Efficacy and safety of oral semaglutide in Russian patients with type 2 diabetes: subgroup analysis of PIONEER 1, 2, 3 trials

INTRODUCTION. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are the treatment options with comprehensive action on different aspects of type 2 diabetes. Due to its peptide nature GLP-1 RAs, until recent time the delivery of these agents into patients’ organism was via injectable devices. In 2019, the first time in history oral semaglutide was registered based on the results of PIONEER clinical trial program, since 2021 this drug is available in Russia. However, the pathophysiology of type 2 diabetes and local treatment approaches may differ in different populations; this can lead to the differences in the efficacy and safety of newly registered drug. Therefore, it is necessary to evaluate the response in different populations. In this paper we report the result of subanalysis of efficacy and safety of oral semaglutide in Russian patients.

OBJECTIVE. The aim of this analysis is to evaluate efficacy and safety of oral semaglutide in Russian patients, who participated in semaglutide clinical development program, as well as to evaluate consistency and applicability of the results obtained from global population in that program.

MATERIALS AND METHODS. Patients from PIONEER 1, 2, 3 were included in the analysis: 150 patients from Russian, 1956 — the rest patients from these trials. Reductions in HbA1c and body weight were analyzed in both cohorts, and treatment differences were tested for interaction. Similarly, the rate of adverse events was analyzed.

RESULTS. Reduction in HbA_1c in oral semaglutide arms in both cohorts showed numerically similar and consistent result. Interaction test showed statistical difference in PIONEER 1 data (p=0.0268) — the effect was due to diminishing influence of substantial response in placebo arm in Russian cohort. In longer-term trials (PIONEER 2 and 3) this finding was not confirmed (p=0.7459 and p=0.4906, respectively). In regard to body weight reduction there were more numerically pronounced results in Russian cohort compared to global population; although statistical significance were not reached in any of the trial (p>0.05). There was lower rate of reported adverse events in Russian patients compared to the rest cohort.

CONCLUSION. This analysis showed similar efficacy and safety of oral semaglutide in Russian patients compared to global population of patients from clinical program.

1. IDF Atlas 9th edition and other resources n.d. Available from: https://diabetesatlas.org/en/resources/ [cited September 7, 2021].

2. Galstyan GR, Shestakova EA, Sklyanik IA. Obesity and type 2 diabetes: can we find a compromised treatment solution? Diabetes mellitus. 2017;20(4):270-278. (In Russ.). doi: https://doi.org/10.2337/DC16-S009

3. Gomes M de B, Giannella Neto D, Mendonça E de, et al. Prevalência de sobrepeso e obesidade em pacientes com diabetes mellitus do tipo 2 no Brasil: estudo multicêntrico nacional. Arq Bras Endocrinol Metabol. 2006;50(1):136-144. doi: https://doi.org/10.1590/S0004-27302006000100019

4. Kwon Y, Kim HJ, Park S, et al. Body Mass IndexRelated Mortality in Patients with Type 2 Diabetes and Heterogeneity in Obesity Paradox Studies: A DoseResponse Meta-Analysis. PLoS One. 2017;12(1):e0168247. doi: https://doi.org/10.1371/JOURNAL.PONE.0168247

5. Edqvist J, Rawshani A, Adiels M, et al. BMI and Mortality in Patients With New-Onset Type 2 Diabetes: A Comparison With Age- and Sex-Matched Control Subjects From the General Population. Diabetes Care. 2018;41(3):485-493. doi: https://doi.org/10.2337/dc17-1309

6. Tobias DK, Pan A, Jackson CL, et al. Body-Mass Index and Mortality among Adults with Incident Type 2 Diabetes. N Engl J Med. 2014;370(3):233-244. doi: https://doi.org/10.1056/NEJMoa1304501

7. Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an openlabel, cluster-randomised trial. Lancet. 2018;391(10120):541-551. doi: https://doi.org/10.1016/S0140-6736(17)33102-1

8. Wald NJ, Bestwick JP, Morris JK. Body weight reduction to avoid the excess risk of type 2 diabetes. Br J Gen Pract. 2012;62(599):e411-e414. doi: https://doi.org/10.3399/bjgp12X649098

9. Apovian CM, Okemah J, O’Neil PM. Body Weight Considerations in the Management of Type 2 Diabetes. Adv Ther. 2019;36(1):44-58. doi: https://doi.org/10.1007/s12325-018-0824-8

10. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728-742. doi: https://doi.org/10.1038/nrendo.2012.140

11. Nauck 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-19-0566

12. DeFronzo RA, Triplitt CL, Abdul-Ghani M, Cersosimo E. Novel Agents for the Treatment of Type 2 Diabetes. Diabetes Spectr. 2014;27(2):100-112. doi: https://doi.org/10.2337/diaspect.27.2.100

