-15 qib.20 Txawm li cas los xij, muaj qhov sib txawv tseem ceeb ntawm peb qhov kev sim thiab kev tshawb fawb empagliflozin. Ua ntej, peb txoj kev tshawb fawb tau loj dua, suav nrog 3549 tus neeg mob piv nrog tsuas yog 72 hauv kev kawm ua ntej. Tsis tas li ntawd, peb piv cov txiaj ntsig ntawm canagliflozin nrog cov placebo, qhov kev tshawb fawb ua ntej tsis suav nrog pawg tswj hwm. Txawm hais tias canagliflozin txo qis GDF-15, kho cov nyhuv kho canagliflozin rau kev hloov hauv GDF-15 qhia tau tias GDF-15 tsis tau piav qhia txog kev tiv thaiv ntawm canagliflozin ntawm cov hlab plawv, HF, thiabraumqhov tshwm sim. Yog li, txawm hais tias GDF-15 yog tus cim prognostic, cov txiaj ntsig zoo ntawm canagliflozin tsis zoo li yuav raug kho los ntawm txoj hauv kev molecular uas sawv cev los ntawm GDF-15.
CISTANCHE yuav txhim kho rau lub raum/ raum mob
Txoj kev taw qhia nqes mus rau qhov GDF-15 cuam tshuam li cas rau cov hlab plawv tsis zoo thiabraumCov txiaj ntsig tau nkag siab tsis tiav, tab sis nws tau xav tias cov txiaj ntsig yuav raug kho los ntawm ntau txoj hauv kev, xws li glial cell-derived neurotrophic factor receptor-like, endothelial nitric oxide synthase, SMAD 2, thiab 7, thiab nuclear factor-kappa B.21. -23 Qee qhov kev tshawb fawb qhia tias GDF-15 raug tso tawm rau hauv qhov chaw ntawm kev puas tsuaj thiab tuaj yeem ua lub luag haujlwm tiv thaiv los ntawm kev txo qis ntawm interstitial fibrosis hauvlub raumthiab tiv thaiv hypertrophy thiab txo qhov tsim ntawm cov kab mob plawv.23–27 Nws tsis paub meej tias qhov nce hauv GDF circulating-15 nyob rau hauv ntau yam kab mob yog cov lus teb rau kev raug mob los tiv thaiv kev puas tsuaj ntxiv los yog ua tsis tiav los tiv thaiv lub plawv thiabraum.GDF-15 tau nce siab hauv ntau yam kab mob ntev xws li ntshav qab zib, mob qog noj ntshav, kab mob plawv, thiab kab mob autoimmune qhia tias nws koom nrog hauv pathophysiology ntawm ntau yam kab mob.10,28–31 Vim tias GDF-15 tau nce siab hauv qhov sib txawv kab mob, kev siv tshuaj kho mob ntawm GDF-15 raws li kev kuaj mob tsuas yog txwv. Txawm li cas los xij, GDF-15 tau pom tias yuav kwv yees qhov kawg ntawm qhov chaw kho mob hauv cov kab mob sib txawv no qhia txog nws qhov kev siv hluav taws xob raws li tus cim kev pheej hmoo.
Txoj kev tshawb no muaj qee qhov kev txwv. Ua ntej, vim qhov tsim ntawm txoj kev tshawb no yog post hoc, tsis muaj causality yuav inferred ntawm GDF-15 thiab qhov tshwm sim. Nws yog qhov zoo li, raws li qhia nrog kev tshuaj xyuas kev kho kom haum xeeb, tias GDF-15 qhia txog lwm txoj hauv kev molecular uas muaj kev cuam tshuam los tiv thaiv kab mob plawv, HF, thiabraumxwm txheej. Qhov thib ob, txawm hais tias peb ntsuas cov qauv uas tau txais thaum lub sijhawm kev sim ntau qhov chaw kho mob loj, cov txiaj ntsig tsuas tuaj yeem siv rau cov neeg mob uas muaj cov yam ntxwv zoo sib xws rau CANVAS trial cohort. Txawm li cas los xij, qhov sib xws hauv kev txheeb xyuas pab pawg thiab cov kev tshawb pom zoo ib yam hauv cov ntaub ntawv txhawb nqa qhov dav dav ntawm GDF-15 raws li qhov muaj feem cuam tshuam rau cov hlab plawv, HF, thiabraumqhov tshwm sim. Thaum kawg, qhov txo qis hauv GDF-15 hauv pawg canagliflozin piv nrog cov placebo pab pawg tom qab 3 xyoos tom qab tuaj yeem yog qhov tshwm sim ntawm kev txhim kho kab mob ntau dua li kev kho mob ntawm canagliflozin ib sé. Hauv kev xaus, peb lees paub qhov kev soj ntsuam kev sib raug zoo ntawm GDF-15 nrog cov hlab plawv, HF, thiabraumCov txiaj ntsig tau tshwm sim hauv cov neeg mob ntshav qab zib hom 2 thiab tsim cov kab mob plawv lossis cov uas muaj kev pheej hmoo siab plawv. Tsis tas li ntawd, kev kho mob nrog canagliflozin txo qis ntawm GDF-15 dhau sijhawm. Cov nyhuv no tau zoo ib yam hauv cov pab pawg neeg mob hauv tsev tab sis tsis tau piav qhia txog kev tiv thaiv ntawm canagliflozin ntawm cov hlab plawv, HF, lossisraumqhov tshwm sim.
