Comparison efficacy of different regimens of insulin therapy in patients with type 2 diabetes and morbid obesity

Introduction. In type 2 diabetes mellitus, an inevitable decrease in the secretion of  β-cells of the pancreas occurs, which requires the  initiation of  insulin therapy. Currently, there have been no studies evaluating the  features of  insulin therapy in patients with diabetes type 2 and morbid obesity.

Objective. To compare the effectiveness of different insulin therapy regimens in patients with type 2 diabetes mellitus and morbid obesity. Materials and methods. 140  patients with diabetes type  2 and morbid obesity were included in  a 24-week prospective, non-blinded, randomized clinical study. The patients were divided into 4  groups: 1  – received basic-bolus insulin therapy in combination with metformin (n = 40); 2 – used prandial insulin in combination with metformin (n = 40); 3 – basal insulin in combination with empagliflozin and metformin (n = 30); 4 – received prandial insulin in combination with empagliflozin and metformin (n = 30). Initially, after 12 and 24 weeks, the level of HbA1c, fasting plasma glucose and during the day, body weight, daily insulin doses, frequency of hypoglycemia, and albumin in daily urine were assessed.

Results. After 24 weeks of treatment, there was no statistically significant difference in the achieved HbA1c level between the groups (p = 0.65); in groups 3 and 4, there was a statistically significant decrease in body weight, daily doses of insulin and frequency of hypoglycemia compared to the first and second treatment groups (p = 0.029, p < 0.001 and p < 0,001, respectively); also registered a decrease in albumin in daily urine by 27% during the study period compared with the first and second treatment groups (p = 0.044).

Conclusions. Administration of iSGLT-2 in combination with both basal and prandial insulin in patients with diabetes type 2 and morbid obesity has advantages over the basic-bolus regimen and the regimen of multiple prandial injections, despite the comparable efficacy.

1. Sluik D., Boeing H., Montonen J., Pischon T., Kaaks R., Teucher B. et al. Associations between general and abdominal adiposity and mortality in individuals with diabetes mellitus. Am J Epidemiol. 2011;174(1):22–34. https://doi.org/10.1093/aje/kwr048.

2. Weng W., Tian Y., Kimball E.S., Kong S.X., Bouchard J., Hobbs T.M. et al. Treatment patterns and clinical characteristics of patients with type 2 diabetes mellitus according to body mass index: findings from an electronic medical records database. BMJ Open Diabetes Res Care. 2017;5(1):e000382. https://doi.org/10.1136/bmjdrc-2016-000382.

3. Dedov I.I., Shestakova M.V., Ametov A.S., Antsiferov M.B., Galstyan G.R., Mayorov A.Y. et al. Initiation and intensification of antihyperglycemic therapy in type 2 diabetes mellitus: Update of Russian Association of Endocrinologists expert consensus document (2015). Diabetes Mellitus. 2015;18(1):5–23. (In Russ.) https://doi.org/10.14341/DM201515-23.

4. Riddle M.C., Barkis G., Blonde L., Boulton J.M., DiMenlio L.A., Gonder-Frederick L. et al. The Standards of Medical Care in Diabetes – 2021. Diabetes Care. 2021;44(1):226–232. https://doi.org/10.2337/dc21-in01.

5. Dedov I.I., Melnichenko G.A., Shestakova M.V., Troshina E.A., Mazurina N.V., Shestakova E.A. et al. Russian National Clinical Recommendations for Morbid Obesity Treatment in Adults. 3rd Revision (Morbid Obesity Treatment in Adults). Obesity and Metabolism. 2018;15(1):53–70. (In Russ.) https://doi.org/10.14341/omet2018153-70.

6. Suzuki K., Mitsuma Y., Sato T., Anraku T., Hatta M. Comparison of сombined tofogliflozin and glargine, tofogliflozin added to insulin, and insulin dose-increase therapy in uncontrolled type 2 diabetes. J Clin Med Res. 2016;8(11):805814. https://doi.org/10.14740/jocmr2741w.

