Glucagon-like Peptide-1 (GLP-1) is a kind of incretin secreted by intestinal L cells, which regulates the secretion of insulin and glucagon according to the body's blood sugar level and maintains blood sugar stability. GLP-1 receptor agonists (GLP-1RA) is a new hypoglycemic drug developed in recent years, which activates GLP1 receptors by simulating natural GLP-1 to achieve the purpose of controlling blood sugar, while GLP-1RA also has multiple clinical benefi ts such as weight control and improvement of non-alcoholic fatty liver, and is gradually becoming the fi rst prescription drug for the treatment of diabetes. GLP-1RA that has been marketed is mainly injectable drugs, and compared with injection administration, oral preparations are convenient to administer, less painful to treat, and better patient compliance. Oral GLP-1RA has become one of the important research and development directions of new diabetes treatment drugs. In this paper, the current research and development status of GLP-1RA oral small molecule and peptide hypoglycemic drugs under research is summarized, the research and application progress of this target drug is analyzed, and evaluation strategies are provided from the aspects of nonclinical effi cacy and safety, in order to provide references for the development and application of similar drugs.
Li Zheng, Yin Maoshan, Wang Yin, Yin Huajing, Wu Shuang, Dai Xuedong, Wang Qingli, Sun Tao, Yu Bing
. Research Progress of Oral Glucagon-Like Peptide-1 Receptor Agonists and Consideration of Non-clinical Evaluation[J]. Chinese Pharmaceutical Affairs, 2023
, 37(7)
: 825
-833
.
DOI: 10.16153/j.1002-7777.2023.07.012
[1] World Health Organization.Diabetes[EB/OL].（2021）[2022-02-28].https://www.who.int/health-topics/diabetes#tab=tab_1.
[2] American Diabetes Association.Diagnosis and Classification of Diabetes Mellitus[J].Diabetes Care，2004，27（Suppl 1）：S5-S10.
[3] American Diabetes Association.Diagnosis and Classification of Diabetes Mellitus[J].Diabetes Care，2014，37（Suppl 1）：S81-S90.
[4] Cosentino F,Grant PJ,Aboyans V,et al.2019 ESC Guidelines on Diabetes,Pre-diabetes,and Cardiovascular Diseases Developed in Collaboration with the EASD [published correction appears in Eur Heart J.2020 Dec 1；41（45）：4317][J].Eur Heart J，2020，41（2）：255-323.
[5] Maahs DM,West NA,Lawrence JM,et al.Epidemiology of Type 1 Diabetes[J].Endocrinol Metab Clin North Am，2010，39（3）：481-497.
[6] International Diabetes Federation.IDF Diabetes Atlas 2021 10th Edtion[R/OL].（2021）[2022-02-28].https://diabetesatlas.org/atlas/tenth-edition/.
[7] Li Y,Teng D,Shi X,et al.Prevalence of Diabetes Recorded in Mainland China Using 2018 Diagnostic Criteria from the American Diabetes Association:National Cross Sectional Study[J/OL].BMJ，2020，369:m997（2020-04-28）[2022-02-28].https://pubmed.ncbi.nlm.nih.gov/32345662/.doi:10.1136/bmj.m997.
[8] International Diabetes Federation and the World Obesity Federation.Obesity and Type 2 Diabetes:A Joint Approach to Halt the Rise[EB/OL].（2022-04-04）[2022-05-12].https://idf.org/our-activities/advocacy-awareness/advocacy-activities/advocacy-events/obesity-and-type2-diabetes-a-joint-approach-to-halt-the-rise.
[9] Hou X,Lu J,Weng J,et al.Impact of Waist Circumference and Body Mass Index on Risk of Cardiometabolic Disorder and Cardiovascular Disease in Chinese Adults:A National Diabetes and Metabolic Disorders Survey[J/OL].PLoS One，2013，8（3）：e57319（2013-03-08）[2022-05-12].https://pubmed.ncbi.nlm.nih.gov/23520466/.doi:10.1371/journal.pone.0057319.
