Semaglutid (GLP-1) 5 mg

▎ GLP-1 Structure

▎ GLP-1 Kev Tshawb Fawb

Kev tshawb fawb keeb kwm ntawm GLP-1 yog dab tsi?

GLP-1 yog tib neeg glucagon-zoo li peptide-1 (GLP-1) analogue, koom nrog hauv chav kawm ntawm GLP-1 receptor agonist tshuaj. GLP-1 yog cov tshuaj hormones uas tshwm sim los ntawm cov kab mob hauv cov hnyuv tom qab noj mov, uas txhawb nqa cov tshuaj insulin secretion thiab inhibits glucagon secretion los tswj cov ntshav qabzib. Txoj kev loj hlob ntawm GLP-1 pib los ntawm kev tshawb fawb tob txog kev ua haujlwm ntawm lub cev ntawm GLP-1. GLP-1 muaj ib nrab-lub neej luv luv hauv lub cev, txog 1-2 feeb, vim nws yooj yim degraded los ntawm dipeptidyl peptidase-4 (DPP-4) enzymes hauv lub cev. Txhawm rau kov yeej qhov kev txwv no, cov kws tshawb fawb tau hloov kho cov qauv ntawm GLP-1, qhia txog cov amino acid hloov pauv thiab ntxiv cov pab pawg tiv thaiv los txhim kho nws qhov tsis kam rau DPP-4 enzymes, yog li ncua nws lub sijhawm ua haujlwm hauv lub cev ^[1] . Hauv cov qauv ntawm GLP-1, alanine ntawm txoj hauj lwm 8 yog hloov los ntawm α-aminoisobutyric acid (Aib), uas tsis tsuas yog txhim kho kev ruaj ntseg ntawm cov tshuaj, tab sis kuj txhim kho nws txoj kev sib khi quab yuam nrog GLP-1 receptors ^[2] . Ib qho tshwj xeeb fatty acid sab saw yog ntxiv rau C-terminus ntawm GLP-1, uas txuas nrog lysine residue ntawm γ-glutamine, txuas ntxiv cov tshuaj ib nrab-lub neej thiab tso cai rau nws txhaj tshuaj ib zaug ib lim piam lossis noj ib hnub ib zaug ^[1] . GLP-1 tau pib tsim los ntawm kev tshawb fawb thiab kev hloov kho ntawm ntuj GLP-1, txhawm rau muab kev kho mob zoo dua rau cov neeg mob ntshav qab zib hom 2 ^{[1, 2]} . Los ntawm cov qauv kev ua kom zoo dua qub, GLP-1 tsis tsuas yog khaws cov kev ua haujlwm ntawm lub cev ntawm GLP-1 tab sis kuj tseem txhim kho nws cov tshuaj pharmacokinetic, dhau los ua GLP-1 receptor agonist ntev ntawm cov nqi kho mob tseem ceeb. Kev txhim kho ntawm GLP-1 yog qhov ua tiav tseem ceeb, nqa cov kev kho tshiab rau cov neeg mob ntshav qab zib hom 2. Los ntawm optimizing cov qauv ntawm ntuj GLP-1, nws kov yeej qhov kev txwv ntawm nws luv luv ib nrab-lub neej thiab txhim kho cov tshuaj stability thiab lub sij hawm ntawm kev ua.

GLP-1 mechanism ntawm kev txiav txim yog dab tsi?

GLP-1 yog qhov ua haujlwm ntev ntawm glucagon-zoo li peptide-1 (GLP-1) receptor agonist, thiab nws cov txheej txheem ntawm kev ua haujlwm yog ua tiav los ntawm cov hauv qab no:

Kev tswj cov ntshav qabzib:

