izindaba

I-hyperlipidemia ehlanganisiwe ibonakala ngokukhuphuka kwamazinga e-plasma e-low-density lipoproteins (LDL) kanye nama-triglyceride-rich lipoprotein, okuholela engcupheni eyandayo yesifo senhliziyo nemithambo yegazi kulesi sibalo sesiguli.
I-ANGPTL3 ivimbela i-lipoprotein lipase ne-endosepiase, kanye nokuthathwa kwesibindi kwama-lipoprotein acebile nge-triglyceride. Abathwali bokwehluka okungasebenzi kwe-ANGPTL3 babenamazinga aphansi e-triglycerides, i-cholesterol ye-LDL, i-cholesterol ephezulu-density lipoprotein (HDL), kanye ne-cholesterol engeyona i-HDL, kanye nengozi ephansi yesifo senhliziyo nemithambo yegazi. I-zodasiran isidakamizwa esincane esiphazamisayo se-RNA (RNAi) esiqondise ukubonakaliswa kwe-ANGPTL3 esibindini.

I-hyperlipidemia ehlanganisiwe ibhekisela emazingeni aphakeme e-low-density lipoprotein cholesterol (LDL-C) nama-triglyceride-rich lipoprotein. Ama-lipoprotein acebile nge-Triglyceride (kuhlanganise nama-chylomicron, ama-lipoprotein aphansi kakhulu (VLDL), kanye ne-cholesterol eyinsalela) adlala indima ebalulekile ekwakhiweni kwesifo se-atherosclerotic. Akukho ukwelashwa okusebenzayo kwe-hyperlipidemia exubile.
Ama-Bates aziwa ngokunciphisa amazinga e-triglyceride (TG), kodwa ukuncipha kunqunyelwe. Ngesikhathi esifanayo, izidakamizwa ezehlisa i-TG ezihlanganisa i-Bates (njenge-eicosapentaenoic acetic acid, njll.) azinawo umthelela omkhulu engcupheni yesifo se-atherosclerotic esibangelwa amazinga e-cholesterol ayinsalela. Ngaphezu kwalokho, izifundo zangaphambilini ezigulini esezivele zithatha ama-statins zikhombisile ukuthi inhlanganisela yezidakamizwa ezinciphisa i-TG ayinciphisi ubungozi bezehlakalo zenhliziyo. Lezi zici zenza ukwelashwa kwe-hyperlipidemia exubile kube nzima kakhulu.
I-ANGPTL3 (i-angiopoietin-like protein 3) ilawula i-lipids kanye ne-lipoprotein metabolism, okuhlanganisa i-TG kanye ne-non-high-density lipoprotein cholesterol (HDL-C), ngokuvimbela ngokubuyisela emuva i-lipoprotein lipase, i-endosepiase, kanye ne-low-density lipoprotein (LDL) ye-hepatic lipoprotein (LDL). Kutholwe ukuthi ukwahluka kokungasebenzi kwe-ANGPTL3 kuholela ekwandeni kwe-lipoprotein lipase nomsebenzi we-endosepiase, okuholela emazingeni aphansi e-plasma lipoprotein ezimeni eziningi, Lokhu kufaka phakathi ama-triglyceride-rich lipoproteins (okungukuthi, ama-Chylomicrons, i-cholesterol eyinsalela, i-VLDL, i-medium density lipoprotein), i-LDLLprotein ephezulu ama-lipoprotein (a), kanye nezingxenye zawo ze-cholesterol. Abantu abane-Heterozygous abaphethe lokhu okuhlukile banengozi encishisiwe cishe ngama-40% yesifo se-atherosclerotic, futhi akukho phenotype yomtholampilo embi etholakele. I-ANGPTL3 ivezwa esibindini, futhi izindlela zokwelapha zokuthulisa izakhi zofuzo eziqondise i-mRNA yayo, ezaziwa ngokuthi izidakamizwa ezincane eziphazamisa i-RNA (siRNA), ziyindlela yokwelapha eyingxube ethembisayo ye-hyperlipidemia.
NgoSepthemba 12, 2024, i-New England Journal of Medicine (NEJM) yashicilela ucwaningo lwe-ARCHES 2 oluqinisekisa ukuthi umuthi we-siRNA i-zodasiran wehlise kakhulu amazinga e-TG ezigulini ezine-hyperlipidemia exubile [1]. I-ARCHES-2 iyisivivinyo esiyi-double blind, esilawulwa yi-placebo, isigaba 2b sokuhlola ibanga lomthamo. Ingqikithi yeziguli ezingama-204 ezine-hyperlipidemia exubile (amazinga e-TG yokuzila ukudla 150-499 mg/dL, amazinga e-LDL-C ³70 mg/dL noma amazinga okungewona awe-HDL-C ³100 mg/dL) abhaliswa. Zahlukaniswa zaba yiqembu le-zodasiran 50 mg, iqembu le-100 mg, iqembu lama-200 mg kanye neqembu lokulawula i-placebo. Iziguli zithole imijovo engaphansi kwe-subcutaneous ngesonto 1 ne-12, futhi zithole i-follow-prophylaxis kuze kube yisonto le-36.
Isiphetho esiyinhloko kwaba ukuguqulwa kwephesenti ku-TG kusukela kwesisekelo kuya kweviki 24. Ucwaningo lwathola ukuthi ngeviki 24, amazinga e-TG eqenjini le-zodasiran ancishiswa kakhulu ngendlela encike kumthamo (amazinga e-TG eqenjini ngalinye le-dose ancishiswe ngamaphesenti angu-51, 57 kanye namaphesenti angu-63, ngokulandelana, uma kuqhathaniswa nalabo abaseqenjini le-placebo) (P <0.0). I-ANGPTL3 nayo yehle ngamaphesenti angama-54, amaphuzu angama-70 namaphesenti angama-74, ngokulandelana. Amazinga we-non-hdl-c ehle ngamaphesenti angu-29, amaphuzu angu-29, namaphesenti angu-36, amazinga e-apolipoprotein B ehle ngamaphesenti angu-19, amaphuzu angu-15, namaphesenti angu-22, futhi amazinga e-LDL-C ehle ngamaphesenti angu-16, amaphuzu angu-14, futhi le miphumela yamaphesenti angu-3, ​​isonto ngalinye, ngamaphesenti angu-20 ngokulandelana. Ngesonto lama-24, zodasiran
Ku-88% weziguli eqenjini le-200 mg, i-TG yokuzila ukudla yayiwele ebangeni elijwayelekile.

