The impact of dapagliflozin on FIB-4 index over 2 years in patients with type 2 diabetes mellitus

Semra Özkan; Deniz Gezer

doi:10.18621/eurj.1631079

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Year 2025, EARLY ONLINE, 1 - 7

Semra Özkan , Deniz Gezer

https://doi.org/10.18621/eurj.1631079

Abstract

References

1. European Association for the Study of the Liver EAftSoD, European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non- Alcoholic Fatty Liver Disease. Obesity Facts. 2016;9(2):65-90. doi: 10.1016/j.jhep.2015.11.004.
2. Portillo-Sanchez P, Bril F, Maximos M, et al. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. J Clin Endocrinol Metab. 2015;100(6):2231-2238. doi: 10.1210/jc.2015-1966.
3. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138-53. doi: 10.1136/gutjnl-2017-313884.
4. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017;65(5):1557-1565. doi: 10.1002/hep.29085.
5. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019;71(4):793-801. doi: 10.1016/j.jhep.2019.06.021.
6. American Diabetes Association. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S34-45. doi: 10.2337/dc19-S004.
7. Castera L, Friedrich-Rust M, Loomba R. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2019;156(5):1264-81.e4. doi: 10.1053/j.gastro.2018.
8. Kotronen A, Peltonen M, Hakkarainen A, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137(3):865-872. doi:10.1053/j.gastro.2009.06.005.
9. Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33. doi: 10.1186/1471-230X-6-33.
10. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ; Nash Clinical Research Network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104-1112. doi: 10.1016/j.cgh.2009.05.033.
11. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-854. doi: 10.1002/hep.21496.
12. Sterling RK, Lissen E, Clumeck N, et al.; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-1325. doi: 10.1002/hep.21178.
13. Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection comparison with liver biopsy and fibrotest. Hepatology. 2007;46(1):32-36. doi: 10.1002/hep.21669.
14. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis. JAMA Intern Med. 2017;177(5):633-640. doi: 10.1001/jamainternmed.2016.9607.
15. Bonora BM, Avogaro A, Fadini GP. Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence. Diabetes Metab Syndr Obes. 2020;13:161-174. doi: 10.2147/DMSO.S233538.
16. Ghezzi C, Yu AS, Hirayama BA, et al. Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule. J Am Soc Nephrol. 2017;28(3):802-810. doi: 10.1681/ASN.2016050510.
17. Li L, Li Q, Huang W, et al. Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway. Front Pharmacol. 2021;12:589273. doi: 10.3389/fphar.2021.589273.
18. Shimizu M, Suzuki K, Kato K, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab. 2019;21(2):285-292. doi: 10.1111/dom.13520.
19. Bolinder J, Ljunggren Ö, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97(3):1020-1031. doi: 10.1210/jc.2011-2260.
20. Jojima T, Tomotsune T, Iijima T, Akimoto K, Suzuki K, Aso Y. Empagliflozin (an SGLT2inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. Diabetol Metab Syndr. 2016;8:45. doi: 10.1186/s13098-016-0169-x.
21. Qiang S, Nakatsu Y, Seno Y, et al. Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. Diabetol Metab Syndr. 2015;7:104. doi: 10.1186/s13098-015-0102-8.
22. Ito D, Shimizu S, Inoue K, et al. Comparison of Ipragliflozin and Pioglitazone Effects on Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Randomized, 24-Week, Open-Label, Active-Controlled Trial. Diabetes Care. 2017;40(10):1364-1372. doi: 10.2337/dc17-0518.
23. Kuchay MS, Krishan S, Mishra SK, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801-1808. doi: 10.2337/dc18-0165. doi: 10.2337/dc18-0165.
24. Tobita H, Yazaki T, Kataoka M, et al. Comparison of dapagliflozin and teneligliptin in nonalcoholic fatty liver disease patients without type 2 diabetes mellitus: a prospective randomized study. J Clin Biochem Nutr. 2021;68(2):173-180. doi: 10.3164/jcbn.20-129.
25. Cho KY, Nakamura A, Omori K, , et al. Favorable effect of sodium-glucose cotransporter 2 inhibitor, dapagliflozin, on non-alcoholic fatty liver disease compared with pioglitazone. J Diabetes Investig. 2021;12(7):1272-1277. doi: 10.1111/jdi.13457.
26. Tobita H, Sato S, Miyake T, Ishihara S, Kinoshita Y. Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study. Curr Ther Res Clin Exp. 2017;87:13-19. doi: 10.1016/j.curtheres.2017.07.002.
27. Jin Z, Yuan Y, Zheng C, Liu S, Weng H. Effects of sodium-glucose co-transporter 2 inhibitors on liver fibrosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: An updated meta-analysis of randomized controlled trials. J Diabetes Complications. 2023;37(8):108558. doi: 10.1016/j.jdiacomp.2023.
28. Scheen AJ. Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: A common comorbidity associated with severe complications. Diabetes Metab. 2019;45(3):213-223. doi: 10.1016/j.diabet.2019.01.008.
29. Lee PCH, Gu Y, Yeung MY, et al. Dapagliflozin and Empagliflozin Ameliorate Hepatic Dysfunction Among Chinese Subjects with Diabetes in Part Through Glycemic Improvement: A Single-Center, Retrospective, Observational Study. Diabetes Ther. 2018;9(1):285-295. doi: 10.1007/s13300-017-0355-3.
30. Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of Sodium-Glucose Cotransport-2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of 43 Randomized Control Trials With 22 528 Patients. J Am Heart Assoc. 2017;6(6):e004007. doi: 10.1161/JAHA.116.004007.

