Effects of sodium-glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors on diabetic retinopathy and its progression: A real-world Korean study

Autoři: Yoo-Ri Chung aff001;  Kyoung Hwa Ha aff002;  Kihwang Lee aff001;  Dae Jung Kim aff002
Působiště autorů: Department of Ophthalmology, Ajou University School of Medicine, Suwon, Korea aff001;  Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea aff002;  Cardiovascular and Metabolic Disease Etiology Research Center, Ajou University School of Medicine, Suwon, Korea aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224549


The sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce the incidence of macrovascular complications of diabetes, while their effect on diabetic retinopathy has not been clarified. We compared the effects of SGLT2is with those of dipeptidyl peptidase-4 inhibitors (DPP4is) on the risk of diabetic retinopathy and its progression in people with type 2 diabetes. We performed a retrospective cohort study among people with type 2 diabetes who started on a SGLT2i or DPP4i from 2014 to 2016 according to the Korean National Health Insurance Service database. Subjects initiated on a SGLT2i or DPP4i were matched on a 1:1 basis according to their propensity scores, and Cox proportional hazards regression models were used to calculate the hazard ratios for the risk of diabetic retinopathy and its progression. After propensity score-matching, 41,430 patients without a history of diabetic retinopathy were identified as new users of a SGLT2i (n = 20,175) or DPP4i (n = 20,175). The hazard ratio (95% CI) for diabetic retinopathy was 0.89 (0.83–0.97) for SGLT2i initiators compared with DPP4i initiators. In patients with a history of diabetic retinopathy (n = 4,663 pairs), there was no significant difference in diabetic retinopathy progression between SGLT2i initiators and DPP4i initiators (hazard ratio 0.94, 95% CI 0.78–1.13). This real-world cohort study showed that SGLT2is might be associated with lower risk of diabetic retinopathy compared with DPP4is. Randomized controlled trials are needed to investigate the long-term effect of SGLT2is in diabetic retinopathy in people with diabetes.

Klíčová slova:

Blood pressure – Cardiovascular diseases – Cohort studies – Diabetic retinopathy – Health insurance


1. Whalen K, Miller S, Onge ES. The role of sodium-glucose co-transporter 2 inhibitors in the treatment of type 2 diabetes. Clin Ther. 2015;37: 1150–1166. doi: 10.1016/j.clinthera.2015.03.004 25891804

2. Zhang M, Zhang L, Wu B, Song H, An Z, Li S. Dapagliflozin treatment for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2014;30: 204–221. doi: 10.1002/dmrr.2479 24115369

3. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373: 2117–2128. doi: 10.1056/NEJMoa1504720 26378978

4. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166: 217–223.e211. doi: 10.1016/j.ahj.2013.05.007 23895803

5. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37: 1526–1534. doi: 10.1093/eurheartj/ehv728 26819227

6. Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL 2 study. J Am Coll Cardiol. 2018;71: 2628–2639. doi: 10.1016/j.jacc.2018.03.009 29540325

7. Patorno E, Goldfine AB, Schneeweiss S, Everett BM, Glynn RJ, Liu J, et al. Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. BMJ. 2018;360: k119. doi: 10.1136/bmj.k119 29437648

8. Udell JA, Yuan Z, Rush T, Sicignano NM, Galitz M, Rosenthal N. Cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter 2 inhibitor: Results from the EASEL population-based cohort study (Evidence for cardiovascular outcomes with sodium glucose cotransporter 2 inhibitors in the real world). Circulation. 2018;137: 1450–1459. doi: 10.1161/CIRCULATIONAHA.117.031227 29133607

9. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL study (Comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136: 249–259. doi: 10.1161/CIRCULATIONAHA.117.029190 28522450

10. Persson F, Nystrom T, Jorgensen ME, Carstensen B, Gulseth HL, Thuresson M, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study. Diabetes Obes Metab. 2018;20: 344–351. doi: 10.1111/dom.13077 28771923

11. Ott C, Jumar A, Striepe K, Friedrich S, Karg MV, Bramlage P, et al. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol. 2017;16: 26. doi: 10.1186/s12933-017-0510-1 28231831

12. Dziuba J, Alperin P, Racketa J, Iloeje U, Goswami D, Hardy E, et al. Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes. Diabetes Obes Metab. 2014;16: 628–635. doi: 10.1111/dom.12261 24443793

13. Shin SJ, Chung S, Kim SJ, Lee EM, Yoo YH, Kim JW, et al. Effect of sodium-glucose co-transporter 2 inhibitor, dapagliflozin, on renal renin-angiotensin system in an animal model of type 2 diabetes. PLoS One. 2016;11: e0165703. doi: 10.1371/journal.pone.0165703 27802313

14. Wang D, Luo Y, Wang X, Orlicky DJ, Myakala K, Yang P, et al. The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents renal and liver disease in Western diet induced obesity mice. Int J Mol Sci. 2018;19.