[10] Wing RR,Lang W,Wadden TA,et al.Benefits of Modest Weight Loss in Improving Cardiovascular Risk Factors in Overweight and Obese Individuals with Type 2 Diabetes[J].Diabetes Care，2011，34（7）：1481-1486.
[11] Bashyam M.Diabetic Medications:Pros and Cons[EB/OL].（2019-12-20）[2022-02-28].https://diabetesconsult.in/diabetic-medications-pros-and-cons/.
[12] Romera I,Cebrián-Cuenca A,álvarez-Guisasola F,et al.A Review of Practical Issues on the Use of Glucagon-Like Peptide-1 Receptor Agonists for the Management of Type 2 Diabetes[J].Diabetes Ther，2019，10（1）：5-19.
[13] Collins L,Costello RA.Glucagon-like Peptide-1 Receptor Agonists [M/OL].In:StatPearls.Treasure Island(FL):StatPearls Publishing（2022-03-31）[2022-05-12].https://www.ncbi.nlm.nih.gov/books/NBK551568/.
[14] AJMC.Challenges in Diabetes Management:Glycemic Control,Medication Adherence,and Healthcare Costs[EB/OL].（2017-08-21）[2022-02-28].https://www.ajmc.com/view/challenges-in-diabetes-management-article.
[15] Brubaker PL,Drucker DJ.Structure-function of the Glucagon Receptor Family of G Protein-coupledReceptors:the Glucagon,GIP,GLP-1,and GLP-2 Receptors[J].Recept Channels，2002，8（3-4）：179-188.
[16] Underwood CR,Garibay P,Knudsen LB,et al.Crystal Structure of Glucagon-like Peptide-1 in Complex with the Extracellular Domain of the Glucagon-like Peptide-1 Receptor[J].J Biol Chem，2010，285（1）：723-730.
[17] Song G,Yang D,Wang Y,et al.Human GLP-1 Receptor Transmembrane Domain Structure in Complex with Allosteric Modulators[J].Nature，2017，546（7657）：312-315.
[18] Wootten D,Reynolds CA,Koole C,et al.A HydrogenBonded Polar Network in the Core of the GlucagonLike Peptide-1 Receptor Is a Fulcrum for Biased Agonism:Lessons from Class B Crystal Structures[J].Mol Pharmacol，2016，89（3）：335-347.
[19] Willard FS,Sloop KW.Physiology and Emerging Biochemistry of the Glucagon-like Peptide-1 Receptor [J/OL].Exp Diabetes Res，2012，2012：470851（2012-05-14）[2022-02-28].https://pubmed.ncbi.nlm.nih.gov/22666230/.doi:10.1155/2012/470851.
[20] 胡中平，程念，杨帆，等.GLP-1R结构和功能及小分子药物筛选研究进展[J].生物技术通报，2017，33（2）：30-40.
[21] Leech CA,Holz GG,Chepurny O,et al.Expression of cAMP-regulated Guanine Nucleotide Exchange Factors in Pancreatic Beta-cells [J].Biochem Biophys Res Commun，2000，278（1）：44-47.
[22] Shukla AK,Xiao K,Lefkowitz RJ.Emerging Paradigms of β-arrestin-dependent Seven Transmembrane Receptor Signaling[J].Trends Biochem Sci，2011，36（9）：457-469.
[23] Luan B,Zhao J,Wu H,et al.Deficiency of a Betaarrestin-2 Signal Complex Contributes to Insulin Resistance[J].Nature，2009，457（7233）：1146-1149.
[24] Gallwitz B,Giorgino F.Clinical Perspectives on the Use of Subcutaneous and Oral Formulations of Semaglutide [J/OL].Front Endocrinol(Lausanne)，2021，12：645507（2021-06-29）[2022-03-01].https://pubmed.ncbi.nlm.nih.gov/34267725/.doi:10.3389/fendo.2021.645507.
