The role of canagliflozin in the prevention of stroke and chronic kidney disease in patients with type 2 diabetes mellitus: an expert council resolution

Over the past 10 years of studying the complications of type 2 diabetes mellitus (DM) and ways to deal with them, significant progress has been made in one of the most important areas of treatment — the prevention of cardiovascular and renal complications. Thus, when using inhibitors of type 2 sodium-glucose cotransporter, a significant reduction in the risks of cardiovascular mortality and progression of chronic heart failure, which occupy the main place in the structure of mortality in this cohort of patients, as well as a positive effect on diabetic nephropathy, one of the most common complications of type 2 diabetes, has been proven. However, there are other complications that significantly affect the duration and quality of life of patients. In particular, these include stroke, which occupies the 2nd-3rd place in the frequency of death of people with type 2 diabetes, and albuminuria, a frequent manifestation of diabetic kidney disease, which is associated with an increased risk of cardiovascular complications (including stroke) and chronic renal failure. Recent studies indicate the important role of sodium-glucose cotransporter type 1 in the development of these complications. Canagliflozin has the highest affinity for these transporters among iSGLT-2 registered in the Russian Federation. This article aims to evaluate the mechanisms of action of canagliflozin and its possible role in the prevention of stroke and albuminuria.

1. Gregg EW, Menke A. Diabetes and Disability. In: Diabetes in America 3rd edition. National Institute of Diabetes and Digestive and Kidney Diseases (US); 2018.

2. Dedov II, Shestakova MV, Vikulova OK, et al.Epidemiological characteristics of diabetes mellitus in the Russian Federation: clinical and statistical analysis according to the Federal diabetes register data of 01.01.2021. Diabetes mellitus. 2021;24(3):204-221. (In Russ.). doi: https://doi.org/10.14341/DM12759

3. Yau K, Dharia A, Alrowiyti I, et al. Prescribing SGLT2 Inhibitors in patients with CKD: Expanding indications and practical considerations. Kidney Int Rep. 2022;7(7):1463-1476. doi: https://doi.org/10.1016/j.ekir.2022.04.094

4. Cardoso R, Graffunder FP, Ternes CMP, et al. SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: A systematic review and meta-analysis. EClinicalMedicine. 2021;(36):100933. doi: https://doi.org/10.1016/j.eclinm.2021.100933

5. Данные Федерального регистра сахарного диабета Московской области [дата обращения: 01.07.2023]. [Data of the Federal Register of Diabetes Mellitus of the Moscow Region [date of access: 07/01/2023] (In Russ.)]

6. Khan MM, Roberson S, Reid K, et al. Prevalence and predictors of stroke among individuals with prediabetes and diabetes in Florida. BMC Public Health. 2022;22(1):243. doi: https://doi.org/10.1186/s12889-022-12666-3

7. Mosenzon O, Cheng AY, Rabinstein AA, et al. Diabetes and stroke: What are the connections? J Stroke. 2023;25(1):26-38. doi: https://doi.org/10.5853/jos.2022.02306

8. Mac Grory B, Piccini JP, Yaghi S, et al. Hyperglycemia, risk of subsequent stroke, and efficacy of dual antiplatelet therapy: A post hoc analysis of the POINT trial. J Am Heart Assoc. 2022;11(3):e023223. doi: https://doi.org/10.1161/JAHA.121.023223

9. All-Russian Society of Neurologists [Internet]. Clinical guidelines «Ischemic stroke and transient ischemic attack in adults» 2021. (In Russ.) Доступно по: https://cr.minzdrav.gov.ru/recomend/171_2. Ссылка активна на 24.07.2023.

10. Daniel K, Wolfe CDA, Busch MA, et al. What Are the Social Consequences of Stroke for Working-Aged Adults? Stroke. 2009;40(6):e431-440. doi: https://doi.org/10.1161/STROKEAHA.108.534487

11. Megherbi S-E, Milan C, Minier D, et al. Association between diabetes and stroke subtype on survival and functional outcome 3 months after stroke: data from the European BIOMED Stroke Project. Stroke. 2003;34(3):688-694. doi: https://doi.org/10.1161/01.STR.0000057975.15221.40

12. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: https://doi.org/10.1056/NEJMoa1611925

13. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi: https://doi.org/10.1056/NEJMoa1811744

14. Li J-W, Arnott C, Heerspink HJL, et al. Effect of canagliflozin on total cardiovascular burden in patients with diabetes and chronic Kidney disease: A post hoc analysis from the CREDENCE trial. J Am Heart Assoc. 2022;11(16):e025045. doi: https://doi.org/10.1161/JAHA.121.025045

