diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM12790diaendo-12790Research ArticleОбзорыReviewПероральный семаглутид — новая ¬инновационная опция в терапии сахарного диабета 2 типаOral semaglutide: the innovation in type 2 diabetes managementhttps://orcid.org/0000-0002-5057-127XШестаковаМ. В.ShestakovaM. V.

Шестакова Марина Владимировна, доктор медицинских наук, профессор, академик РАН

117036, Москва, ул. Дм. Ульянова, д. 11

eLibrary SPIN: 7584-7015

Marina V. Shestakova, MD, PhD, Professor

11 Dm. Ulyanova street, Moscow, 117036

eLibrary SPIN: 7584-7015

nephro@endocrincentr.ruhttps://orcid.org/0000-0002-3433-0142ШамхаловаМ. Ш.ShamkhalovaM. Sh.

Шамхалова Минара Шамхаловна, доктор медицинских наук

Москва

eLibrary SPIN: 4942-5481

Minara S. Shamkhalova, MD, PhD

Moscow

eLibrary SPIN: 4942-5481

 

shamkhalova@mail.ruhttps://orcid.org/0000-0001-6581-4521ГалстянГ. Р.GalstyanG. R.

Галстян Гагик Радикович, доктор медицинских наук, профессор

Москва

eLibrary SPIN: 9815-7509

Gagik R. Galstyan, MD, PhD, Professor

Moscow

eLibrary SPIN: 9815-7509

galstyangagik964@gmail.comhttps://orcid.org/0000-0002-6762-5238РуяткинаЛ. А.RuyatkinaL. A.

Руяткина Людмила Александровна, доктор медицинских наук, профессор

Новосибирск

eLibrary SPIN: 1895-7664

Lyudmila A. Ruyatkina, MD, PhD, Professor

Novosibirsk

eLibrary SPIN: 1895-7664

larut@list.ruhttps://orcid.org/0000-0001-7041-0732СуплотоваЛ. А.SuplotovaL. A.

Суплотова Людмила Александровна, доктор медицинских наук, профессор

Тюмень

Ludmila A. Suplotova, MD, PhD, Professor

Tyumen

suplotovala@mail.ruНациональный медицинский исследовательский центр эндокринологииРоссияEndocrinology Research CentreRussian FederationНовосибирский государственный медицинский университетRussian FederationNovosibirsk State Medical UniversityRussian FederationТюменский государственный медицинский университетRussian FederationTyumen State Medical UniversityRussian Federation202104082021243273281Copyright © Шестакова М.В., Шамхалова М.Ш., Галстян Г.Р., Руяткина Л.А., Суплотова Л.А., 20212021Шестакова М.В., Шамхалова М.Ш., Галстян Г.Р., Руяткина Л.А., Суплотова Л.А.Shestakova M.V., Shamkhalova M.S., Galstyan G.R., Ruyatkina L.A., Suplotova L.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/12790

Пероральный семаглутид — первый в классе агонистов рецепторов глюкагоноподобного пептида-1, доступный в форме для приема внутрь. В рамках клинической программы (PIONEER) по изучению эффектов перорального семаглутида было продемонстрировано дозозависимое действие препарата, и в максимальной дозе 14 мг пероральный семаглутид снижал уровень гликированного гемоглобина (HbA1c) на -1,4%, а массу тела — вплоть до 5 кг от исходных значений. Эффективность перорального семаглутида превосходила эмпаглифлозин 25 мг, лираглутид 1,8 мг и ситаглиптин 100 мг как по степени снижения уровня HbA1c, так и по снижению массы тела, что было продемонстрировано в соответствующих исследованиях клинической программы. С точки зрения сердечно-сосудистых исходов пероральный семаглутид доказал свою безопасность. Пероральная форма имеет свои особенности применения, которые следует учитывать для максимальной эффективности препарата, так как эффективная концентрация препарата зависит от корректности выполнения этих условий. Препарат необходимо принимать ежедневно натощак, запивая половиной стакана воды, за полчаса до приема пищи или других препаратов. Наиболее частые нежелательные явления на терапии семаглутидом (тошнота, диарея и рвота), характерные для класса, носили транзиторный характер и, как правило, проявлялись при повышении дозы препарата.

