Sodium Glucose Cotransporter-2 Inhibitors Tiv Thaiv Lub Cardiorenal Axis: Hloov Kho Ntawm Cov Mechanistic Insights Tsis ntev los no cuam tshuam rau lub raum Physiology Ⅱ

5. SGLT2 inhibition: kev hloov hauv lub raum physiology ua rau cov hlab plawv?

Raws li tau hais los saum no, cov txiaj ntsig zoo ntawmSGLT2 inhibitionntawm 3- MACE thiablub plawv tsis ua hauj lwm tshwm simtau ntau yam tsis tau xav txog. Tsis yog qhov xav tsis thoob, cov txheej txheem uas tsav (cov) cov txiaj ntsig CV no tsis paub meej thiab tau ua rau ntau qhov kev xav uas tau tshuaj xyuas lwm qhov (xws li [41,49,50]). Ib qho kev xav hauv nruab nrab yog ua raws li SGLT2 inhibitor-induced ntim contraction, raws li kev kho kom haum xeeb tsom xam los ntawm EMPAREG OUTCOME txoj kev tshawb fawb pom tias hematocrit yog qhov zoo tshaj plaws kwv yees rau CV txiaj ntsig [51]. Kev nce hematocrit tau raug npaj los ua tus cim rau plasma ntim. Nyob rau hauv kab, nws tau pom tias siv radioactively sau npe albumin, uas dapagliflozin nce plasma ntim [52]. Txoj kev xav yog tias qhov ntim ntim no yog qhov thib ob rau kev nce natriuresis. Ob qhov kev tshawb fawb yav dhau los tau pom tias muaj kev ncua ntev, tab sis qhov me me hauv cov zis sodium tawm tom qab SGLT2 inhibition, txawm li cas los xij, muaj kev tswj hwm kev noj zaub mov noj sodium [53,54]. Hauv cov neeg ua haujlwm noj qab haus huv nrog kev noj zaub mov tsis tu ncua (110 mmol / hnub), dapagliflozin ua rau muaj kev hloov pauv me me (hnub 1; 20 mmol) nce hauv natriuresis, uas qis dua li sodium excretion tshwm sim los ntawm bumetanide [55], cov tshuaj uas yog tsis paub yuav ua rau kom hematocrit. Ib qho kev txwv ntawm no yog kev tswj tsis tau cov kua dej thiab tsis ua raws li cov ntsiav tshuaj sodium uas tuaj yeem ua rau xeev siab thiab ntuav. Hauv cov neeg uas muaj lub plawv tsis ua haujlwm, ob txoj kev tshawb fawb tau pom tias muaj kev cuam tshuam tsawg kawg ntawm SGLT2 inhibition ntawm cov cim ntawm sodium homeostasis. Griffin et al. qhia txog kev nce ntxiv hauv fractional sodium excretion (24 teev cov zis tsis tau sau, tsis tas siv sodium kom tsawg) [56], thaum tsis muaj kev hloov pauv hauv 24 h sodium excretion tau qhia los ntawm Mordi li al. Hauv txoj kev tshawb fawb tom kawg, kev nce ntxiv hauv cov zis ntim tau pom, txawm li cas los xij, qhov no nyuaj los txhais tau tias sodium thiab kua dej tsis tau saib xyuas [57]. Hauv kev tshawb fawb DAPASALT tsis ntev los no, cov neeg muaj T2D thiablub raum ua haujlwmtau txais kev noj zaub mov raws cai (150 mmol / hnub), thiab cov zis ntim thiab natriuresis tau ua tib zoo saib xyuas siv ntau yam 24 teev tso zis [58]. Dapagliflozin tag nrho tsis hloov 24- teev tso zis thiab sodium, txawm hais tias ib qho me me ntawm sodium excretion tau pom nyob rau thawj hnub ntawm kev kho mob. Glucose excretion ntawm qhov tod tes tau muaj zog ntxiv thaum nce fractional lithium excretion paub tseeb tias inhibition ntawm proximal tubular muaj nuj nqi. Plasma ntim tsis tau txo qis thaum kho tab sis tau nce ntxiv tom qab tso tseg. Txawm hais tias cov teebmeem me me ntawm natriuresis thiab ntshav ntim, systolic ntshav siab tau txo qis los ntawm 6 mmHg, qhia tias lwm yam cuam tshuam rau SGLT2 inhibitor-induced ntshav siab.