GLP-1 yog ib qho tshiab GLP-1 receptor agonist (GLP-1RA). Nws lub luag haujlwm tseem ceeb yog txhawm rau txo qis kev xav tau ntawm cov zaub mov los ntawm inhibiting qab los noj mov, txo qhov kev nyiam rau cov zaub mov muaj roj, thiab hloov kho qhov chaw noj zaub mov hypothalamic kom txo tau cov zaub mov noj. Nws kuj ua rau kom satiety, ncua lub plab khoob, thiab txo cov plab hnyuv motility, yog li ua tiav qhov hnyav. Qhov kev txo qhov hnyav no txhim kho cov tshuaj insulin rhiab heev thiab pab tswj cov ntshav qabzib ^[3] . GLP-1 induces poob ceeb thawj nyob rau hauv nas los ntawm kev faib neural pathways. Cov kev tshawb fawb pom tias nws ua rau lub paj hlwb, septal nucleus, thiab hypothalamus tab sis tsis hla cov ntshav-hlwb barrier. Hloov chaw, nws cuam tshuam nrog lub hlwb los ntawm cov kab mob hauv lub cev thiab cov chaw ventricular-proximal. GLP-1 activates c-Fos nyob rau hauv kaum lub hlwb cheeb tsam, nrog rau cov hindbrain cheeb tsam ncaj qha mus rau lub hom phiaj thiab theem nrab cheeb tsam xws li lub lateral parabrachial nucleus yam tsis muaj kev cuam tshuam ncaj qha GLP-1R. Kev tshuaj xyuas tsis siv neeg qhia tias kev ua kom muaj feem cuam tshuam nrog rau sab nraud parabrachial nucleus neurons tswj kev noj mov, yog li tswj cov ntshav qabzib ^[4] .

Txoj cai ntawm plab hnyuv:

GLP-1 ua haujlwm ntawm GLP-1 receptors hauv plab, siv txoj hauv kev vagus hlab ntsha los hloov kho lub plab zom mov. Nws inhibits antral contractions, bolsters pyloric sphincter nro, thiab prolongs gastric zaub mov tuav, ncua duodenal nkag thiab tiv thaiv postprandial ntshav qabzib spikes, ua rau kom ntau ruaj khov ^[5] . Tsis tas li ntawd, GLP-1 cuam tshuam rau hauv nruab nrab GLP-1 receptors, tshwj xeeb tshaj yog nyob rau hauv hypothalamic arcuate thiab paraventricular nuclei. Nws inhibits qab los noj mov-stimulating yam xws li neuropeptide Y (NPY) thiab agouti-txog protein (AgRP), thaum activating proopiomelanocortin (POMC) neurons los boost alpha-melanocyte-stimulating hormone (α-MSH) secretion ^[5] . Cov kev ua no txhawb kom satiety, txo cov kev tshaib kev nqhis, thiab txo cov zaub mov kom tsawg, pab tswj qhov hnyav thiab tsis ncaj ncees rau kev tswj ntshav qabzib.

Kev tiv thaiv kab mob plawv:

GLP-1 txhawb kev tso tawm ntawm nitric oxide (NO) thiab lwm yam vasodilators los ntawm vascular endothelial hlwb, txhim kho vasodilation thiab ntshav khiav. Nws kuj inhibits o thiab oxidative kev nyuaj siab, txo endothelial puas thiab atherosclerosis. Los ntawm kev txo qis qab los noj mov thiab noj zaub mov, nws pab kom poob phaus, txhim kho lipid ntshav qab zib, txo qis triglycerides thiab qis lipoprotein cholesterol (LDL-C), thiab nce siab lipoprotein cholesterol (HDL-C). Tsis tas li ntawd, nws yuav pab tau cov ntshav siab los ntawm kev hloov kho lub raum hemodynamics thiab neuroendocrine muaj nuj nqi, txo qis kev pheej hmoo siab kub siab thiab txo cov kab mob plawv ^[6] .

GLP-1 thiab kev tswj hwm kev hloov pauv ntawm WAT rau BAT hloov pauv thiab ua kom BAT.

Source: PubMed ^[13]

Cov kev sim thiab kev tshawb fawb tseem ceeb

Nyob rau hauv cov nqe lus ntawm cov qauv tshuaj tsim thiab optimization, thaum lub sij hawm tsim ntawm GLP-1, ib txoj kev ntawm reversible binding rau albumin tau txais yuav kom ncua lub sij hawm ntawm kev ua ntawm cov tshuaj. Los ntawm kev txiav txim siab kev sib xyaw ua ke ntawm fatty acids thiab linkers, lub peev xwm khi rau albumin tau ua kom siab tshaj plaws thaum tswj hwm qhov ua tau zoo ntawm GLP-1 receptor (GLP-1R) (Knudsen LB, 2019).