15. Ang F, Rapattoni W, Bajaj HS, et al. Effects of canagliflozin on cardiovascular and kidney outcomes and mortality in primary and secondary cardiovascular prevention: pooled analysis from the CANVAS program and CREDENCE trial. Eur Heart J. 2022;43(S2):2295-2306. doi: https://doi.org/10.1093/eurheartj/ehac544.2324

16. Odutayo A, da Costa BR, Pereira TV., et al. Sodium-glucose cotransporter 2 inhibitors, all-cause mortality, and cardiovascular outcomes in adults with type 2 diabetes: A bayesian meta-analysis and meta-regression. J Am Heart Assoc. 2021;10(18):2295-2306. doi: https://doi.org/10.1161/JAHA.120.019918

17. Tsai W-H, Chuang S-M, Liu S-C, et al. Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis. Sci Rep. 2021;11(1):15364. doi: https://doi.org/10.1038/s41598-021-94945-4

18. Qiu M, Ding L-L, Zhou H-R. Comparative efficacy of five SGLT2i on cardiorenal events: A network meta-analysis based on ten CVOTs. Am J Cardiovasc Drugs. 2022;22(1):69-81. doi: https://doi.org/10.1007/s40256-021-00484-8

19. Zeng Q, Zhou Q, Liu W, et al. Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure. Front Cardiovasc Med. 2021;8(18):2295-2306. doi: https://doi.org/10.3389/fcvm.2021.636152

20. Koepsell H. Glucose transporters in brain in health and disease. Pflugers Arch. 2020;472(9):1299-1343. doi: https://doi.org/10.1007/s00424-020-02441-x

21. Pawlos A, Broncel M, Wozniak E, et al. Neuroprotective effect of SGLT2 inhibitors. Molecules. 2021;26(23):7213. doi: https://doi.org/10.3390/molecules26237213

22. Sayour AA, Olah A, Ruppert M, et al. Pharmacological selectivity of SGLT2 inhibitors and cardiovascular outcomes in patients with type 2 diabetes: a meta-analysis. Eur Heart J. 2022;43(S2):2295-2306. doi: https://doi.org/10.1093/eurheartj/ehac544.2688

23. Meng Q, Shen Y, Liu D, et al. Efficacy of canagliflozin combined with antidiabetic drugs in treating type 2 diabetes mellitus: Meta-analysis of randomized control trials. J Diabetes Investig. 2016;7(3):359-365. doi: https://doi.org/10.1111/jdi.12417

24. Cefalu WT, Leiter LA, Yoon K-H, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382(9896):941-950. doi: https://doi.org/10.1016/S0140-6736(13)60683-2

25. Pfeifer M, Townsend RR, Davies MJ, et al. Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure and markers of arterial stiffness in patients with type 2 diabetes mellitus: a post hoc analysis. Cardiovasc Diabetol. 2017;16(1):29. doi: https://doi.org/10.1186/s12933-017-0511-0

26. Geng Q, Hou F, Zhang Y, et al. Effects of different doses of canagliflozin on blood pressure and lipids in patients with type 2 diabetes: a meta-analysis. J Hypertens. 2022;40(5):996-1001. doi: https://doi.org/10.1097/HJH.0000000000003106

27. Zuo Q, Zhang G, He L, et al. Canagliflozin attenuates hepatic steatosis and atherosclerosis progression in Western Diet-Fed ApoE-Knockout Mice. Drug Des Devel Ther. 2022;(16):4161-4177. doi: https://doi.org/10.2147/DDDT.S388823

28. Nasiri-Ansari N, Dimitriadis GK, Agrogiannis G, et al. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc Diabetol. 2018;17(1):106. doi: https://doi.org/10.1186/s12933-018-0749-1

29. Yaribeygi H, Maleki M, Reiner 2, et al. Mechanistic view on the effects of SGLT2 inhibitors on lipid metabolism in diabetic milieu. J Clin Med. 2022;11(21):6544. doi: https://doi.org/10.3390/jcm11216544

30. Ramirez AJ, Sanchez MJ, Sanchez RA. Diabetic patients with essential hypertension treated with amlodipine: blood pressure and arterial stiffness effects of canagliflozin or perindopril. J Hypertens. 2019;37(3):636-642. doi: https://doi.org/10.1097/HJH.0000000000001907