Oral semaglutide is the first-in-class glucagon-like peptide-1 receptor agonist available in the form of pills administered per os. PIONEER — the clinical trial program assessing the efficacy and safety of oral semaglutide — demonstrated the dose-­dependent efficacy of the drug: the reduction of up to -1,4% in terms of glucose-lowering effects and the decrease of up to 5 kg in terms of weight loss. Moreover, oral semaglutide is superior in this regard compared to empagliflozin 25 mg, liraglutide 1,8 mg and sitagliptin 100 mg according to the dedicated trials of clinical program. From the cardiovascular perspective oral semaglutide has been proven to be safe. Therapeutic concentration of semaglutide in oral form is reached under ­several conditions: taking tablets on a daily basis in a fasting state with up to half a glass of water and waiting 30 minutes before drinking, eating, or taking other drugs. Most frequent adverse events were GLP-1 associated gastrointestinal reactions (­nausea, vomiting and diarrhea), most of the events were transient and occurred generally during dose escalation.

сахарный диабет 2-го типапероральный семаглутидгликемический контрольсердечно-сосудистая безопасностьtype 2 diabetes mellitusoral semaglutideglycemic controlcardiovascular safetyReferencesRodbard HW. The Clinical Impact of GLP-1 Receptor Agonists in Type 2 Diabetes: Focus on the Long-Acting Analogs. Diabetes Technol Ther. 2018;20(S2):S2-33-S2-41. doi: https://doi.org/10.1089/dia.2018.0103Rodbard HW. The Clinical Impact of GLP-1 Receptor Agonists in Type 2 Diabetes: Focus on the Long-Acting Analogs. Diabetes Technol Ther. 2018;20(S2):S2-33-S2-41. doi: https://doi.org/10.1089/dia.2018.0103Nauck MA, Meier JJ. Management of endocrine disease: Are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol. 2019;181(6):R211-R234. doi: https://doi.org/10.1530/EJE-19-0566Nauck MA, Meier JJ. Management of endocrine disease: Are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol. 2019;181(6):R211-R234. doi: https://doi.org/10.1530/EJE-19-0566American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020. Diabetes Care. 2020;43(S1):S98-S110. doi: https://doi.org/10.2337/dc20-S009American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020. Diabetes Care. 2020;43(S1):S98-S110. doi: https://doi.org/10.2337/dc20-S009Дедов И.И., Шестакова М.В., Майоров А.Ю., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом: Клинические рекомендации (Вып. 9) // Сахарный диабет. — 2019. — Т. 22. — №S1. — С. 1-144. doi: https://doi.org/10.14341/DM221S1Dedov II, Shestakova MV, Mayorov AYu, et al. Standards of specialized diabetes care. Diabetes Mellitus. 2019;22(S1):1-144 (In Russ.). doi: https://doi.org/10.14341/DM221S1Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. J Am Coll Cardiol. 2019;74(10):e177-e232. doi: https://doi.org/10.1016/j.jacc.2019.03.010Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. J Am Coll Cardiol. 2019;74(10):e177-e232. doi: https://doi.org/10.1016/j.jacc.2019.03.010Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017. Cardiovasc Diabetol. 2018;17(1):83. doi: https://doi.org/10.1186/s12933-018-0728-6Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017. Cardiovasc Diabetol. 2018;17(1):83. doi: https://doi.org/10.1186/s12933-018-0728-6Mosenzon O, et al. CAPTURE: a cross-sectional study of the contemporary (2019) prevalence of cardiovascular disease in adults with type 2 diabetes across 13 countries. Abstract # 158 (Conference proceedigs). 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), ELECTR NETWORK. 2020.Mosenzon O, et al. CAPTURE: a cross-sectional study of the contemporary (2019) prevalence of cardiovascular disease in adults with type 2 diabetes across 13 countries. Abstract # 158 (Conference proceedigs). 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), ELECTR NETWORK. 2020.Lipska KJ, Yao X, Herrin J, et al. Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006–2013. Diabetes Care. 2017;40(4):468-475. doi: https://doi.org/10.2337/dc16-0985Lipska KJ, Yao X, Herrin J, et al. Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006–2013. Diabetes Care. 2017;40(4):468-475. doi: https://doi.org/10.2337/dc16-0985Gagliardino JJ, Atanasov PK, Chan JCN, et al. Resource use associated with type 2 diabetes in Africa, the Middle East, South Asia, Eurasia and Turkey: results from the International Diabetes Management Practice Study (IDMPS). BMJ Open Diabetes Res Care. 2017;5(1):1-10. doi: https://doi.org/10.1136/bmjdrc-2016-000297Gagliardino JJ, Atanasov PK, Chan JCN, et al. Resource use associated with type 2 diabetes in Africa, the Middle East, South Asia, Eurasia and Turkey: results from the International Diabetes Management Practice Study (IDMPS). BMJ Open Diabetes Res Care. 2017;5(1):1-10. doi: https://doi.org/10.1136/bmjdrc-2016-000297Shestakova M, et al. Epidemiology of diabetes in Russian Federation: What has changed over 2007-2019 yr? Abstract #339 (Conference proceedigs). 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), ELECTR NETWORK. 2020.Shestakova M, et al. Epidemiology of diabetes in Russian Federation: What has changed over 2007-2019 yr? Abstract #339 (Conference proceedigs). 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), ELECTR NETWORK. 2020.Pantalone KM, Misra-Hebert AD, Hobbs TM, et al. Antidiabetic treatment patterns and specialty care utilization among patients with type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol. 2018;17(1):54. doi: https://doi.org/10.1186/s12933-018-0699-7Pantalone KM, Misra-Hebert AD, Hobbs TM, et al. Antidiabetic treatment patterns and specialty care utilization among patients with type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol. 2018;17(1):54. doi: https://doi.org/10.1186/s12933-018-0699-7Vikulova O, et al. Glucose lowering medications use according to cardiac complications in patients with type 2 diabetes in real clinical practice. Abstract # 890. (Conference proceedigs) 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD, ELECTR NETWORK. 2020.Vikulova O, et al. Glucose lowering medications use according to cardiac complications in patients with type 2 diabetes in real clinical practice. Abstract # 890. (Conference proceedigs) 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD, ELECTR NETWORK. 2020.Rybelsus. Prescribing information. Novo Nordisk Inc; 2020. [Internet]. Accessed April 20, 2020. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdfRybelsus. Prescribing information. Novo Nordisk Inc; 2020. [Internet]. Accessed April 20, 2020. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdfРебелсас®. ЛП-006910. [Internet]. Available from: http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=5906891a-6bf5-4eda-9ddf-982fe3d32f4b&t=Ребелсас®. ЛП-006910. [Internet]. Available from: http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=5906891a-6bf5-4eda-9ddf-982fe3d32f4b&t=Buckley ST, Bækdal TA, Vegge A, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018;10(467):eaar7047. doi: https://doi.org/10.1126/scitranslmed.aar7047Buckley ST, Bækdal TA, Vegge A, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018;10(467):eaar7047. doi: https://doi.org/10.1126/scitranslmed.aar7047Brayden DJ, Gleeson J, Walsh EG. A head-to-head multi-parametric high content analysis of a series of medium chain fatty acid intestinal permeation enhancers in Caco-2 cells. Eur J Pharm Biopharm. 2014;88(3):830-839. doi: https://doi.org/10.1016/j.ejpb.2014.10.008Brayden DJ, Gleeson J, Walsh EG. A head-to-head multi-parametric high content analysis of a series of medium chain fatty acid intestinal permeation enhancers in Caco-2 cells. Eur J Pharm Biopharm. 2014;88(3):830-839. doi: https://doi.org/10.1016/j.ejpb.2014.10.008Granhall C, Donsmark M, Blicher TM, et al. Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes. Clin Pharmacokinet. 2019;58(6):781-791. doi: https://doi.org/10.1007/s40262-018-0728-4Granhall C, Donsmark M, Blicher TM, et al. Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes. Clin Pharmacokinet. 2019;58(6):781-791. doi: https://doi.org/10.1007/s40262-018-0728-4Davies M, Pieber TR, Hartoft-Nielsen M-L, Hansen OKH, Jabbour S, Rosenstock J. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes. JAMA. 2017;318(15):1460. doi: https://doi.org/10.1001/jama.2017.14752Davies M, Pieber TR, Hartoft-Nielsen M-L, Hansen OKH, Jabbour S, Rosenstock J. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes. JAMA. 2017;318(15):1460. doi: https://doi.org/10.1001/jama.2017.14752fda.gov [Internet]. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials. [cited 2021 May 18]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM582738.pdf. (Ссылка активна на июнь 2021 года).fda.gov [Internet]. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials. [cited 2021 May 18]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM582738.pdf. (Ссылка активна на июнь 2021 года).Aroda VR, Saugstrup T, Buse JB, et al. Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example. Diabetes, Obes Metab. 2019;21(10):2203-2210. doi: https://doi.org/10.1111/dom.13804Aroda VR, Saugstrup T, Buse JB, et al. Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example. Diabetes, Obes Metab. 2019;21(10):2203-2210. doi: https://doi.org/10.1111/dom.13804Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019;42(9):1724-1732. doi: https://doi.org/10.2337/dc19-0749Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019;42(9):1724-1732. doi: https://doi.org/10.2337/dc19-0749Rodbard HW, Rosenstock J, Canani LH, et al. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019;42(12):2272-2281. doi: https://doi.org/10.2337/dc19-0883Rodbard HW, Rosenstock J, Canani LH, et al. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019;42(12):2272-2281. doi: https://doi.org/10.2337/dc19-0883Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50. doi: https://doi.org/10.1016/S0140-6736(19)31271-1Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50. doi: https://doi.org/10.1016/S0140-6736(19)31271-1Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea. JAMA. 2019;321(15):1466-1480. doi: https://doi.org/10.1001/jama.2019.2942Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea. JAMA. 2019;321(15):1466-1480. doi: https://doi.org/10.1001/jama.2019.2942Pieber TR, Bode B, Mertens A, et al. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):528-539. doi: https://doi.org/10.1016/S2213-8587(19)30194-9Pieber TR, Bode B, Mertens A, et al. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):528-539. doi: https://doi.org/10.1016/S2213-8587(19)30194-9Buse JB, Bode BW, Mertens A, et al. Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial. BMJ Open Diab Res Care. 2020;8:e001649. doi: https://doi.org/10.1136/bmjdrc-2020-001649Buse JB, Bode BW, Mertens A, et al. Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial. BMJ Open Diab Res Care. 2020;8:e001649. doi: https://doi.org/10.1136/bmjdrc-2020-001649Zinman B, Aroda VR, Buse JB, et al. Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care. 2019;42(12):2262-2271. doi: https://doi.org/10.2337/dc19-0898Zinman B, Aroda VR, Buse JB, et al. Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care. 2019;42(12):2262-2271. doi: https://doi.org/10.2337/dc19-0898Pratley RE, Crowley MJ, Gislum M, et al. Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses. Diabetes Ther. 2021;12(4):1099-1116. doi: https://doi.org/10.1007/s13300-020-00994-9Pratley RE, Crowley MJ, Gislum M, et al. Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses. Diabetes Ther. 2021;12(4):1099-1116. doi: https://doi.org/10.1007/s13300-020-00994-9Baekdal TA, Thomsen M, Kupčová V, Hansen CW, Anderson TW. Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment. J Clin Pharmacol. 2018;58(10):1314-1323. doi: https://doi.org/10.1002/jcph.1131Baekdal TA, Thomsen M, Kupčová V, Hansen CW, Anderson TW. Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment. J Clin Pharmacol. 2018;58(10):1314-1323. doi: https://doi.org/10.1002/jcph.1131Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):515-527. doi: https://doi.org/10.1016/S2213-8587(19)30192-5.Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):515-527. doi: https://doi.org/10.1016/S2213-8587(19)30192-5.Meier JJ, Granhall C, Hoevelmann U, et al. 1013-P: Effect of Upper Gastrointestinal Disease on the Pharmacokinetics of Oral Semaglutide in Subjects with Type 2 Diabetes. Diabetes. 2019;68(S1):1013-P. doi: https://doi.org/10.2337/db19-1013-PMeier JJ, Granhall C, Hoevelmann U, et al. 1013-P: Effect of Upper Gastrointestinal Disease on the Pharmacokinetics of Oral Semaglutide in Subjects with Type 2 Diabetes. Diabetes. 2019;68(S1):1013-P. doi: https://doi.org/10.2337/db19-1013-PBækdal TA, Breitschaft A, Navarria A, Hansen CW. A randomized study investigating the effect of omeprazole on the pharmacokinetics of oral semaglutide. Expert Opin Drug Metab Toxicol. 2018;14(8):869-877. doi: https://doi.org/10.1080/17425255.2018.1488965Bækdal TA, Breitschaft A, Navarria A, Hansen CW. A randomized study investigating the effect of omeprazole on the pharmacokinetics of oral semaglutide. Expert Opin Drug Metab Toxicol. 2018;14(8):869-877. doi: https://doi.org/10.1080/17425255.2018.1488965Li J, He K, Ge J, Li C, Jing Z. Efficacy and safety of the glucagon-like peptide-1 receptor agonist oral semaglutide in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2021;172:108656. doi: https://doi.org/10.1016/j.diabres.2021.108656Li J, He K, Ge J, Li C, Jing Z. Efficacy and safety of the glucagon-like peptide-1 receptor agonist oral semaglutide in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2021;172:108656. doi: https://doi.org/10.1016/j.diabres.2021.108656Desouza C, Amod A, Kallenbach K, et al. 930-P: Efficacy of Oral Semaglutide According to Race: An Exploratory Subgroup Analysis of the PIONEER Trial Program. Diabetes. 2020;69(S1):930-P. doi: https://doi.org/10.2337/db20-930-PDesouza C, Amod A, Kallenbach K, et al. 930-P: Efficacy of Oral Semaglutide According to Race: An Exploratory Subgroup Analysis of the PIONEER Trial Program. Diabetes. 2020;69(S1):930-P. doi: https://doi.org/10.2337/db20-930-PAroda VR, Bauer R, Hertz CL, et al. 932-P: Efficacy and Safety of Oral Semaglutide by Baseline Age in the PIONEER Clinical Trial Program. Diabetes. 2020;69(S1):932-P. doi: https://doi.org/10.2337/db20-932-PAroda VR, Bauer R, Hertz CL, et al. 932-P: Efficacy and Safety of Oral Semaglutide by Baseline Age in the PIONEER Clinical Trial Program. Diabetes. 2020;69(S1):932-P. doi: https://doi.org/10.2337/db20-932-PHaluzik M, et al. Efficacy of oral semaglutide according to diabetes duration: an exploratory subgroup analysis of the PIONEER trial programme. (Conference proceedigs). Abstract # 890. EASD 2019. Barcelona.Haluzik M, et al. Efficacy of oral semaglutide according to diabetes duration: an exploratory subgroup analysis of the PIONEER trial programme. (Conference proceedigs). Abstract # 890. EASD 2019. Barcelona.Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: https://doi.org/10.1056/NEJMoa1607141.Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: https://doi.org/10.1056/NEJMoa1607141.Jodar E, Seufert J, Damgaard LH, et al. SUSTAIN 6: a post-hoc analysis of the effect of semaglutide on cardiovascular outcomes over time in subjects with type 2 diabetes, European Heart Journal/ 2017;38(1):3910. doi: https://doi.org/10.1093/eurheartj/ehx504.3910Jodar E, Seufert J, Damgaard LH, et al. SUSTAIN 6: a post-hoc analysis of the effect of semaglutide on cardiovascular outcomes over time in subjects with type 2 diabetes, European Heart Journal/ 2017;38(1):3910. doi: https://doi.org/10.1093/eurheartj/ehx504.3910Verma S, Bain SC, Honoré JB, et al. Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: Results from the LEADER and SUSTAIN 6 clinical trials. Diabetes, Obes Metab. 2020;22(11):2193-2198. doi: https://doi.org/10.1111/dom.14140.Verma S, Bain SC, Honoré JB, et al. Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: Results from the LEADER and SUSTAIN 6 clinical trials. Diabetes, Obes Metab. 2020;22(11):2193-2198. doi: https://doi.org/10.1111/dom.14140.Verma S, Bain SC, Monk Fries T, et al. Duration of diabetes and cardiorenal efficacy of liraglutide and semaglutide: A post hoc analysis of the LEADER and SUSTAIN 6 clinical trials. Diabetes, Obes Metab. 2019;21(7):1745-1751. doi: https://doi.org/10.1111/dom.13698Verma S, Bain SC, Monk Fries T, et al. Duration of diabetes and cardiorenal efficacy of liraglutide and semaglutide: A post hoc analysis of the LEADER and SUSTAIN 6 clinical trials. Diabetes, Obes Metab. 2019;21(7):1745-1751. doi: https://doi.org/10.1111/dom.13698Leiter LA, Bain SC, Hramiak I, et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovasc Diabetol. 2019;18(1):73. doi: https://doi.org/10.1186/s12933-019-0871-8.Leiter LA, Bain SC, Hramiak I, et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovasc Diabetol. 2019;18(1):73. doi: https://doi.org/10.1186/s12933-019-0871-8.fda.gov [Internet]. Guidance for Industry. Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. [cited 2021 May 18]. Available from: https://www.fda.gov/media/71297/download.fda.gov [Internet]. Guidance for Industry. Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. [cited 2021 May 18]. Available from: https://www.fda.gov/media/71297/download.Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841-851. doi: https://doi.org/10.1056/NEJMoa1901118Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841-851. doi: https://doi.org/10.1056/NEJMoa1901118Husain M, Bain SC, Jeppesen OK, et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes, Obes Metab. 2020;22(3):442-451. doi: https://doi.org/10.1111/dom.13955Husain M, Bain SC, Jeppesen OK, et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes, Obes Metab. 2020;22(3):442-451. doi: https://doi.org/10.1111/dom.13955Verma S, Fainberg U, Husain M, et al. Applying rewind cvd criteria to SUSTAIN 6 and PIONEER 6: an exploratory analysis of CV outcomes with semaglutide. J Am Coll Cardiol. 2020;75(11):1922. doi: https://doi.org/10.1016/S0735-1097(20)32549-3Verma S, Fainberg U, Husain M, et al. Applying rewind cvd criteria to SUSTAIN 6 and PIONEER 6: an exploratory analysis of CV outcomes with semaglutide. J Am Coll Cardiol. 2020;75(11):1922. doi: https://doi.org/10.1016/S0735-1097(20)32549-3Evans LM, Mellbin L, Johansen P, Lawson J, Paine A, Sandberg A. A population‐adjusted indirect comparison of cardiovascular benefits of once‐weekly subcutaneous semaglutide and dulaglutide in the treatment of patients with type 2 diabetes, with or without established cardiovascular disease. Endocrinol Diabetes Metab. 2021;4(3). doi: https://doi.org/10.1002/edm2.259Evans LM, Mellbin L, Johansen P, Lawson J, Paine A, Sandberg A. A population‐adjusted indirect comparison of cardiovascular benefits of once‐weekly subcutaneous semaglutide and dulaglutide in the treatment of patients with type 2 diabetes, with or without established cardiovascular disease. Endocrinol Diabetes Metab. 2021;4(3). doi: https://doi.org/10.1002/edm2.259clinicaltrials.gov [Internet]. A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL). [cited 2021 May 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT03914326.clinicaltrials.gov [Internet]. A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL). [cited 2021 May 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT03914326.

The authors declare that there are no conflicts of interest present.