Cardiovasc Prev Pharmacother.  2022 Jul;4(3):114-122. 10.36011/cpp.2022.4.e15.

Effect of the addition of thiazolidinedione to sodium-glucose cotransporter 2 inhibitor therapy on lipid levels in type 2 diabetes mellitus: a retrospective study using Korean National Health Insurance Service data

• Park T
• Han K
• Shin D
• Park J

• KMID: 2532277
• DOI: http://doi.org/10.36011/cpp.2022.4.e15

Abstract

Background
Dyslipidemia is common in patients with type 2 diabetes mellitus (T2D) and contributes to an increased risk of cardiovascular disease. Previous studies have shown that treatment with thiazolidinediones (TZDs) and sodium-glucose cotransporter-2 inhibitors (SGLT2-i) may help to improve dyslipidemia in T2D patients. In this study, we investigated whether patients treated with TZD and SGLT2-i showed greater improvement in high-density lipoprotein cholesterol (HDL-C) levels than those treated with only SGLT2-i.
Methods
From the National Health Insurance Service database of Korea, we extracted all patients who first received SGTL2-i from 2014 to 2016. Propensity score matching was performed to balance the two groups: group A (SGTL2-i and TZD, regardless of other antidiabetic medications) and group B (SGTL2-i only without TZD, regardless of other antidiabetic medications). Posttreatment HDL-C levels were compared by the Student t-test.
Results
In total, 1,400 T2D patients (700 in each group) were matched by propensity score matching. There was a significant posttreatment increase in HDL-C in group A (49.54±20.03 to 51.6±12.92 mg/dL, P=0.007), but not in group B (49.14±13.52 to 49.1±2.15 mg/dL, P=0.937). Group A also showed significantly higher posttreatment HDL-C levels than group B (51.4±12.92 vs. 49.1±12.15 mg/dL, P<0.001). Regarding the secondary endpoints, posttreatment triglyceride levels were lower (P<0.001), but total cholesterol (P=0.131) and low-density lipoprotein cholesterol levels (P=0.054) were not different after treatment.
Conclusions
The combination of SGTL2-i and TZD may be more effective in ameliorating dyslipidemia in T2D patients than SGLT2-i alone. However, further studies are needed to confirm this finding.

Keyword

Type 2 diabetes mellitus; Dyslipidemias; Sodium-glucose transporter 2 inhibitors; 2, 4-Thiazolidinedione; Combination therapy

Figure

• 

  Fig. 1. Patient disposition. SGLT2-I, sodium-glucose cotransporter-2 inhibitors; TZD, thiazolidinedione.

• 

  Fig. 2. Insurance benefits for antidiabetic agents in Korea based on the Health Insurance Review and Assessment Service. Pioglitazone is 100% covered by the patient. MET, metformin; SU, sulfonylurea; a-GI, alpha-glucosidase inhibitors; TZD, thiazolidinedione; DPP4-i, dipeptidyl peptidase-4 inhibitors; SGLT2-i, sodium-glucose cotransporter 2 inhibitors.

Reference

1. Schramm TK, Gislason GH, Kober L, Rasmussen S, Rasmussen JN, Abildstrom SZ, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation. 2008; 117:1945–54.

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. Rhee EJ, Kim HC, Kim JH, Lee EY, Kim BJ, Kim EM, et al. 2018 guidelines for the management of dyslipidemia in Korea. Korean J Intern Med. 2019; 34:1171.

4. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2019; 139:e1082–143.

5. Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008; 371:117–25.

6. Schofield JD, Liu Y, Rao-Balakrishna P, Malik RA, Soran H. Diabetes dyslipidemia. Diabetes Ther. 2016; 7:203–19.

7. Kashiwagi A, Shiga T, Akiyama N, Kazuta K, Utsuno A, Yoshida S, et al. Efficacy and safety of ipragliflozin as an add-on to pioglitazone in Japanese patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study (the SPOTLIGHT study). Diabetol Int. 2015; 6:104–116.

8. Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009; 5:150–9.

9. Farbstein D, Levy AP. HDL dysfunction in diabetes: causes and possible treatments. Expert Rev Cardiovasc Ther. 2012; 10:353–61.

10. Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet. 2014; 383:999–1008.

11. Yamashita S, Tsubakio-Yamamoto K, Ohama T, Nakagawa-Toyama Y, Nishida M. Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions. J Atheroscler Thromb. 2010; 17:436–51.

12. Filippas-Ntekouan S, Tsimihodimos V, Filippatos T, Dimitriou T, Elisaf M. SGLT-2 inhibitors: pharmacokinetics characteristics and effects on lipids. Expert Opin Drug Metab Toxicol. 2018; 14:1113–21.

13. Chen MB, Wang H, Cui WY, Xu HL, Zheng QH. Effect of SGLT inhibitors on weight and lipid metabolism at 24 weeks of treatment in patients with diabetes mellitus: a systematic review and network meta-analysis. Medicine (Baltimore). 2021; 100:e24593.

14. Cha SA, Park YM, Yun JS, Lim TS, Song KH, Yoo KD, et al. A comparison of effects of DPP-4 inhibitor and SGLT2 inhibitor on lipid profile in patients with type 2 diabetes. Lipids Health Dis. 2017; 16:58.

15. Bae J, Park T, Kim H, Lee M, Cha BS. Lobeglitazone: a novel thiazolidinedione for the management of type 2 diabetes mellitus. Diabetes Metab J. 2021; 45:326–36.

16. Rizzo M, Christ ER, Rini GB, Spinas GA, Berneis K. The differential effects of thiazolidindiones on atherogenic dyslipidemia in type 2 diabetes: what is the clinical significance? Expert Opin Pharmacother. 2008; 9:2295–303.

17. Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012; 35:1473–8.

18. Forst T, Guthrie R, Goldenberg R, Yee J, Vijapurkar U, Meininger G, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab. 2014; 16:467–77.

19. Filipova E, Uzunova K, Kalinov K, Vekov T. Effects of pioglitazone therapy on blood parameters, weight and BMI: a meta-analysis. Diabetol Metab Syndr. 2017; 9:90.

20. Kovacs CS, Seshiah V, Merker L, Christiansen AV, Roux F, Salsali A, et al. Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. Clin Ther. 2015; 37:1773–88. e1.

21. Seong SC, Kim YY, Park SK, Khang YH, Kim HC, Park JH, et al. Cohort profile: the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea. BMJ Open. 2017; 7:e016640.

22. Shin DW, Cho J, Park JH, Cho B. National General Health Screening Program in Korea: history, current status, and future direction. Precis Future Med. 2022; 6:9–31.

23. Stuart EA, Lee BK, Leacy FP. Prognostic score-based balance measures can be a useful diagnostic for propensity score methods in comparative effectiveness research. J Clin Epidemiol. 2013; 66(8 Suppl):S84–90.e1.

24. Kim SG, Kim DM, Woo JT, Jang HC, Chung CH, Ko KS, et al. Efficacy and safety of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 24-weeks: a multicenter, randomized, double-blind, parallel-group, placebo controlled trial. PLoS One. 2014; 9:e92843.

25. Ovalle F, Bell DS. Effect of thiazolidinediones on high-density lipoprotein subfractions. Endocr Pract. 2002; 8:102–4.

26. Hirano T. Pathophysiology of diabetic dyslipidemia. J Atheroscler Thromb. 2018; 25:771–82.

27. Kim SH, Kim SG, Kim DM, Woo JT, Jang HC, Chung CH, et al. Safety and efficacy of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 52 weeks: an open-label extension study. Diabetes Res Clin Pract. 2015; 110:e27–30.

28. Jin SM, Park CY, Cho YM, Ku BJ, Ahn CW, Cha BS, et al. Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension. Diabetes Obes Metab. 2015; 17:599–602.