15. Satirapoj B. Sodium-glucose cotransporter 2 inhibitors with renoprotective effects. Kidney Dis (Basel). 2017;3: 24–32.

16. Wong CW, Wong TY, Cheng CY, Sabanayagam C. Kidney and eye diseases: common risk factors, etiological mechanisms, and pathways. Kidney Int. 2014;85: 1290–1302. doi: 10.1038/ki.2013.491 24336029

17. Stitt AW, Curtis TM, Chen M, Medina RJ, McKay GJ, Jenkins A, et al. The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res. 2016;51: 156–186. doi: 10.1016/j.preteyeres.2015.08.001 26297071

18. Bandello F, Lattanzio R, Zucchiatti I, Del Turco C. Pathophysiology and treatment of diabetic retinopathy. Acta Diabetol. 2013;50: 1–20. doi: 10.1007/s00592-012-0449-3 23277338

19. Cho EH, Park SJ, Han S, Song JH, Lee K, Chung YR. Sodium-glucose cotransporter 2 inhibitors with renoprotective effects. J Diabetes Res. 2018;2018: 6807219. doi: 10.1155/2018/6807219

20. Noh J. The diabetes epidemic in Korea. Endocrinol Metab (Seoul). 2016;31: 349–353.

21. Cheol Seong S, Kim YY, Khang YH, Heon Park J, Kang HJ, Lee H, et al. Data resource profile: The national health information database of the National Health Insurance Service in South Korea. Int J Epidemiol. 2017;46: 799–800. doi: 10.1093/ije/dyw253 27794523

22. Bressler SB, Liu D, Glassman AR, Blodi BA, Castellarin AA, Jampol LM, et al. Change in diabetic retinopathy through 2 years: Secondary analysis of a randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab. JAMA Ophthalmol. 2017;135: 558–568. doi: 10.1001/jamaophthalmol.2017.0821 28448655

23. Austin PC. An Introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46: 399–424. doi: 10.1080/00273171.2011.568786 21818162

24. Normand ST, Landrum MB, Guadagnoli E, Ayanian JZ, Ryan TJ, Cleary PD, et al. Validating recommendations for coronary angiography following acute myocardial infarction in the elderly: a matched analysis using propensity scores. J Clin Epidemiol. 2001;54: 387–398. doi: 10.1016/s0895-4356(00)00321-8 11297888

25. Kosiborod M, Birkeland KI, Cavender MA, Fu AZ, Wilding JP, Khunti K, et al. Rates of myocardial infarction and stroke in patients initiated on SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice: results from the CVD-REAL study. Diabetes Obes Metab. 2018;20: 1983–1987. doi: 10.1111/dom.13299 29569378

26. Zheng Y, He M, Congdon N. The worldwide epidemic of diabetic retinopathy. Indian J Ophthalmol. 2012;60: 428–431. doi: 10.4103/0301-4738.100542 22944754

27. Congdon NG, Friedman DS, Lietman T. Important causes of visual impairment in the world today. Jama. 2003;290: 2057–2060. doi: 10.1001/jama.290.15.2057 14559961

28. Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35: 556–564. doi: 10.2337/dc11-1909 22301125

29. Ko SH, Kim DJ, Park JH, Park CY, Jung CH, Kwon HS, et al. Trends of antidiabetic drug use in adult type 2 diabetes in Korea in 2002–2013: Nationwide population-based cohort study. Medicine (Baltimore). 2016;95: e4018.

30. Chung YR, Park SW, Kim JW, Kim JH, Lee K. Protective effects of dipeptidyl peptidase-4 inhibitors on progression of diabetic retinopathy in patients with type 2 diabetes. Retina. 2016;36: 2357–2363. doi: 10.1097/IAE.0000000000001098 27285457

31. Lee CS, Kim YG, Cho HJ, Park J, Jeong H, Lee SE, et al. Dipeptidyl peptidase-4 inhibitor increases vascular leakage in retina through VE-cadherin phosphorylation. Sci Rep. 2016;6: 29393. doi: 10.1038/srep29393 27381080

32. Tang H, Li G, Zhao Y, Wang F, Gower EW, Shi L, et al. Comparisons of diabetic retinopathy events associated with glucose-lowering drugs in patients with type 2 diabetes mellitus: A network meta-analysis. Diabetes Obes Metab. 2018;20: 1262–1279. doi: 10.1111/dom.13232 29369494

33. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375: 323–334. doi: 10.1056/NEJMoa1515920 27299675

34. Kadowaki T, Nangaku M, Hantel S, Okamura T, von Eynatten M, Wanner C, et al. Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: results from the EMPA-REG OUTCOME((R)) trial. J Diabetes Investig. 2019;10: 760–770. doi: 10.1111/jdi.12971 30412655

35. Gupta SK. Intention-to-treat concept: A review. Perspect Clin Res. 2011;2: 109–112. doi: 10.4103/2229-3485.83221 21897887

36. Mancini SJ, Boyd D, Katwan OJ, Strembitska A, Almabrouk TA, Kennedy S, et al. Canagliflozin inhibits interleukin-1beta-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci Rep. 2018;8: 5276. doi: 10.1038/s41598-018-23420-4 29588466

37. Wakisaka M, Nagao T. Sodium glucose cotransporter 2 in mesangial cells and retinal pericytes and its implications for diabetic nephropathy and retinopathy. Glycobiology. 2017 forthcoming.