7. Wilding J.P., Woo V., Rohwedder K., Sugg J., Parikh S. Dapagliflozin 006 Study Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014;16(2):124–136. https://doi.org/10.1111/dom.12187

8. . 8. Rosenstock J., Jelaska A., Zeller C., Kim G., Broedl U.C., Woerle H.J. et al. Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, doubleblind, placebo-controlled trial. Diabetes Obes Metab. 2015;17(10):936–948. https://doi.org/10.1111/dom.12503.

9. Sertbas M., Sertbas Y., Okuroglu N., Akyildiz A.B., Sancak S., Ozdemir A. Effıcacy and safety of dapagliflozin on diabetic patients receiving high-doses of insulin. Pak J Med Sci. 2019;35(2):399–403. https://doi.org/10.12669/pjms.35.2.21.

10. Yang Y., Chen S., Pan H., Zou Y., Wang B., Wang G. et al. Safety and efficiency of SGLT2 inhibitor combining with insulin in subjects with diabetes: Systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2017;96(21):e6944. https://doi.org/10.1097/MD.0000000000006944

11. Cho Y.K., Kim Y.J., Kang Y.M., Lee S.E., Park J.Y., Lee W.J. et al. Comparison between sodium-glucose cotransporter 2 inhibitors and pioglitazone as additions toinsulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta-analysis. J Diabetes Investig. 2018;9(4):882–892. https://doi.org/10.1111/jdi.12787.

12. Yanai H., Adachi H., Hakoshima M., Katsuyama H. An effective insulin therapy in combination with sodium-glucose cotransporter 2 inhibitors. J Clin Med Res. 2019;11(1):76–79. https://doi.org/10.14740/jocmr3676.

13. Thomas M.C., Cherney D.Z.I. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia. 2018;61(10):2098– 2107. https://doi.org/10.1007/s00125-018-4669-0.

14. Lee P.C., Ganguly S., Goh S.Y. Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms. Obes Rev. 2018;19(12):1630–1641. https://doi.org/10.1111/obr.12755

15. . 15. Abdul-Ghani M.A., DeFronzo R.A., Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans. Diabetes. 2013;62(10):3324–3328. https://doi.org/10.2337/db13-0604.

16. Ferrannini E., Baldi S., Frascerra S., Astiarraga B., Heise T., Bizzotto R. et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190–1195. https://doi.org/10.2337/db15-1356.

17. Kashiwagi A., Maegawa H. Metabolic and hemodynamic effects of sodiumdependent glucose cotransporter 2 inhibitors on cardio-renal protection in the treatment of patients with type 2 diabetes mellitus. J Diabetes Investig. 2017;8(4):416–427. https://doi.org/10.1111/jdi.12644.

18. Sakai S., Kaku K., Seino Y., Inagaki N., Haneda M., Sasaki T. et al. Efficacy and Safety of the SGLT2 Inhibitor Luseogliflozin in Japanese Patients With Type 2 Diabetes Mellitus Stratified According to Baseline Body Mass Index: Pooled Analysis of Data From 52-Week Phase III Trials. Clin Ther. 2016;38(4):843–862.e9. https://doi.org/10.1016/j.clinthera.2016.01.017.

19. Shatskov A., Rezvani G., Mansfield T. Efficacy and safety of dapagliflozin in patients with type 2 diabetes: outcome by body mass index. In: American Diabetic Association 76th Scientific Sessions 2016. New Orleans, Louisiana, USA, 1014 June 2016. Available at: https://ada.scientificposters.com/apprizr.cfm?bKCOsb7hrpJc2bVJSbe2aUU33p2%2BQ%-2FAWOznDBQz496Yir3QEmFsQzSStuD2Qk2MncZ%2FSFToTdxQ%3D.

20. Iemitsu K., Iizuka T., Takihata M., Takai M., Nakajima S., Minami N. et al. Factors Influencing Changes in Hemoglobin A1c and Body Weight During Treatment of Type 2 Diabetes With Ipragliflozin: Interim Analysis of the ASSIGN-K Study. J Clin Med Res. 2016;8(5):373–378. https://doi.org/10.14740/jocmr2492w.

21. Zhang L., Feng Y., List J., Kasichayanula S., Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metab. 2010;12(6):510–516. https://doi.org/10.1111/j.1463-1326.2010.01216.x.

22. Heerspink H.J., Perkins B.A., Fitchett D.H., Husain M., Cherney D.Z. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016;134(10):752–772. https://doi.org/10.1161/CIRCULATIONAHA.116.021887.

23. Thomas M.C. Renal effects of dapagliflozin in patients with type 2 diabetes. Ther Adv Endocrinol Metab. 2014;5(3):53–61. https://doi.org/10.1177/2042018814544153.

24. Martynov S.A., Shamkhalova M.Sh. Role of Sodium-Glucose Cotransporter 2 Inhibitors in Preventing of Renal Impairment Progression in Patients with Type 2 Diabetes. Effective Pharmacotherapy. 2021;17(5):16–23. (In Russ.) Available at: https://umedp.ru/articles/rol_ingibitorov_natriyglyukoznogo_kotransportera_2_v_zamedlenii_progressirovaniya_pochechnoy_nedosta.html.

25. Piperidou A., Sarafidis P., Boutou A., Thomopoulos C., Loutradis C., Alexandrou M.E. et al. The effect of SGLT-2 inhibitors on albuminuria and proteinuria in diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. J Hypertens. 2019;37(7):1334–1343. https://doi.org/10.1097/HJH.0000000000002050

26. Luo Y., Lu K., Liu G., Wang J., Laurent I., Zhou X. The Effects of Novel Antidiabetic Drugs on Albuminuria in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin Drug Investig. 2018;38(12):1089–1108. https://doi.org/10.1007/s40261-018-0707-4

27. . 27. Salukhov V.V., Demidova T.Yu. Empagliflozin as a new management strategy on outcomes in patients with type 2 diabetes mellitus. Diabetes Mellitus. 2016;19(6):494–510. (In Russ.) https://doi.org/10.14341/DM8216.

28. Gagnon-Auger M., du Souich P., Baillargeon J.P., Martin E., Brassard P., Ménard J. et al. Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study. Diabetes Care. 2010;33(12):2502–2507. https://doi.org/10.2337/dc10-1126.

29. Morello C.M. Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus. Int J Gen Med. 2011;4:827–835. https://doi.org/10.2147/IJGM.S26889.

30. Plank J., Bodenlenz M., Sinner F., Magnes C., Görzer E., Regittnig W. et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care. 2005;28(5):1107–1112. https://doi.org/10.2337/diacare.28.5.1107.

31. Becker R.H., Frick A.D. Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet. 2008;47(1):7–20. https://doi.org/10.2165/00003088-200847010-00002.

32. Lindholm A., Jacobsen L.V. Clinical pharmacokinetics and pharmacodynamics of insulin aspart. Clin Pharmacokinet. 2001;40(9):641–659. https://doi.org/10.2165/00003088-200140090-00002.

33. Gin H., Hanaire-Broutin H. Reproducibility and variability in the action of injected insulin. Diabetes Metab. 2005;31(1):7–13. https://doi.org/10.1016/s1262-3636(07)70160-x.

34. Barnett A.H. How well do rapid-acting insulins work in obese individuals?. Diabetes Obes Metab. 2006;8(4):388–395. https://doi.org/10.1111/j.1463-1326.2005.00525.x.

35. Frid A.H., Kreugel G., Grassi G., Halimi S., Hicks D., Hirsch L.J. et al. New Insulin Delivery Recommendations. Mayo Clin Proc. 2016;91(9):1231–1255. https://doi.org/10.1016/j.mayocp.2016.06.010.

36. Mayorov A.Yu., Melnikova O.G., Koteshkova O.M., Misnikova I.V., Chernikova N.A. Injection and infusion techniques in the treatment of diabetes mellitus. Moscow; 2018. 61 p. (In Russ.) Available at: https://rae-org.ru/system/files/documents/pdf/mr102.pdf.

37. Saryusz-Wolska M., Szymańska-Garbacz E., Pawłowski M., Loba J., Czupryniak L. Splitting high dose of insulin and injecting it in two sites improves blood glucose control. Diabetologia. 2011;54(1 Suppl.):52. https://doi.org/10.1007/s00125-011-2276-4.