[25] Ravi AD,Sadhna D,Nagpaal D,et al.Needle Free InjectionTechnology:A Complete Insight[J].Int J Pharm Investig，2015，5（4）：192-199.
[26] Giorgino F,Penfornis A,Pechtner V,et al.Adherence to Antihyperglycemic Medications and Glucagon-like Peptide 1-receptor Agonists in Type 2 Diabetes:Clinical Consequences and Strategies for Improvement[J].Patient Prefer Adherence，2018，12：707-719.
[27] Drucker DJ.Advances in Oral Peptide Therapeutics[J].Nat Rev Drug Discov，2020，19（4）：277-289.
[28] Zelikin AN,Ehrhardt C,Healy AM.Materials and Methods for Delivery of Biological Drugs[J].Nat Chem，2016，8（11）：997-1007.
[29] Malkov D,Angelo R,Wang HZ,et al.Oral Delivery of Insulin with the Eligen Technology：Mechanistic Studies[J].Curr Drug Deliv，2005，2（2）：191-197.
[30] Buckley ST,B?kdal TA,Vegge A,et al.Transcellular Stomach Absorption of a Derivatized Glucagon-like Peptide-1 Receptor Agonist[J/OL].Sci Transl Med,2018,10(467):eaar7047（2018-11-14）[2022-03-01].https://pubmed.ncbi.nlm.nih.gov/30429357/.doi:10.1126/scitranslmed.aar7047.
[31] Chae SY,Jin CH,Shin HJ,et al.Preparation,Characterization,and Application of Biotinylated and Biotin-PEGylated Glucagon-like Peptide-1 Analogues for Enhanced Oral Delivery[J].Bioconjug Chem，2008，19（1）：334-341.
[32] Bucheit JD,Pamulapati LG,Carter N,et al.Oral Semaglutide:A Review of the First Oral Glucagon-Like Peptide 1 Receptor Agonist[J].Diabetes Technol Ther，2020，22（1）：10-18.
[33] Novo Nordisk.Novo Nordisk to Enter Phase 3 Development in Alzheimer's Disease with Oral Semaglutide[EB/OL].（2020-12-16）[2022-03-01].https://www.globenewswire.com/news-release/2020/12/16/2146164/0/en/Novo-Nordisk-to-enter-phase-3-development-inAlzheimer-s-disease-with-oral-semaglutide.html.
[34] Oramed Pharmaceuticals Inc.Breakthrough Technology for a Brighter Future[EB/OL].（2014-02-27）[2022-03-01].http://media.corporate-ir.net/media_files/IROL/18/180902/presentations/2014-02-27-Oramed-CorporatePresentation-Feb-2014.pdf.
[35] Oramed Pharmaceuticals Inc.Oramed Initiates Phase I OralGLP-1 Study Under IND[EB/OL].（2019-01-22）[2022-03-01].https://chinese.oramed.com/oramed-initiatesphase-i-oral-glp-1-study-under-ind/.
[36] Oramed Pharmaceuticals Inc.Oramed Issues Letter to Shareholders[EB/OL].（2021-01-27）[2022-03-01].https://www.nasdaq.com/press-release/oramed-issuesletter-to-shareholders-2021-01-27.
[37] Fernandez L,Bustos RH,Zapata C,et al.Immunogenicity in Protein and Peptide Based-Therapeutics:An Overview[J].Curr Protein Pept Sci，2018，19（10）：958-971.
[38] NIH.ChemlDplus[M/OL].Bethesda,MD,USA:National Center for Biotechnology Information,2018[2022-03-02].https://chem.nlm.nih.gov/chemidplus/rn/2230198-02-2.
[39] Pfizer.Internal Medicine Presentation[EB/OL].（2020）[2022-03-02].https://s28.q4cdn.com/781576035/files/doc_presentation/2020/09/14/Internal-Medicine_FINAL.pdf.