13. 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. Diabetes Ther. 2019;10(1):5-19. doi: https://doi.org/10.1007/s13300-018-0535-9

14. Dedov 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/DM221S1

15. Spain CV, Wright JJ, Hahn RM, et al. Self-reported Barriers to Adherence and Persistence to Treatment With Injectable Medications for Type 2 Diabetes. Clin Ther. 2016;38(7):1653-1664.e1. doi: https://doi.org/10.1016/j.clinthera.2016.05.009

16. Drucker DJ. Advances in oral peptide therapeutics. Nat Rev Drug Discov. 2020;19(4):277-289. doi: https://doi.org/10.1038/s41573-019-0053-0

17. Mahato RI, Narang AS, Thoma L, Miller DD. Emerging Trends in Oral Delivery of Peptide and Protein Drugs. Crit Rev Ther Drug Carrier Syst. 2003;20(2-3):153-214. doi: https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v20.i23.30

18. 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):153-214. doi: https://doi.org/10.1126/scitranslmed.aar7047

19. Sorli C, Harashima S, Tsoukas GM, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-260. doi: https://doi.org/10.1016/S2213-8587(17)30013-X

20. Ahrén B, Masmiquel L, Kumar H, et al. Efficacy and safety of onceweekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017;5(5):341-354. doi: https://doi.org/10.1016/S2213-8587(17)30092-X

21. Ahmann AJ, Capehorn M, Charpentier G, et al. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care. 2018;41(2):258-266. doi: https://doi.org/10.2337/dc17-0417

22. Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety of onceweekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, mul. Lancet Diabetes Endocrinol. 2017;5(5):355-366. doi: https://doi.org/10.1016/S2213-8587(17)30085-2

23. Rodbard HW, Lingvay I, Reed J, et al. Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial. J Clin Endocrinol Metab. 2018;103(6):2291-2301. doi: https://doi.org/10.1210/jc.2018-00070

24. 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

25. Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6(4):275-286. doi: https://doi.org/10.1016/S2213-8587(18)30024-X

26. Lingvay I, Catarig A-M, Frias JP, et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(11):834-844. doi: https://doi.org/10.1016/S2213-8587(19)30311-0

27. Zinman B, Bhosekar V, Busch R, et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7(5):356-367. doi: https://doi.org/10.1016/S2213-8587(19)30066-X

28. Capehorn MS, Catarig A-M, Furberg JK, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab. 2020;46(2):100-109. doi: https://doi.org/10.1016/j.diabet.2019.101117

29. 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. 2019;58(6):781-791. doi: https://doi.org/10.1007/s40262-018-0728-4

30. Davies M, Pieber TR, Hartoft-Nielsen M-L, et al. 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.2017.14752

31. FDA approves first oral GLP-1 treatment for type 2 diabetes | FDA n.d. Available from: https://www.fda.gov/news-events/pressannouncements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes [cited September 24, 2021

32. RYBELSUS ® (semaglutid), tabletki. Instruktsiya po meditsinskomu primeneniyu lekarstvennogo preparata n.d. (In Russ.)

33. OZEMPIC ® (semaglutid), rastvor dlya podkozhnogo vvedeniya. Instruktsiya po meditsinskomu primeneniyu lekarstvennogo preparata n.d. (In Russ.)

34. Nauck MA, Meier JJ. Pioneering oral peptide therapy for patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2019;7(7):500-502. doi: https://doi.org/10.1016/S2213-8587(19)30182-2

35. Aroda 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/dc19-0749

36. Rodbard 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/dc19-0883

37. Rosenstock 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. doi: https://doi.org/10.1001/jama.2019.2942

38. Stratton IM. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412. https://doi.org/10.1136/bmj.321.7258.405

39. Laiteerapong N, Ham SA, Gao Y, et al. The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care. 2019;42(3):416-426. doi: https://doi.org/10.2337/dc17-1144

40. An J, Nichols GA, Qian L, et al. Time in suboptimal glycemic control over 10 years for patients newly diagnosed with type 2 diabetes. J Diabetes Complications. 2020;34(8):107607. doi: https://doi.org/10.1016/j.jdiacomp.2020.107607

41. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701. doi: https://doi.org/10.2337/dci18-0033

42. Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020;43(2):487-493. doi: https://doi.org/10.2337/dci19-0066

43. Davies MJ, Bianchi C, Del Prato S. Use of incretin-based medications: what do current international recommendations suggest with respect to GLP-1 receptor agonists and DPP-4 inhibitors? Metabolism. 2020;107(2):154242. doi: https://doi.org/10.1016/j.metabol.2020.154242