The impact of dapagliflozin on FIB-4 index over 2 years in patients with type 2 diabetes mellitus

Year 2025, EARLY ONLINE, 1 - 7

Semra Özkan , Deniz Gezer

https://doi.org/10.18621/eurj.1631079

Abstract

Objectives: Dapagliflozin belongs to the sodium-glucose co-transporter 2 inhibitor drug group used in the treatment of type 2 diabetes. This study aimed to investigate the effects of dapagliflozin and simultaneous dapagliflozin+pioglitazone therapy on the FIB-4 index, associated with liver inflammation and fibrosis, at the end of the first and second years.

Methods: This retrospective study, conducted between 01.01.2017 and 01.01.2020, included 386 patients using dapagliflozin alone (DAPA Group) and 122 patients using dapagliflozin in combination with pioglitazone (DAPA+PIO Group). ALT, AST, and FIB-4 index were compared at baseline, at week 52, and at week 104.

Results: The DAPA group consisted of 243 females (63%) and 143 males (37%) with a mean age of 59.8±6 years. The DAPA+PIO group consisted of 61 females (50%) and 61 males (50%) with a mean age of 58.3±5 years. No significant differences were observed between the groups in ALT, AST, hemoglobin levels, and platelet counts at the baseline, at the 52nd week, and at the 104th week (P>0.05). Statistically significant decreases in fasting blood glucose and HbA1C levels were observed in both groups at baseline, week 52, and week 104 (P<0.001). Furthermore, both groups exhibited no statistically significant changes in the FIB-4 index during the first and second years compared to baseline (P>0.05).

Conclusions: Dapagliflozin, either alone or in combination with pioglitazone, did not alter the FIB-4 index associated with liver fibrosis and inflammation over 1 and 2 years in patients with type 2 diabetes. Despite experimental evidence indicating its potential to reduce liver fibrosis, clinical data remain inconclusive. Future prospective studies with longer durations are necessary for a clearer understanding.

Keywords

Type 2 diabetes mellitus, dapagliflozin, pioglitazone, liver, FIB-4 index

Ethical Statement

This study was approved by the Mersin University Clinical Research Ethics Committee (Decision no. 2023/861, date: 13.12.2023). Since the study was retrospective, written informed consent was not required.

