Authors : Richa Kahol; Anjali Jain; Niti Sharma; Sunil Kumar Mishra

Volume/Issue : Volume 9 - 2024, Issue 6 - June

Google Scholar : https://tinyurl.com/85xfxnra

Scribd : https://tinyurl.com/yed459c5

DOI : https://doi.org/10.38124/ijisrt/IJISRT24JUN1950

Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.

Abstract : T2DM has emerged as a global disorder. Although there are many treatment options available for T2DM patients, still several patients complaint about inadequate blood sugar levels. Diabetes management is not limited to just lowering of blood glucose level, it needs a multifactorial approach in treatment. Glucagon- like peptide-1 receptor agonists (GLP-1RA) are a new category of T2DM drugs that acts on various targets such as body weight reduction, renal and cardiovascular benefits. Despite of being so beneficial the major drawback of semaglutide has been its subcutaneous route of administration. Majority of the patients are unable to continue semaglutide for long because of their reluctance towards daily injectable. To avoid this oral semaglutide is introduced. Oral semaglutide is a GLP- 1RA which is displays high glycaemic control. However, in order to increase its bioavailability, it needs to be co formulated with sodium N-(8-[2-hydroxybenzyol] amino) caprylate (SNAC). Oral semaglutide has gone through a very intense series of clinical trials known as, Peptide Innovation for Early Diabetes Treatment (PIONEER). These trials have established benefits of oral semaglutide regarding reduction in glycaemic levels and body weight. It is deemed to be fit for regular consumption. In this review we discuss many aspects of oral semaglutide such as, its chemical structure, route of administration, challenges associated with the oral form of semaglutide, dosage, mechanism of oral bioavailability, robust indications, its placement in the line of defence, drug- drug interaction, various clinical trials (Phase trials and PIONEER studies) including their results. It also summarizes the benefits of oral semaglutide beyond glycaemic control and some future scope of research in the field.

References :