31. Uthman L, Kuschma M, Romer G, et al. Novel anti-inflammatory effects of canagliflozin involving Hexokinase II in lipopolysaccharide-stimulated human coronary artery endothelial cells. Cardiovasc Drugs Ther. 2021;35(6):1083-1094. doi: https://doi.org/10.1007/s10557-020-07083-w

32. Li C, Yu J, Hockham C, et al. Canagliflozin and atrial fibrillation in type 2 diabetes mellitus: A secondary analysis from the CANVAS Program and CREDENCE trial and meta-analysis. Diabetes Obes Metab. 2022;24(10):1927-1938. doi: https://doi.org/10.1111/dom.14772

33. Pinto LC, Rados DV, Remonti LR, et al. Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. Arch Endocrinol Metab. 2022;66(1):68-76. doi: https://doi.org/10.20945/2359-3997000000440

34. Zaccardi F, Webb DR, Htike ZZ, et al. Efficacy and safety of sodiumglucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18(8):783-794. doi: https://doi.org/10.1111/dom.12670

35. The Instructions for Use of INVOKANA® LP-002977. (In Russ.). Доступно по: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=7e19c450-bd8a-4fa4-a9f1-f789b8515544&t=). Ссылка активна на 23.10.2023.

36. Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Suppl. 2022;12(1):7-11. doi: https://doi.org/10.1016/j.kisu.2021.11.003

37. Sundstrom J, Bodegard J, Bollmann A, et al. Prevalence, outcomes, and cost of chronic kidney disease in a contemporary population of 2-4 million patients from 11 countries: The CaReMe CKD study. Lancet Reg Heal-Eur. 2022;20(1):100438. doi: https://doi.org/10.1016/j.lanepe.2022.100438

38. Standards of specialized diabetes care. 11th edition. Ed by Dedov II, Shestakova MV, Mayorov AYu. Moscow, 2023 (In Russ.) doi: https://doi.org/10.14341/DM13042

39. Matsushita K, Coresh J, Sang Y, et al. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol. 2015;3(7):514-525. doi: https://doi.org/10.1016/S2213-8587(15)00040-6

40. Tonneijck L, Muskiet MHA, Smits MM, et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017;28(4):1023-1039. doi: https://doi.org/10.1681/ASN.2016060666

41. Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-2045. doi: https://doi.org/10.2215/CJN.11491116

42. D'Amico G, Bazzi C. Pathophysiology of proteinuria. Kidney Int. 2003;63(3):809-825. doi: https://doi.org/10.1046/j.1523-1755.2003.00840.x

43. Balazki P, Schaller S, Eissing T, et al. A quantitative systems pharmacology kidney model of diabetes associated renal hyperfiltration and the effects of SGLT inhibitors. CPT Pharmacometrics Syst Pharmacol. 2018;7(12):788-797. doi: https://doi.org/10.1002/psp4.12359

44. Kluger AY, Tecson KM, Lee AY, et al. Class effects of SGLT2 inhibitors on cardiorenal outcomes. Cardiovasc Diabetol. 2019;18(1):99. doi: https://doi.org/10.1186/s12933-019-0903-4

45. Gohda T, Murakoshi M. Sodium-glucose cotransporter-2 inhibitors— miracle drugs for the treatment of chronic Kidney disease irrespective of the diabetes status: Lessons from the dedicated kidney disease-focused CREDENCE and DAPA-CKD trials. Int J Mol Sci. 2022;23(22):13749. doi: https://doi.org/10.3390/ijms232213749

46. Durkin M, Blais J. Linear projection of estimated glomerular filtration rate decline with canagliflozin and implications for dialysis utilization and cost in diabetic nephropathy. Diabetes Ther. 2021;12(2):499-508. doi: https://doi.org/10.1007/s13300-020-00953-4

47. Tziomalos K, Athyros VG. Diabetic nephropathy: New risk factors and improvements in diagnosis. Rev Diabet Stud. 2015;12(1-2):110-118. doi: https://doi.org/10.1900/RDS.2015.12.110

48. Zhang J, Wei J, Jiang S, et al. Macula densa SGLT1-NOS1-tubuloglomerular feedback pathway, a new mechanism for glomerular hyperfiltration during hyperglycemia. J Am Soc Nephrol. 2019;30(4):578-593. doi: https://doi.org/10.1681/ASN.2018080844

49. Hsieh C-Y, Sung S-F. From Kidney Protection to Stroke Prevention: The Potential Role of Sodium Glucose Cotransporter-2 Inhibitors. Int J Mol Sci. 2022;24(1):351. doi: https://doi.org/10.3390/ijms24010351