References

1. European Association for the Study of the Liver EAftSoD, European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non- Alcoholic Fatty Liver Disease. Obesity Facts. 2016;9(2):65-90. doi: 10.1016/j.jhep.2015.11.004.
2. Portillo-Sanchez P, Bril F, Maximos M, et al. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. J Clin Endocrinol Metab. 2015;100(6):2231-2238. doi: 10.1210/jc.2015-1966.
3. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138-53. doi: 10.1136/gutjnl-2017-313884.
4. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017;65(5):1557-1565. doi: 10.1002/hep.29085.
5. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019;71(4):793-801. doi: 10.1016/j.jhep.2019.06.021.
6. American Diabetes Association. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S34-45. doi: 10.2337/dc19-S004.
7. Castera L, Friedrich-Rust M, Loomba R. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2019;156(5):1264-81.e4. doi: 10.1053/j.gastro.2018.
8. Kotronen A, Peltonen M, Hakkarainen A, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137(3):865-872. doi:10.1053/j.gastro.2009.06.005.
9. Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33. doi: 10.1186/1471-230X-6-33.
10. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ; Nash Clinical Research Network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104-1112. doi: 10.1016/j.cgh.2009.05.033.
11. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-854. doi: 10.1002/hep.21496.
12. Sterling RK, Lissen E, Clumeck N, et al.; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-1325. doi: 10.1002/hep.21178.
13. Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection comparison with liver biopsy and fibrotest. Hepatology. 2007;46(1):32-36. doi: 10.1002/hep.21669.
14. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis. JAMA Intern Med. 2017;177(5):633-640. doi: 10.1001/jamainternmed.2016.9607.
15. Bonora BM, Avogaro A, Fadini GP. Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence. Diabetes Metab Syndr Obes. 2020;13:161-174. doi: 10.2147/DMSO.S233538.
16. Ghezzi C, Yu AS, Hirayama BA, et al. Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule. J Am Soc Nephrol. 2017;28(3):802-810. doi: 10.1681/ASN.2016050510.
17. Li L, Li Q, Huang W, et al. Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway. Front Pharmacol. 2021;12:589273. doi: 10.3389/fphar.2021.589273.
18. Shimizu M, Suzuki K, Kato K, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab. 2019;21(2):285-292. doi: 10.1111/dom.13520.
19. Bolinder J, Ljunggren Ö, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97(3):1020-1031. doi: 10.1210/jc.2011-2260.
20. Jojima T, Tomotsune T, Iijima T, Akimoto K, Suzuki K, Aso Y. Empagliflozin (an SGLT2inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. Diabetol Metab Syndr. 2016;8:45. doi: 10.1186/s13098-016-0169-x.
21. Qiang S, Nakatsu Y, Seno Y, et al. Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. Diabetol Metab Syndr. 2015;7:104. doi: 10.1186/s13098-015-0102-8.
22. Ito D, Shimizu S, Inoue K, et al. Comparison of Ipragliflozin and Pioglitazone Effects on Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Randomized, 24-Week, Open-Label, Active-Controlled Trial. Diabetes Care. 2017;40(10):1364-1372. doi: 10.2337/dc17-0518.
23. Kuchay MS, Krishan S, Mishra SK, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801-1808. doi: 10.2337/dc18-0165. doi: 10.2337/dc18-0165.
24. Tobita H, Yazaki T, Kataoka M, et al. Comparison of dapagliflozin and teneligliptin in nonalcoholic fatty liver disease patients without type 2 diabetes mellitus: a prospective randomized study. J Clin Biochem Nutr. 2021;68(2):173-180. doi: 10.3164/jcbn.20-129.
25. Cho KY, Nakamura A, Omori K, , et al. Favorable effect of sodium-glucose cotransporter 2 inhibitor, dapagliflozin, on non-alcoholic fatty liver disease compared with pioglitazone. J Diabetes Investig. 2021;12(7):1272-1277. doi: 10.1111/jdi.13457.
26. Tobita H, Sato S, Miyake T, Ishihara S, Kinoshita Y. Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study. Curr Ther Res Clin Exp. 2017;87:13-19. doi: 10.1016/j.curtheres.2017.07.002.
27. Jin Z, Yuan Y, Zheng C, Liu S, Weng H. Effects of sodium-glucose co-transporter 2 inhibitors on liver fibrosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: An updated meta-analysis of randomized controlled trials. J Diabetes Complications. 2023;37(8):108558. doi: 10.1016/j.jdiacomp.2023.
28. Scheen AJ. Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: A common comorbidity associated with severe complications. Diabetes Metab. 2019;45(3):213-223. doi: 10.1016/j.diabet.2019.01.008.
29. Lee PCH, Gu Y, Yeung MY, et al. Dapagliflozin and Empagliflozin Ameliorate Hepatic Dysfunction Among Chinese Subjects with Diabetes in Part Through Glycemic Improvement: A Single-Center, Retrospective, Observational Study. Diabetes Ther. 2018;9(1):285-295. doi: 10.1007/s13300-017-0355-3.
30. Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of Sodium-Glucose Cotransport-2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of 43 Randomized Control Trials With 22 528 Patients. J Am Heart Assoc. 2017;6(6):e004007. doi: 10.1161/JAHA.116.004007.

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Details

Primary Language	English
Subjects	Endocrinology, Internal Diseases
Journal Section	Original Articles
Authors	Semra Özkan 0000-0003-2223-197X Deniz Gezer 0000-0002-9036-0135
Early Pub Date	May 31, 2025
Publication Date
Submission Date	February 9, 2025
Acceptance Date	May 7, 2025
Published in Issue	Year 2025 EARLY ONLINE

Cite

AMA	Özkan S, Gezer D. The impact of dapagliflozin on FIB-4 index over 2 years in patients with type 2 diabetes mellitus. Eur Res J. Published online May 1, 2025:1-7. doi:10.18621/eurj.1631079

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