1. Yusufi et al 2023: Yusufi, Faiz N. K.; Ahmed, Aquil; Ahmad, Jamal; Alexiou, Athanasios; Ashraf, Ghulam M.; Yusufi, Ahad Noor Khan.Impact of Type 2 Diabetes Mellitus with a Focus on Asian Indians Living in India and Abroad: A Systematic Review.Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders), Volume 23, Number 5, 2023, pp. 609-616(8)
2. Niman S, Hardy J, Goldfaden RF, Reid J, Ali MS, Sutton D, Choksi R. A Review on the Efficacy and Safety of Oral Semaglutide. Drugs in R&D (2021) 21:133–148 https://doi.org/10.1007/s40268-021-00341-8
3. Eliaschewitz FG and Canani LH, Advances in GLP‑1 treatment: focus on oral semaglutide, Diabetol Metab Syndr (2021) 13:99 https://doi.org/10.1186/s13098-021-00713-9
4. Mahapatra MK, Karuppasamy M, Sahoo BM. Semaglutide, a glucagon like peptide‑1 receptor agonist with cardiovascular benefits for management of type 2 diabetes. Reviews in Endocrine and Metabolic Disorders. https://doi.org/10.1007/s11154-021-09699-1
5. Kalra S, Das S, Zargar AH. A review of oral semaglutide available evidence: A new era of management of diabetes with peptide in a pill form. Indian J Endocr Metab 2022;26:98-105.
6. Rosenstock J, Nino A, Soffer J, Erskine L, Acusta A, Dole J, Carr MC, Mallory J, Home P. Impact of a Weekly Glucagon-Like Peptide 1 Receptor Agonist, Albiglutide, on Glycemic Control and on Reducing Prandial Insulin Use in Type 2 Diabetes Inadequately Controlled on Multiple Insulin Therapy: A Randomized Trial. Diabetes Care. 2020;43(10):2509–18. https:// doi. org/ 10. 2337/ dc19- 2316.
7. Novo Nordisk. Company Announcements: Ozempic R (semaglutide) approved in the US. 2017. https:// www. novon ordisk. com/ conte nt/ nncorp/ global/ en/ news- and- media/ news- and- ir- mater ials/ news- detai ls. html? id= 712. Assessed 2 May 2020.
8. Drucker DJ. Advances in oral peptide therapeutics. Nat Rev Drug Discov.2020;19(4):277–89.
9. Reed J, Bain S, Kanamarlapudi V. Recent advances in understanding the role of glucagon-like peptide 1. F1000Res. 2020. https:// doi. org/ 10. 12688/ f1000 resea rch. 20602.1.
10. Aroda VR, et al. Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1–7 trials. Diabetes Metab. 2019;45(5):409–18.
11. U.S. Food and Drug Administration (FDA). FDA approves first oral GLP-1treatment for type 2 diabetes. 2019. https:// www. fda. gov/ news- events/press- annou nceme nts/ fda- approves- first- oral- glp-1- treat ment- type-2-diabetes. Accessed 1 Jan 2021.
12. Granhall 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. 2018;58(6):781–91.
13. Davies M, Pieber TR, Hartoft-Nielsen ML, 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: a randomized clinical trial. JAMA. 2017;318(15):1460–70.
14. Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SØ, et al. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: The PIONEER 2 trial. Diabetes Care 2019;42:2272‑81.
15. Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, 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: The PIONEER 3 randomized clinical trial. JAMA 2019;321:1466‑80.
16. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841‑51.
17. Pieber TR, Bode B, Mertens A, Cho YM, Christiansen E, Hertz CL, et al. PIONEER 7 investigators. 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;7:528-39. doi: 10.1016/S2213-8587(19)30194-9. Epub 2019 Jun 9. Erratum in: Lancet Diabetes Endocrinol. 2019 Sep;7(9):e21. PMID: 31189520.
18. Zinman B, Aroda VR, Buse JB, Cariou B, Harris SB, Hoff ST, 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;42:2262‑71.
19. American Diabetes Association. 9 Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98–110. https:// doi. org/ 10. 2337/ dc20- S009.
20. Mosenzon O, Blicher TM, Rosenlund S, Eriksson JW, Heller S, Hels OH, 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 [published correction appears in Lancet Diabetes Endocrinol 2019;7:e21]. Lancet Diabetes Endocrinol 2019;7:515‑27.
21. Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, 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;42:1724‑32
22. Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American association of clinical endocrinologists and American college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary. Endocr Pract 2020;26:107‑39.
23. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes‑2022. Diabetes Care 2022;45(Suppl 1):S125‑43
24. Liu Y, Luo X. New practice in semaglutide on type-2 diabetes and obesity: clinical evidence and expectation. Front. Med. 2022, 16(1): 17–24. https://doi.org/10.1007/s11684-021-0873-2
25. Husain M, Bain SC, Jeppesen OK, Lingvay I, Sorrig R, Treppendahl MB, Vilsboll T. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab. 2020;22(3):442–51. https:// doi. org/ 10. 1111/ dom. 13955
26. Iorga RA, Bacalbasa N, Carsote M, Bratu OG, Stanescu AMA, Bungau S, Pantis C, Diaconu CC. Metabolic and cardiovascular benefits of GLP-1 agonists, besides the hypoglycemic effect (Review). Exp Ther Med. 2020;20(3):2396–400. https:// doi. org/ 10. 3892/ etm. 2020. 8714.
27. ClinicalTrials.gov. A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease (FLOW); NCT03819153. 2019. https:// clini caltr ials. gov/ ct2/ show/ NCT03 819153. Accessed 5 Aug 2021.
28. Chubb B, et al. Once-daily oral semaglutide versus injectable GLP-1 RAs in people with type 2 diabetes inadequately controlled on basal insulin: systematic review and network meta-analysis. Diabetes Ther. 2021;12(5):1325–39.