Diabetes Metab J.  2022 Jul;46(4):567-577. 10.4093/dmj.2021.0160.

Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitor and Thiazolidinedione Treatment on Risk of Stroke among Patients with Type 2 Diabetes Mellitus

• Lee SE
• Nam H
• Choi HS
• Kim H
• Kyoung DS
• Kim KA

• KMID: 2531961
• DOI: http://doi.org/10.4093/dmj.2021.0160

Abstract

Background
Although cardiovascular outcome trials using sodium-glucose cotransporter-2 inhibitors (SGLT-2i) showed a reduction in risk of 3-point major adverse cardiovascular events (MACE), they did not demonstrate beneficial effects on stroke risk. Additionally, meta-analysis showed SGLT-2i potentially had an adverse effect on stroke risk. Contrarily, pioglitazone, a type of thiazolidinedione (TZD), has been shown to reduce recurrent stroke risk. Thus, we aimed to compare the effect of SGLT-2i and TZD on the risk of stroke in type 2 diabetes mellitus (T2DM) patients.
Methods
Using the Korean National Health Insurance Service data, we compared a 1:1 propensity score-matched cohort of patients who used SGLT-2i or TZD from January 2014 to December 2018. The primary outcome was stroke. The secondary outcomes were myocardial infarction (MI), cardiovascular death, 3-point MACE, and heart failure (HF).
Results
After propensity-matching, each group included 56,794 patients. Baseline characteristics were well balanced. During the follow-up, 862 patients were newly hospitalized for stroke. The incidence rate of stroke was 4.11 and 4.22 per 1,000 person-years for the TZD and SGLT-2i groups respectively. The hazard ratio (HR) of stroke was 1.054 (95% confidence interval [CI], 0.904 to 1.229) in the SGLT-2i group compared to the TZD group. There was no difference in the risk of MI, cardiovascular death, 3-point MACE between groups. Hospitalization for HF was significantly decreased in SGLT-2i-treated patients (HR, 0.645; 95% CI, 0.466 to 0.893). Results were consistent regardless of prior cardiovascular disease.
Conclusion
In this real-world data, the risk of stroke was comparable in T2DM patients treated with SGLT-2i or TZD.

Keyword

Sodium-glucose transporter 2 inhibitors; Stroke; Thiazolidinediones

Figure

• 

  Fig. 1. Flow chart of study population. SGLT-2i, sodium-glucose cotransporter-2 inhibitor; TZD, thiazolidinedione; LDL, low density lipoprotein.

• 

  Fig. 2. Cumulative incidence of stroke in sodium-glucose cotransporter-2 inhibitor (SGLT-2i) and thiazolidinedione (TZD) groups. Cumulative incidence and number at risk of (A) total stroke, (B) ischemic stroke, and (C) hemorrhagic stroke in SGLT-2i-treated and TZD-treated groups.

• 

  Fig. 3. Risk of cardiovascular outcomes in sodium-glucose cotransporter-2 inhibitor (SGLT-2i) and thiazolidinedione (TZD) groups. Hazard ratio and 95% confidence interval for cardiovascular outcomes. MI, myocardial infarction; CV, cardiovascular; MACE, major adverse cardiovascular events; HF, heart failure. aBold denotes statistical significance at the P<0.05 level.

• 

  Fig. 4. Outcomes according to subgroups in sodium-glucose cotransporter-2 inhibitor (SGLT-2i) and thiazolidinedione (TZD) groups. Subgroup analyses to investigate whether effects of drugs differ between subgroups of study population. Event rates were calculated as the number of events divided by the total number of population in the group. (A) Stroke, (B) ischemic stroke, (C) hemorrhagic stroke, (D) myocardial infarction (MI), (E) cardiovascular (CV) death, (F) 3-point major adverse cardiovascular events (MACE), and (G) heart failure (HF). CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate.

Reference

1. Martin-Timon I, Sevillano-Collantes C, Segura-Galindo A, Del Canizo-Gomez FJ. Type 2 diabetes and cardiovascular disease: have all risk factors the same strength? World J Diabetes. 2014; 5:444–70.

2. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018; 17:83.

3. Ueshima H, Sekikawa A, Miura K, Turin TC, Takashima N, Kita Y, et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation. 2008; 118:2702–9.

4. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care. 2020; 43(Suppl 1):S98–110.

5. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, 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; 41:2669–701.

6. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380:347–57.

7. 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; 377:644–57.

8. 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; 373:2117–28.

9. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020; 383:1425–35.

10. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundstrom J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016; 4:411–9.

11. Arnott C, Li Q, Kang A, Neuen BL, Bompoint S, Lam CS, et al. Sodium-glucose cotransporter 2 inhibition for the prevention of cardiovascular events in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. J Am Heart Assoc. 2020; 9:e014908.

12. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019; 393:31–9.

13. Wilcox R, Bousser MG, Betteridge DJ, Schernthaner G, Pirags V, Kupfer S, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke. 2007; 38:865–73.

14. Lee YH, Han K, Ko SH, Ko KS, Lee KU; Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Data analytic process of a nationwide population-based study using national health information database established by National Health Insurance Service. Diabetes Metab J. 2016; 40:79–82.

15. Noh J. The diabetes epidemic in Korea. Endocrinol Metab (Seoul). 2016; 31:349–53.

16. Lee SE, Han K, Baek JY, Ko KS, Lee KU, Koh EH, et al. Association between diabetic retinopathy and Parkinson disease: the Korean National Health Insurance Service Database. J Clin Endocrinol Metab. 2018; 103:3231–8.

17. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009; 28:3083–107.

18. Marx N, McGuire DK, Perkovic V, Woerle HJ, Broedl UC, von Eynatten M, et al. Composite primary end points in cardiovascular outcomes trials involving type 2 diabetes patients: should unstable angina be included in the primary end point? Diabetes Care. 2017; 40:1144–51.

19. Malhotra K, Katsanos AH, Lambadiari V, Goyal N, Palaiodimou L, Kosmidou M, et al. GLP-1 receptor agonists in diabetes for stroke prevention: a systematic review and meta-analysis. J Neurol. 2020; 267:2117–22.

20. Fisher M. The challenge of mixed cerebrovascular disease. Ann N Y Acad Sci. 2010; 1207:18–22.

21. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993; 24:35–41.

22. Ohira T, Shahar E, Chambless LE, Rosamond WD, Mosley TH Jr, Folsom AR. Risk factors for ischemic stroke subtypes: the Atherosclerosis Risk in Communities study. Stroke. 2006; 37:2493–8.

23. Ryu WS, Schellingerhout D, Hong KS, Jeong SW, Jang MU, Park MS, et al. White matter hyperintensity load on stroke recurrence and mortality at 1 year after ischemic stroke. Neurology. 2019; 93:e578–89.

24. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Med. 2017; 130(6S):S30–9.

25. Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest. 2006; 116:1813–22.

26. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011; 14:575–85.

27. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2000; 106:523–31.

28. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, MassiBenedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomized controlled trial. Lancet. 2005; 366:1279–89.

29. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016; 374:1321–31.

30. 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; 375:323–34.

31. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJ, Mann JF, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013; 382:339–52.

32. Giugliano D, Ceriello A, De Nicola L, Perrone-Filardi P, Cosentino F, Esposito K. Primary versus secondary cardiorenal prevention in type 2 diabetes: which newer anti-hyperglycaemic drug matters? Diabetes Obes Metab. 2020; 22:149–57.

33. Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019; 7:776–85.

34. Benedetto U, Head SJ, Angelini GD, Blackstone EH. Statistical primer: propensity score matching and its alternatives. Eur J Cardiothorac Surg. 2018; 53:1112–7.

35. Gordon DL, Bendixen BH, Adams HP Jr, Clarke W, Kappelle LJ, Woolson RF. Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke: implications for clinical trials. The TOAST Investigators. Neurology. 1993; 43:1021–7.