NYEM QHOV NO kom tau txais tshuaj ntsuab FORMULATION OF CISTANCHE FOR IMPROVE KIDNEY FUNCTION

Lub raum muaj peev xwm hloov tau mus rau (tshuaj-vim) kev hloov pauv hauv tubular physiology ua rau lawv tswj hwm sodium thiab dej sib npaug. Los ntawm qhov kev xav ntawd, nws tsis zoo li tias SGLT2 inhibitors ua rau lub sijhawm ntev ntawm cov zis sodium thiab dej poob. Txawm hais tias muaj kev cuam tshuam tsis tu ncua ntawm cov tubular muaj nuj nqi thiab glycosuria, cov zis ntim feem ntau khaws cia tas li los ntawm ntau lub tshuab. Ua ntej, SGLT2 inhibitors qhib RAAS ua rau distal sodium retention, thib ob, SGLT2 inhibitors txo cov dej dawb thiab nce copeptin secretion thiab thib peb, yuav txuag dej los ntawm urea metabolism [43,59]. Kev soj ntsuam soj ntsuam uas tsim cov lus nug nrog qhov ntim ntawm kev cog lus los ntawm SGLT2 inhibitor kev kho mob thiab nws cov txiaj ntsig ntawm CV cov txiaj ntsig suav nrog (1) tsis muaj kev cuam tshuam ntawm cov hauv paus eGFR ntawm CV teebmeem [23,24,60] thiab (2) thiab tsuas yog me ntsis qis dua NT-proBNP. Cov concentrations uas tau pom thaum kho SGLT2 kuj zoo li ua lub luag haujlwm me [61]. Tseeb, ob peb lwm cov txheej txheem tau raug npaj los qhia txog qhov txiaj ntsig CV ntawm SGLT2 inhibitor kev kho mob, xws limitochondrial tsis ua haujlwm,txo oxidative kev nyuaj siab,txo kev ua haujlwm ntawm sodium-hydrogenexchanger isoform 3 (NHE3) thiab hloov pauv myocardial substrate metabolism [62]. Ib qho kev soj ntsuam zoo ntxiv yog tias txawm tias txo qis hauv cov ntshav siab thiab sib cav hemoconcentration, tsis muaj qhov sib npaug ntawm lub plawv dhia nrog SGLT2 inhibition. Mechanistically, qhov no tej zaum yuav tshwm sim los ntawm inhibition ntawm SLGT2 ntawm lub sympathetic paj hlwb raws li qhia nyob rau hauv elegant nas cov kev tshawb fawb [63]. Qhov no tuaj yeem tsim cov tshuaj SGLT2 sib nrug los ntawm cov tshuaj diuretics.

Los xaus, lub luag haujlwm ntawm kev hloov pauv hauvlub raum sodium tuavinduced los ntawm SGLT2 inhibitors tseem enigmatic, tshwj xeeb nws pab rau CV tiv thaiv uas tau pom nrog SGLT2 inhibition. Ib qho tseem ceeb ntawm no yog qhov tsis muaj cov kev tshawb fawb loj dua uas tau ntsuas (tsis kwv yees) cov ntshav plasma thiab tau ua cov kev sim nruj uas ntsuas qhov ntsuas sodium nyob rau hauv ntau haiv neeg xws li plawv tsis ua hauj lwm thiab cov neeg mob DKD. Cov laj thawj vim li cas hematocrit nce siab thaum kho SGLT2 tam sim no tsis meej thiab tseem tuaj yeem cuam tshuam rau erythropoiesis raws li tau tham saum toj no.

6. Cov cheeb tsam ntawm kev tshawb fawb tsis tu ncua

Ntau qhov kev sim tshuaj tam sim no txuas ntxiv nrog rau SGLT2 inhibition. Ib lo lus nug tseem ceeb yog yuav ua li cas SGLT2 inhibition ua ke nrog lwm yam (muaj peev xwm) cov tshuaj tiv thaiv raum. Hauv qhov kev sim ua tiav, SGLT2 inhibitors tau pib nyob rau sab saum toj ntawm RAAS thaiv. Yog li ntawd, kev sib cuam tshuam ntawm cov tshuaj no tseem kawm tsis zoo. Ob txoj kev tshawb fawb tsis ntev los no tau ua tiav rau cov neeg mob ntshav qab zib hom 1 thiab hom 2 uas tau tshawb xyuas qhov kev cuam tshuam ntawm RAAS blockers thiab SGLT2 inhibitors [NCT04238702; NCT02632747] (Table 2). Tsis tas li ntawd, qhov tshiab mineralocorticoid receptor antagonist (MRA) finerenone tau tshwm sim tsis ntev los no hauv Finerenone hauv Kev txo qis raum tsis ua haujlwm thiab kab mob kev loj hlob hauv ntshav qab zib raum (FIDELIO-DKD) sim, txhawm rau txo CKD kev nce qib hauv cov neeg mob ntshav qab zib hom 2 [64]. Txawm li cas los xij, MRA muaj qhov cuam tshuam ntawm hyperkalemia, txwv tsis pub siv. Nyob rau hauv qhov teeb meem no, nws yog qhov nthuav kom nco ntsoov tias SGLT2 inhibitors txo qhov kev pheej hmoo ntawm hyperkalemia, tsis muaj kev pheej hmoo ntawm hypokalemia [65]. Kev sib cuam tshuam ntawm finerenone thiab SGLT2 inhibitors yog tam sim no txuas ntxiv los soj ntsuam lawv cov teebmeem kev kho mob thiab kev nyab xeeb profile.

Hauv xyoo tas los no, glucagon-zoo li peptide (GLP-1) receptor agonists, uas txo cov ntshav qabzib hauv cov ntshav los ntawm kev txhawb nqa ntawm insulin secretion, txo qis ntawm glucagon ntau lawm, txo cov plab hnyuv, thiab nce satiety, tau pom tias txo qis. albuminuria hauv cov neeg mob ntshav qab zib hom 2 [66]. Txoj kev tshawb fawb FLOW tam sim no [NCT03819153] tseem tab tom tshawb nrhiav qhov cuam tshuam ntawm GLP-1 receptor agonists ntawm lub raum tshwm sim hauv cov neeg mob ntshav qab zib hom 2, ntau yam uas tseem yuav tau kho nrog SGLT2 inhibitors, tso cai rau kev kawm txog lawv cov kev cuam tshuam.

Thaum kawg, endothelin-receptor agonists (ERA) tau pom tias txhim kho lub raum cov txiaj ntsig, txawm li cas los xij, ntawm kev siv cov kua dej ntau ntxiv, edema thiab congestive plawv tsis ua haujlwm [67]. Tej zaum nws yuav xav tias SGLT2 inhibitors tuaj yeem cuam tshuam cov teebmeem ntawm ERA kev kho mob. Tam sim no tab tom tshawb nrhiav [NCT04724837]. Yog li, cov kev tshawb fawb saum toj no yuav pab kom nkag siab seb (1) kev sib xyaw ua ke ntawm SGLT2 inhibition thiab lwm yam tshuaj tiv thaiv raum muaj nuj nqis ntxiv thiab (2) tuaj yeem muab cov ntaub ntawv muaj kev nyab xeeb zoo dua los ntawm kev tawm tsam ntawm cov xwm txheej xws li kev cai dej nyab.