Nyob rau hauv cov nqe lus ntawm kev siv tshuaj, GLP-1 muaj superior yuag poob. GLP-1 yog glucagon-zoo li peptide-1 receptor agonist (GLP-1 RA) nrog kev tshem tawm ntev ib nrab-lub neej, tso cai rau kev txhaj tshuaj subcutaneous txhua lub lim tiam. Nws cov nyhuv poob yog qhov zoo kawg li. Hauv cov neeg mob uas muaj ntshav qab zib hom 2 (T2DM), kev txhaj tshuaj subcutaneous txhua lub limtiam ntawm GLP-1 zoo li muaj txiaj ntsig zoo rau kev poob phaus dua li lwm lub limtiam GLP-1RAs. Hauv theem II kev tshawb nrhiav tshuaj rau cov neeg mob rog rog yam tsis muaj T2DM, kev txhaj tshuaj subcutaneous ib hnub ntawm GLP-1 tau zoo dua rau qhov hnyav dua li cov placebo thiab ib hnub ib zaug 3.0mg liraglutide. Kev poob phaus los ntawm GLP-1 hauv txoj kev tshawb fawb no tau dhau los ntawm cov qauv tshuaj tiv thaiv kev rog uas tau teeb tsa los ntawm European Medicines Agency (EMA) thiab US Food and Drug Administration (FDA), tsis muaj teeb meem kev nyab xeeb, qhia tias kev txhaj tshuaj subcutaneous ib hnub ntawm GLP-1 muaj peev xwm los ua cov tshuaj yuag yav tom ntej ^[7] .

GLP-1 tuaj yeem txhim kho kev ua haujlwm plawv thiab siv rau kev kho mob plawv. Cov txiaj ntsig ntawm STEP-HFpEF kev sim tau tshaj tawm, nyob rau hauv uas koob tshuaj antidiabetic glucagon zoo li peptide 1 agonist GLP-1 tau txhim kho cov tsos mob ntawm lub plawv tsis ua hauj lwm nrog kev khaws cia ejection feem (HFpEF) thiab txo N-terminal pro-B-hom natriuretic peptide (NT-proBNP) qib. Txoj kev tshawb no tau sim cov txiaj ntsig ntawm kev kho mob GLP-1 mob rau ntawm tib neeg txoj cai atrial trabeculae thiab pom tias GLP-1 nce qhov nro ntawm tib neeg atrial trabeculae ntau dua peb zaug hauv kev siv tshuaj, yam tsis muaj kev xav rau arrhythmias. Cov nyhuv no feem ntau yuav yog vim muaj kev nce ntxiv ntawm sarcoplasmic reticulum Ca2+ uptake. Kev kho mob siab GLP-1 hauv cov neeg mob plawv tsis ua haujlwm tuaj yeem txhim kho atrial muaj nuj nqi thiab yog li txo cov tsos mob ^[8] .

GLP-1 tab tom kawm txog kev kho mob tsis muaj cawv steatohepatitis (NASH). Nws txoj kev tsim qauv tsim nyog tau ua rau muaj txiaj ntsig zoo rau kev txhim kho cov ntshav qabzib, qhov hnyav, ntshav siab, lipids, β-cell muaj nuj nqi, thiab cov hlab plawv hauv cov neeg mob ntshav qab zib hom 2. Tsis tas li ntawd, kev tsim kho qhov ncauj ntawm GLP-1 tuaj yeem muab cov txiaj ntsig ntxiv rau cov neeg mob hais txog kev ua raws li kev kho mob ^[9] .

Qhov sib txawv ntawm qhov hnyav poob los ntawm GLP-1 thoob plaws tib neeg

Kev poob phaus cuam tshuam rau cov neeg laus uas muaj kab mob plawv, rog dhau lossis rog yam tsis muaj ntshav qab zib: 

Hauv kev sim SELECT cardiovascular cov txiaj ntsig, GLP-1 txo qis cov xwm txheej mob plawv loj (MACE) los ntawm 20% hauv 17,604 cov neeg laus uas muaj kab mob plawv, rog dhau lossis rog, thiab tsis muaj ntshav qab zib ^[10] . Hauv qhov kev ntsuam xyuas ua ntej no, cov kws tshawb fawb tau tshuaj xyuas qhov cuam tshuam ntawm GLP-1 ntawm qhov hnyav, qhov tshwm sim ntawm anthropometric, kev nyab xeeb, thiab kev ua siab ntev los ntawm qhov ntsuas lub cev qhov hnyav (BMI). Cov neeg mob tau txais GLP-1 tau ntsib kev poob phaus ntau dua 65 lub lis piam, txuas ntxiv mus txog 4 xyoos. Ntawm 208 lub lis piam, GLP-1 tau ua rau qhov hnyav dua qhov hnyav (-10.2%), lub duav ncig (-7.7 cm), thiab lub duav-rau-qhov siab (-6.9%) piv rau cov placebo (-1.5%, -1.3 cm, thiab -1.0%, feem; txhua qhov kev sib piv yog cov txiv neej lub cev hnyav, txhua hom poj niam cev xeeb tub. thiab cov cheeb tsam GLP-1 tau cuam tshuam nrog tsawg dua cov xwm txheej tsis zoo rau txhua pawg BMI (<30, 30 txog <35, 35 txog <40, thiab ≥40 kg / m²), GLP-1 muaj qhov tshwm sim tsis zoo (cov xwm txheej hauv 100 tus neeg-xyoos: 43.23, 451.54, 43.23, 451.54, 43.23, 451.54. 50.48, 49.66, 52.73, thiab 60.85 rau cov placebo).

Kev poob phaus cuam tshuam rau cov neeg rog lossis rog rog uas tsis muaj ntshav qab zib:  

Kev tshuaj xyuas zoo tau ntsuas qhov ua tau zoo thiab kev nyab xeeb ntawm GLP-1 hauv cov neeg rog lossis rog rog yam tsis muaj ntshav qab zib ^[11] . Qhov kev tshuaj xyuas no tau tsim cov txiaj ntsig los ntawm ntau qhov kev sim tshuaj ntsuam xyuas, qhia txog GLP-1 qhov cuam tshuam rau kev poob phaus, metabolic tsis, thiab tag nrho cov txiaj ntsig kev noj qab haus huv. Cov kev tshawb pom tau qhia tias GLP-1 tau cuam tshuam nrog kev poob phaus thiab kev txhim kho hauv kev noj qab haus huv ntsig txog kev rog, qhia tias nws muaj peev xwm ua qhov kev xaiv zoo rau cov neeg mob rog. 

Kev poob ceeb thawj hauv cov neeg mob uas tsis yog mob ntshav qab zib (Cov pov thawj los ntawm ntau RCTs): 

Plaub randomized tswj kev sim (RCTs) nrog rau cov neeg mob uas qhov hnyav ntawm 96-105 kg tau soj ntsuam txhua lub lim tiam 2.4 mg subcutaneous GLP-1 ntxiv rau kev ua neej nyob (kev tawm tswv yim, noj zaub mov, kev ua si lub cev) rau kev poob phaus ^[12] . Ib qho RCT hauv cov neeg mob uas tsis muaj ntshav qab zib (N = 1,961) tau tshaj tawm qhov kev poob qis ntawm 15% (15 kg) vs. 2% (3 kg) nrog cov placebo tom qab 68 lub lis piam (kuj tseem ceeb). Qhov feem pua ​​​​ntawm cov neeg mob ua tiav ≥5% poob phaus yog 86% vs. 32% (tus naj npawb xav tau los kho [NNT] = 2), thiab ≥10% poob phaus yog 69% vs. 12% (NNT = 2). Poob poob siab ntawm ~ 60 lub lis piam. Gastrointestinal adverse events (AEs) tshwm sim nyob rau hauv 74% vs. 48% (tus naj npawb xav tau los ua mob [NNH] = 3). Kev txiav tawm vim yog AEs yog 7% vs. 3% (NNH = 25). Cov txiaj ntsig zoo sib xws tau pom hauv lwm RCT nrog kev cuam tshuam kev ua neej hnyav (N = 611): GLP-1 ntxias 16% (17 kg) vs. 6% (6 kg) poob phaus. Hauv kev tshawb nrhiav tshuaj RCT hauv cov neeg mob uas tsis yog ntshav qab zib mellitus (N = 1,210), txhua lub lis piam 2.4 mg GLP-1, 1.0 mg GLP-1, lossis cov placebo yielded qhov hnyav poob ntawm 10%, 7%, thiab 3% tom qab 68 lub lis piam. Cov txiaj ntsig ua tiav ≥5% poob phaus yog 69% (2.4 mg), 57% (1.0 mg), thiab 29% (placebo). Rau 2.4 mg vs. 1.0 mg, NNT = 9. AE profiles tau zoo sib xws hauv cov koob tshuaj. Hauv kev saib xyuas qhov hnyav RCT (N = 803), cov neeg uas tsis yog ntshav qab zib tau txais 2.4 mg GLP-1 txhua lub lim tiam rau 20 lub lis piam, tom qab ntawd tau randomized txuas ntxiv GLP-1 lossis hloov mus rau cov placebo. Tom qab 48 lub lis piam, txuas ntxiv GLP-1 cov neeg siv poob 8% piv rau cov neeg siv placebo nce 7%. 

Hauv cov ntsiab lus, GLP-1 yog GLP-1 receptor agonist nrog ntau daim ntawv thov tus nqi. Hauv kev kho mob ntshav qab zib, nws khi rau GLP-1 receptors los txhawb cov tshuaj insulin secretion thiab inhibit glucagon tso tawm, tswj cov ntshav qab zib kom zoo thiab muab kev kho mob tseem ceeb rau cov neeg mob ntshav qab zib hom 2. Hauv kev kho mob rog rog, GLP-1 tuaj yeem txo qis kev noj qab haus huv los ntawm cov txheej txheem xws li kev noj qab haus huv hauv nruab nrab thiab ua rau lub plab zom mov qeeb, pab cov neeg mob rog rog thiab txhim kho lawv cov txheej txheem metabolic. Tsis tas li ntawd, GLP-1 qhia tau hais tias muaj peev xwm thov kev cia siab rau hauv kev tiv thaiv thiab kho cov kab mob plawv, thiab nws txoj kev txhim kho ntawm cov kab mob plawv muaj txoj hauv kev tshiab los txo cov xwm txheej ntawm cov hlab plawv. Qhov tshwm sim ntawm GLP-1 tsis yog tsuas yog txhawb txoj kev kho mob rau cov kab mob sib xws, tab sis kuj ua rau muaj kev cia siab tshiab rau kev txhim kho cov neeg mob lub neej thiab kev noj qab haus huv.

Hais Txog Tus Sau

Cov ntaub ntawv hais saum toj no yog txhua yam tshawb fawb, kho thiab sau los ntawm Cocer Peptides.

Scientific Journal Author

Hegner P yog tus kws tshawb fawb ntawm University of Regensburg. Nws txoj haujlwm nthuav dav Chemistry, Cardiovascular System, thiab Cardiology. Hauv Chemistry, nws tshawb nrhiav cov kev cuam tshuam cuam tshuam rau kev mob plawv. Hauv kev tshawb fawb Cardiovascular System, nws soj ntsuam lub plawv thiab hlab ntsha, nrhiav kev kho mob kev pom. Nws txoj kev tshawb fawb Cardiology tsom rau kev tiv thaiv kab mob plawv, kuaj mob, thiab kev kho mob.

Hegner qhov kev koom tes tseem ceeb heev. Nws cov kev pom tshuaj lom neeg tau txhawb nqa cov tshuaj kho mob plawv tshiab. Nws txoj haujlwm ntawm lub plawv thiab cov hlab ntsha mechanisms tau txhim kho kev nkag siab ntawm cov kab mob plawv. Clinically, nws cov kev tshawb fawb tau txhim kho kev tswj kab mob plawv, tsa cov qauv kev saib xyuas neeg mob. Zuag qhia tag nrho, Hegner txoj kev qhuab qhia ntau txoj hauv kev txhawb nqa cov tshuaj mob plawv, muab kev cia siab rau txo cov kab mob thiab cov txiaj ntsig zoo ntawm tus neeg mob. Hegner P tau teev nyob rau hauv kev siv ntawm cov ntaub ntawv pov thawj [8].

▎ Cov Lus Qhia Tseem Ceeb

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[2] Ma H, Huang W, Wang X, et al. Cov qauv kev pom zoo rau kev ua haujlwm ntawm GLP-1R los ntawm ib qho me me molecule agonist [J]. Cell Research, 2020,30(12):1140-1142.DOI:10.1038/s41422-020-0384-8.

[3] Kim HS, Jung C H. Oral GLP-1, Thawj Qhov Ncauj Glucagon-zoo li Peptide-1 Receptor Agonist: Nws Puas Yuav Ua Tau Khawv koob rau Hom 2 Ntshav Qab Zib?[J]. International Journal of Molecular Sciences, 2021,22(18).DOI:10.3390/ijms22189936.

[4] Gabery S, Salinas CG, Paulsen SJ, et al. GLP-1 txo qis lub cev hnyav hauv cov nas los ntawm kev faib cov neural [J]. Jci Insight, 2020,5(6).DOI:10.1172/jci.insight.133429.

[5] Katsurada K, Yada T. Neural teebmeem ntawm plab- thiab lub hlwb-derived glucagon-zoo li peptide-1 thiab nws cov receptor agonist [J]. Phau ntawv Journal of diabetes Investigation, 2016,7:64-69.DOI:10.1111/jdi.12464.

[6] Ryan DH, Lingvay I, Colhoun HM, et al. GLP-1 cuam tshuam rau cov txiaj ntsig ntawm cov hlab plawv hauv cov neeg muaj rog lossis rog (SELECT) qhov laj thawj thiab tsim [J]. American Heart Journal, 2020,229:61-69.DOI:10.1016/j.ahj.2020.07.008.

[7] Christou GA, Katsiki N, Blundell J, et al. GLP-1 raws li kev cog lus tshuaj tiv thaiv kev rog [J]. Obesity Reviews, 2019,20(6):805-815.DOI:10.1111/obr.12839.

[8] Hegner P, Seitz S, Schopka S, et al. GLP-1 txhim kho kev ua haujlwm contractile hauv tib neeg atrium [J]. European Heart Journal, 2024,45.DOI:10.1093/eurheartj/ehae666.3729.

[9] Knudsen LB, Lau J. The Discovery and Development of Liraglutide and GLP-1[J]. Frontiers hauv Endocrinology, 2019,10.DOI:10.3389/fendo.2019.00155.

[10] Ryan DH, Lingvay I, Deanfield J, et al. Kev poob phaus ntev ntev ntawm GLP-1 hauv kev rog rog yam tsis muaj ntshav qab zib hauv SELECT sim [J]. Nature Medicine, 2024,30(7):2049-2057.DOI:10.1038/s41591-024-02996-7.

[11] Alanazi M, Alshahrani JA, Aljaberi AS, et al. Qhov cuam tshuam ntawm GLP-1 hauv cov tib neeg uas muaj rog lossis rog dhau yam tsis muaj ntshav qab zib [J]. Cureus Journal of Medical Science, 2024,16(8).DOI:10.7759/cureus.67889.

[12] Ojeniran M, Dube B, Paige A, et al. GLP-1 rau poob phaus [J]. Canadian Family Physician, 2021,67(11):842.DOI:10.46747/cfp.6711842.

[13] Papakonstantinou I, Tsioufis K, Katsi V. Spotlight on the Mechanism of Action of GLP-1[J]. Cov teeb meem tam sim no hauv Molecular Biology, 2024,46(12): 14514-14541.DOI: 10.3390/cimb46120872.

Tag nrho cov kab lus thiab cov ntaub ntawv ntawm cov khoom lag luam muab rau ntawm lub vev xaib no tsuas yog rau cov ntaub ntawv tshaj tawm kev tshaj tawm thiab cov hom phiaj kev kawm.  

Cov khoom muab rau hauv lub vev xaib no yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro. Kev tshawb fawb hauv vitro (Latin: * hauv iav *, lub ntsiab lus hauv iav) yog ua los ntawm tib neeg lub cev. Cov khoom no tsis yog tshuaj, tsis tau txais kev pom zoo los ntawm US Food and Drug Administration (FDA), thiab yuav tsum tsis txhob siv los tiv thaiv, kho, lossis kho txhua yam mob, kab mob, lossis mob. Nws raug txwv nruj raws li txoj cai los qhia cov khoom no rau hauv tib neeg lossis tsiaj lub cev hauv txhua daim ntawv.