[40] Saxena AR,Gorman DN,Esquejo RM,et al.Danuglipron(PF-06882961)in Type 2 Diabetes:A Randomized,Placebo-controlled,Multiple Ascending-dose Phase 1 Trial[J].Nat Med，2021，27（6）：1079-1087.
[41] Kawai T,Sun B,Yoshino H,et al.Structural Basis for GLP1 Receptor Activation by LY3502970,an Orally Active Nonpeptide Agonist[J].Proc Natl Acad Sci USA，2020，117（47）：29959-29967.
[42] Clinicaltrials.gov.Multiple Escalating Oral Doses Study of PF-07081532 in Adult Participants With Type 2 Diabetes Mellitus[EB/OL].（2021-09-22）[2022-03-02].https://clinicaltrials.gov/ct2/show/NCT04305587.
[43] Chugai Pharmaceutical Co.,Ltd.Chugai and Lilly Enter into a License Agreement for Oral GLP-1 Agonist,OWL833[EB/OL].（2018-09-27）[2022-03-02].https://www.chugaipharm.co.jp/english/news/detail/20180927080000_551.html#:~:text=TOKYO%20 %2F%20INDIANAPOLIS%2C%20IN%2C%20-%20 Chugai%20Pharmaceutical%20Co.%2C,studied%20 for%20the%20treatment%20of%20type%202%20diabetes.
[44] Eli Lilly.Diabetes & Obesity（Investment Community Meeting，2021）[EB/OL].[2022-03-02].https://investor.lilly.com/static-files/34f9ec12-02a9-4452-843e0501309bde98.
[45] Eli Lilly.Medicines in Development[EB/OL].[2022-05-12].https://www.lilly.com/discovery/clinical-developmentpipeline.
[46] Freeman J,Gustafson S,Dunn I,et al.Oral Small Molecule GLP-1 Receptor(GLP-1R)Agonists for Type 2 Diabetes(T2DM)with Negligible Nausea and Vomiting[EB/OL].（2016）[2022-03-02].http://vtvtherapeutics.com/wp-content/uploads/pdf/GLP_Poster_ LaJolla_2016_19APR2016_FINAL.pdf.
[47] Freeman J,Dunn I,Valcarce C.Beyond Topline Results for the Oral(Non-Peptide)GLP-1R Agonist TTP273 in Type 2 Diabetes:How much and When?[EB/OL]（2017-09-13）[2022-03-02].https://www.easd.org/virtualmeeting/home.html#!resources/beyond-topline-results-for-theoral-non-peptide-glp-1r-agonist-ttp273-in-type-2-diabetes-how-much-and-when.
[48] SCOHIA PHARMA,Inc.SCO-094（GLP-1R/GIPR Dual Agonist）[EB/OL].[2022-05-12].https://www.scohia.com/eng/sys/pipeline/sco-094/.
[49] Müller TD,Finan B,Bloom SR,et al.Glucagon-likePeptide 1(GLP-1)[J].Mol Metab，2019，30：72-130.
[50] Evaluate Pharma.Rybelsus[EB/OL].[2022-03-14].https://app.evaluate.com/ux/WebReport/tabbedsummarypage.aspx?lType=modData&itemId=121367&compId=1002&reporti ngCurrency=&sceName=&showTabs=1398.
[51] Yuliantie E,Darbalaei S,Dai A,et al.Pharmacological Characterization of Mono-,Dual-and Tri-peptidic Agonists at GIP and GLP-1 Receptors[J/OL].Biochem Pharmacol,2020,177:114001（2020-04-29）[2022-05-12].https://pubmed.ncbi.nlm.nih.gov/32360365/.doi:10.1016/j.bcp.2020.114001.
[52] Cho YM,Merchant CE,Kieffer TJ.Targeting the Glucagon Receptor Family for Diabetes and Obesity Therapy[J].Pharmacol Ther，2012，135（3）：247-278.
[53] Ipp E,Genter P,Childress K.Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes[J].N Engl J Med，2017，376（9）：890-891.