Hais txog kev tshawb fawb txog kev siv tshuab, CROCODILE [NCT04074668] tseem tab tom tshawb xyuas lub raum oxygenation, perfusion thiab noj, nrog rau cov tshuaj insulin rhiab heev thiab kev ua haujlwm mitochondrial hauv cov neeg mob uas muaj ntshav qab zib hom 1 thiab kev tswj hwm kev noj qab haus huv. Txhawm rau tshawb xyuas cov txheej txheem ntawm lub raum puas hauv hom 1 mob ntshav qab zib mellitus, lub raum biopsies tau ua. Txoj kev tshawb fawb ROCKIES tsis tu ncua [NCT04027530] yuav muab kev pom rau lub luag haujlwm ntawm lub raum hypoxia hauv lub raum mob ntshav qab zib thiab yuav ntsuas qhov cuam tshuam ntawm SGLT2 inhibition ntawm lub raum cov ntaub so ntswg oxygenation thiab oxygen noj, nrog rau kev hloov pauv hauv intrarenal hemodynamics thiab perfusion hauv hom 2 mob ntshav qab zib. cov neeg mob (Table 2).

Qhov kev sim tsis tu ncua ATTEMPT [NCT04333823] yuav ntsuas lub raum kev cuam tshuam ntawm SGLT2 inhibition ntawm qhov tshwm sim thaum ntxov thiab kev loj hlob ntawm cov teeb meem ntshav qab zib hauv cov hluas uas muaj ntshav qab zib hom 1. Qhov kev sim ADAPT [NCT04794517] tseem niaj hnub soj ntsuam seb dapagliflozin ameliorates hyperfiltration thiab txo cov protein uria piv rau cov placebo, hauv cov neeg mob uas tsis muaj ntshav qab zib CKD (theem IV CKD) thiab proteinuria (0.5 g / 24 h) (Table 2).

Table 2 Kev soj ntsuam tsis tu ncua nrog SGLT2 inhibition.

7. Cov lus xaus

Hauv kev xaus, SGLT2 inhibitors tau txais lub luag haujlwm tseem ceeb hauv kev kho mob ntshav qab zib hom 2,mob raum mobnrog rau cov mob ntshav qab zib raum, thiab lub plawv tsis ua haujlwm nrog txo qis ejection feem. Qhov no yog tsav los ntawm cov kev sim loj ntawm cov hlab plawv thiab lub raum tau ua nyob rau ob peb xyoos dhau los uas tau pom tias muaj txiaj ntsig zoo rau cov txiaj ntsig ntawm cov hlab plawv (3-point MACE), kab mob raum kawg, mus pw hauv tsev kho mob rau lub plawv tsis ua haujlwm, thiab kev tuag ntawm cov hlab plawv. hauv cov neeg uas muaj thiab tsis muaj ntshav qab zib. Cov txheej txheem hauv qab ntawm cov txiaj ntsig no tau tshawb xyuas ntau, tab sis tseem nyob twj ywm tsis to taub. Hais txog lubraum tiv thaiv nyhuvntawm SGLT2i nyob rau hauv cov neeg mob ntshav qab zib, ntau yam kev tshawb fawb qhia tau hais tias akho lub raum hyperfiltrationvim yog postglomerual vasodilation hauv cov neeg laus uas muaj ntshav qab zib hom 2 tom qab SGLT2i tso nyiaj rau kev tiv thaiv. Lwm qhov kev tsom xam ntawm kev tshawb fawb yog qhov ua tau txo qis ntawm lub raum hypoxia los ntawm SGLT2 inhibition, ntxiv rau cov txiaj ntsig me me. Hais txog kev tiv thaiv kab mob plawv, nws tau ntev xav tias qhov ntim ntawm plasma contraction tom qab natriuresis feem ntau yuav yog lub hauv paus txheej txheem. Cov kev tshawb fawb tsis ntev los no ua tib zoo tshuaj xyuas cov ncauj lus no txawm li cas los xij tau ua rau muaj kev tsis ntseeg txog lub tswv yim no thiab cov kev sim siv tshuab yav tom ntej tuaj yeem ua rau pom kev ntxiv rau cov txheej txheem ntawm kev ua ntawm cov tshuaj no. Nyob rau lub sijhawm no, cov neeg mob uas muaj kab mob plawv thiab / lossis mob raum tau txais txiaj ntsig los ntawm cov neeg ua haujlwm no hauv kev kho mob.

Cov ntaub ntawv

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