Imicibisholo ebomvu osukwini 1 no-12 ibonisa ukuphathwa kwe-zodasiran noma i-placebo.

Amazinga we-TG yokuzila ukudla ehle afinyelela evamile ngeviki lama-24 (150
mg/dL noma ngaphansi)
Insika ngayinye imelela isiguli esisodwa.

Ucwaningo luphinde lwaqaphela ukuthi i-zotasiran yayiphephile kuwo wonke amaqembu omthamo, ngeziguli ezi-2 kuphela eziyekisa ucwaningo ngenxa yezehlakalo ezingezinhle (1 eqenjini le-placebo no-1 eqenjini le-zotasiran le-100 mg). Zonke izehlakalo ezimbi kakhulu eqenjini le-zotasiran zilulame ekupheleni kocwaningo, futhi kwaba nokufa oyedwa eqenjini le-placebo. Okuwukuphela kwesigameko esibi esikhathazayo kwaba ukwenyuka kwe-HBA1c eqenjini le-zotasiran le-200 mg uma kuqhathaniswa ne-placebo (ushintsho olusho ukusuka kwesisekelo kuya kwesonto lama-24 [±SD], 0.38±0.66% vs. -0.03±0.88% ezigulini ezinesifo sikashukela esivele sikhona). Iziguli ezingenaso isifo sikashukela zazingu-0.12±0.19% vs. -0.03±0.19%).
Ikakhulukazi, cishe zonke iziguli ocwaningweni (96%) zaziphathwa nge-statins (37% yazo okwakuyi-statins ye-dose ephezulu), i-1% yayiphathwa nge-proprotein-converting enzyme subtilysin 9 inhibitor (PCSK9i), kanti i-21% yayiphathwa nge-fibrate. Ngakho-ke, ukungezwa kwe-zodasiran ngesisekelo sohlelo lokwelapha oluvamile lwamanje kusenemiphumela ephawulekayo yokwehlisa i-lipid, ehlinzeka ngohlelo olusha lokwelapha i-hyperlipidemia exubile esikhathini esizayo.
Evikini lama-24, umthamo omkhulu wama-200 mg we-zotasiran ocwaningweni wehlise amazinga e-cholesterol ayinsalela ngo-34.4 mg/dL uma kuqhathaniswa ne-placebo. Ngokusekelwe kumamodeli amanje, lokhu kuncipha kulindeleke ukuthi kunciphise izenzakalo ezinkulu ezimbi zenhliziyo ngamaphesenti angu-20. I-zodasiran inamandla okusetshenziswa njenge-monotherapy yazo zonke izingxenye ze-lipoprotein ukunciphisa ingozi yezenzakalo zenhliziyo nemithambo yegazi ezigulini. Ngakho-ke ucwaningo olwengeziwe luyadingeka ukuze kutholwe amandla alo muthi ekwehliseni ubungozi besifo se-atherosclerotic.
Ucwaningo lwe-MUIR lweSigaba 2b, olungaboni kabili, olungahleliwe, olulawulwa yi-placebo, olushicilelwe ngesikhathi esisodwa ku-NEJM, lusebenzise esinye isidakamizwa se-siRNA, i-plozasiran, ukwelapha i-hyperlipidemia exubile [2]. I-plozasiran yakhelwe ukunciphisa ukuvezwa kwe-APOC3, i-apolipoprotein C3 (APOC3) efaka izakhi zofuzo, umlawuli we-TG metabolism, esibindini, ngaleyo ndlela yehlise i-TG kanye namazinga e-cholesterol asele. Ukwehliswa kwe-TG namazinga e-cholesterol ayinsalela abonwa ocwaningweni ayefana nalawo atholakala ocwaningweni lwe-ARCHES-2. Ngakho-ke, kucatshangelwa ukuthi ezigulini ezine-hyperlipidemia exubile, le mithi yomibili inemiphumela efanayo ekwehliseni izinga le-triglyceride-rich lipoprotein kanye ne-cholesterol eyinsalela.
Imiphumela yezifundo ezimbili ze-siRNA ibonisa ukuthi leli yikilasi elithembisa kakhulu lezidakamizwa elizoletha izinketho ezintsha zokwelapha i-hyperlipidemia exubile futhi lithuthukise imiphumela yenhliziyo nemithambo yegazi ezigulini.