38. Herat LY, Matthews VB, Rakoczy PE, Carnagarin R, Schlaich M. Focusing on sodium glucose cotransporter-2 and the sympathetic nervous system: Potential impact in diabetic retinopathy. Int J Endocrinol. 2018;2018: 9254126. doi: 10.1155/2018/9254126 30123269

39. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377: 644–657. doi: 10.1056/NEJMoa1611925 28605608

40. Takakura S, Toyoshi T, Hayashizaki Y, Takasu T. Effect of ipragliflozin, an SGLT2 inhibitor, on progression of diabetic microvascular complications in spontaneously diabetic Torii fatty rats. Life Sci. 2016;147: 125–131. doi: 10.1016/j.lfs.2016.01.042 26829386

41. Beitelshees AL, Leslie BR, Taylor SI. Sodium-glucose cotransporter 2 inhibitors: A case study in translational research. Diabetes. 2019;68: 1109–1120. doi: 10.2337/dbi18-0006 31109940

42. Tsujimoto T, Kajio H, Sugiyama T. Favourable changes in mortality in people with diabetes: US NHANES 1999–2010. Diabetes Obes Metab. 2018;20: 85–93. doi: 10.1111/dom.13039 28640432

43. Chew EY, Davis MD, Danis RP, Lovato JF, Perdue LH, Greven C, et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology. 2014;121: 2443–2451. doi: 10.1016/j.ophtha.2014.07.019 25172198

44. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317: 703–713. 9732337

45. Sun W, Gerhardinger C, Dagher Z, Hoehn T, Lorenzi M. Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects. Diabetes. 2005;54: 3418–3426. doi: 10.2337/diabetes.54.12.3418 16306357

46. Kern TS, Engerman RL. Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. Diabetes. 2001;50: 1636–1642. doi: 10.2337/diabetes.50.7.1636 11423486

47. The DAMAD Study Group. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. Diabetes. 1989;38: 491–498. 2647556

48. Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman RR, Manley SE, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia. 2001;44: 156–163. doi: 10.1007/s001250051594 11270671

49. Liu Y, Wang M, Morris AD, Doney AS, Leese GP, Pearson ER, et al. Glycemic exposure and blood pressure influencing progression and remission of diabetic retinopathy: a longitudinal cohort study in GoDARTS. Diabetes Care. 2013;36: 3979–3984. doi: 10.2337/dc12-2392 24170761

50. Rudnisky CJ, Wong BK, Virani H, Tennant MTS. Risk factors for progression of diabetic retinopathy in Alberta First Nations communities. Can J Ophthalmol. 2017;52 Suppl 1: S19–S29.

51. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376: 419–430. doi: 10.1016/S0140-6736(10)60576-4 20594588

52. Inzucchi SE, Wanner C, Hehnke U, Zwiener I, Kaspers S, Clark D, et al. Retinopathy outcomes with empagliflozin versus placebo in the EMPA-REG OUTCOME Trial. Diabetes Care. 2019;42: e53–e55. doi: 10.2337/dc18-1355 30705060

53. Empagliflozin reduces progression of diabetic retinopathy in patients with high risk of diabetic macular edema. Database: ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/show/NCT02985242.

54. Kohner EM. The effect of diabetic control on diabetic retinopathy. Eye (Lond). 1993;7: 309–311.

55. Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363: 233–244. doi: 10.1056/NEJMoa1001288 20587587

56. Wang Z, Sun J, Han R, Fan D, Dong X, Luan Z, et al. Efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as monotherapy or add-on to metformin in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Obes Metab. 2018;20: 113–120. doi: 10.1111/dom.13047 28656707

57. Goldenberg RM. Choosing dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, or both, as add-ons to metformin: Patient baseline characteristics are crucial. Clin Ther. 2017;39: 2438–2447. doi: 10.1016/j.clinthera.2017.10.016 29174215

58. Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: A meta-analysis. JAMA. 2016;316: 313–324. doi: 10.1001/jama.2016.9400 27434443

59. Kohner EM. Microvascular disease: what does the UKPDS tell us about diabetic retinopathy? Diabet Med. 2008;25 Suppl 2: 20–24.

60. Krick TW, Bressler NM. Recent clinically relevant highlights from the Diabetic Retinopathy Clinical Research Network. Curr Opin Ophthalmol. 2018;29: 199–205. doi: 10.1097/ICU.0000000000000472 29528861

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden