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Sodium-glucose cotransporter 2 inhibitors for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: A nationwide propensity-score matched cohort study

  • Jinyoung Kim
    Affiliations
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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  • Kyungdo Han
    Affiliations
    Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
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  • Bongsung Kim
    Affiliations
    Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
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  • Ki-Hyun Baek
    Affiliations
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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  • Ki-Ho Song
    Affiliations
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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  • Mee Kyoung Kim
    Correspondence
    Corresponding authors at: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeongdeungpo-gu, Seoul 07345, Republic of Korea.
    Affiliations
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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  • Hyuk-Sang Kwon
    Correspondence
    Corresponding authors at: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeongdeungpo-gu, Seoul 07345, Republic of Korea.
    Affiliations
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Published:November 25, 2022DOI:https://doi.org/10.1016/j.diabres.2022.110187

      Highlights

      • Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed significant reductions in fatty liver index (FLI) and its components compared to dipeptidyl peptidase 4 (DPP4) inhibitors in type 2 diabetes patients.
      • We further analyzed the change in FLI according to drug adherence measured by the medication possession ratio, and the change increased cumulatively with the duration of drug use.
      • We suggest that SGLT2 inhibitors may have beneficial effects in reducing the prevalence of nonalcoholic fatty liver disease in type 2 diabetes.

      Abstract

      Aims

      This study was to determine the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes.

      Methods

      We used data from the Korean National Health Insurance Service from 2014 to 2017. New drug users were screened, dipeptidyl peptidase 4 inhibitors (DPP4i) were set as the active comparator, and the differences between the two groups were corrected through propensity score matching. NAFLD was evaluated by the fatty liver index (FLI), which was calculated using body mass index, waist circumference, triglycerides, and gamma glutamyl peptidase.

      Results

      After 1:1 matching, 25,371 patients in each group who received medication for an average of 299 days were analyzed. Despite similar baseline FLI of each group, the FLI of the SGLT2i users was 44.4 ± 26.7 and the FLI of the DPP4i users was 48.9 ± 27.3 (P value < 0.001) after treatment. SGLT2i showed more significant decrements than DPP4i in all components of FLI. The more the adherence to the SGLT2i increased, the greater the decrease in FLI.

      Conclusions

      SGLT2i showed a significant reduction in FLI and its components. We suggest that SGLT2i may have beneficial effects in reducing the prevalence of NAFLD in type 2 diabetes.

      Keywords

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      References

        • Cusi K.
        • Isaacs S.
        • Barb D.
        • Basu R.
        • Caprio S.
        • Garvey W.T.
        • et al.
        American association of clinical endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the american association for the study of liver diseases (AASLD).
        Endocr Pract. 2022; 28: 528-562
        • Fabbrini E.
        • Sullivan S.
        • Klein S.
        Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications.
        Hepatology. 2010; 51: 679-689https://doi.org/10.1002/hep.23280
      1. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012;142:711–25 e6. doi: 10.1053/j.gastro.2012.02.003.

        • Adams L.A.
        • Lymp J.F.
        • St. Sauver J.
        • Sanderson S.O.
        • Lindor K.D.
        • Feldstein A.
        • et al.
        The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
        Gastroenterology. 2005; 129: 113-121
        • Cho Y.
        • Lee Y.H.
        State-of-the-art overview of the pharmacological treatment of non-alcoholic steatohepatitis.
        Endocrinol Metab (Seoul). 2022; 37: 38-52
        • Kahn S.E.
        • Hull R.L.
        • Utzschneider K.M.
        Mechanisms linking obesity to insulin resistance and type 2 diabetes.
        Nature. 2006; 444: 840-846https://doi.org/10.1038/nature05482
        • Taylor R.
        Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause.
        Diabetologia. 2008; 51: 1781-1789https://doi.org/10.1007/s00125-008-1116-7
        • Targher G.
        • Corey K.E.
        • Byrne C.D.
        • Roden M.
        The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments.
        Nat Rev Gastroenterol Hepatol. 2021; 18: 599-612https://doi.org/10.1038/s41575-021-00448-y
        • Younossi Z.M.
        • Golabi P.
        • de Avila L.
        • Paik J.M.
        • Srishord M.
        • Fukui N.
        • 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: 793-801
        • Bril F.
        • Cusi K.
        Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action.
        Diabetes Care. 2017; 40: 419-430https://doi.org/10.2337/dc16-1787
      2. Tacelli M, Celsa C, Magro B, Giannetti A, Pennisi G, Spatola F, et al. Antidiabetic drugs in NAFLD: the accomplishment of two goals at Once? Pharmaceuticals (Basel) 2018;11. doi: 10.3390/ph11040121.

        • Tahara A.
        • Kurosaki E.
        • Yokono M.
        • Yamajuku D.
        • Kihara R.
        • Hayashizaki Y.
        • et al.
        Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice.
        Eur J Pharmacol. 2013; 715: 246-255
        • Qiang S.
        • Nakatsu Y.
        • Seno Y.
        • Fujishiro M.
        • Sakoda H.
        • Kushiyama A.
        • et al.
        Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus.
        Diabetol Metab Syndr. 2015; 7https://doi.org/10.1186/s13098-015-0102-8
        • Eriksson J.W.
        • Lundkvist P.
        • Jansson P.-A.
        • Johansson L.
        • Kvarnström M.
        • Moris L.
        • et al.
        Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study.
        Diabetologia. 2018; 61: 1923-1934
        • Kuchay M.S.
        • Krishan S.
        • Mishra S.K.
        • Farooqui K.J.
        • Singh M.K.
        • Wasir J.S.
        • 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: 1801-1808
        • Ito D.
        • Shimizu S.
        • Inoue K.
        • Saito D.
        • Yanagisawa M.
        • Inukai 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: 1364-1372
        • Shibuya T.
        • Fushimi N.
        • Kawai M.
        • Yoshida Y.
        • Hachiya H.
        • Ito S.
        • et al.
        Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study.
        Diabetes Obes Metab. 2018; 20: 438-442
        • Kim M.K.
        • Han K.
        • Lee S.H.
        Current trends of big data research using the Korean National Health Information Database.
        Diabetes Metab J. 2022; 46: 552-563https://doi.org/10.4093/dmj.2022.0193
        • Bedogni G.
        • Bellentani S.
        • Miglioli L.
        • Masutti F.
        • Passalacqua M.
        • Castiglione A.
        • et al.
        The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.
        BMC Gastroenterol. 2006; 6: 33https://doi.org/10.1186/1471-230X-6-33
        • Koehler E.M.
        • Schouten J.N.
        • Hansen B.E.
        • Hofman A.
        • Stricker B.H.
        • Janssen H.L.
        External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study.
        Clin Gastroenterol Hepatol. 2013; 11: 1201-1204https://doi.org/10.1016/j.cgh.2012.12.031
        • Cuthbertson D.J.
        • Weickert M.O.
        • Lythgoe D.
        • Sprung V.S.
        • Dobson R.
        • Shoajee-Moradie F.
        • et al.
        External validation of the fatty liver index and lipid accumulation product indices, using 1H-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals.
        Eur J Endocrinol. 2014; 171: 561-569
        • Cramer J.A.
        • Benedict A.
        • Muszbek N.
        • Keskinaslan A.
        • Khan Z.M.
        The significance of compliance and persistence in the treatment of diabetes, hypertension and dyslipidaemia: a review.
        Int J Clin Pract. 2008; 62: 76-87https://doi.org/10.1111/j.1742-1241.2007.01630.x
        • Lau D.T.
        • Nau D.P.
        Oral antihyperglycemic medication nonadherence and subsequent hospitalization among individuals with type 2 diabetes.
        Diabetes Care. 2004; 27: 2149-2153https://doi.org/10.2337/diacare.27.9.2149
        • Pradhan R.
        • Yin H.
        • Yu O.
        • Azoulay L.
        Glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors and risk of nonalcoholic fatty liver disease among patients with type 2 diabetes.
        Diabetes Care. 2022; 45: 819-829https://doi.org/10.2337/dc21-1953
        • Scheen A.J.
        Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus.
        Nat Rev Endocrinol. 2020; 16: 556-577https://doi.org/10.1038/s41574-020-0392-2
        • Lee P.C.
        • Ganguly S.
        • Goh S.Y.
        Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms.
        Obes Rev. 2018; 19: 1630-1641https://doi.org/10.1111/obr.12755
        • Scheen A.J.
        SGLT2 versus DPP4 inhibitors for type 2 diabetes.
        Lancet Diabetes Endocrinol. 2013; 1: 168-170https://doi.org/10.1016/s2213-8587(13)70095-0
        • Min S.H.
        • Yoon J.-H.
        • Hahn S.
        • Cho Y.M.
        Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta-analysis.
        Diabetes Metab Res Rev. 2017; 33: e2818https://doi.org/10.1002/dmrr.2818
        • Ferré P.
        • Foufelle F.
        Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c.
        Diabetes Obes Metab. 2010; 12: 83-92https://doi.org/10.1111/j.1463-1326.2010.01275.x
        • Monami M.
        • Lamanna C.
        • Desideri C.M.
        • Mannucci E.
        DPP-4 inhibitors and lipids: systematic review and meta-analysis.
        Adv Ther. 2012; 29: 14-25https://doi.org/10.1007/s12325-011-0088-z
      3. Komiya C, Tsuchiya K, Shiba K, Miyachi Y, Furuke S, Shimazu N, et al. Ipragliflozin improves hepatic steatosis in obese mice and liver dysfunction in type 2 diabetic patients irrespective of body weight reduction. PLoS One 2016;11:e0151511. doi: 10.1371/journal.pone.0151511.

        • Moon J.S.
        • Hong J.H.
        • Jung Y.J.
        • Ferrannini E.
        • Nauck M.A.
        • Lim S.
        SGLT-2 inhibitors and GLP-1 receptor agonists in metabolic dysfunction-associated fatty liver disease.
        Trends Endocrinol Metab. 2022; 33: 424-442https://doi.org/10.1016/j.tem.2022.03.005
        • Androutsakos T.
        • Nasiri-Ansari N.
        • Bakasis A.-D.
        • Kyrou I.
        • Efstathopoulos E.
        • Randeva H.S.
        • et al.
        SGLT-2 inhibitors in NAFLD: expanding their role beyond diabetes and cardioprotection.
        Int J Mol Sci. 2022; 23: 3107
        • Leng W.
        • Wu M.
        • Pan H.
        • Lei X.
        • Chen L.
        • Wu Q.
        • et al.
        The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus.
        Ann Transl Med. 2019; 7: 429
      4. Honda Y, Imajo K, Kato T, Kessoku T, Ogawa Y, Tomeno W, et al. The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice. PLoS One 2016;11:e0146337. doi: 10.1371/journal.pone.0146337.

        • McCoy R.G.
        • Van Houten H.K.
        • Karaca-Mandic P.
        • Ross J.S.
        • Montori V.M.
        • Shah N.D.
        Second-line therapy for type 2 diabetes management: the treatment/benefit paradox of cardiovascular and kidney comorbidities.
        Diabetes Care. 2021; 44: 2302-2311https://doi.org/10.2337/dc20-2977
        • Basile J.N.
        The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular risk in patients with type 2 diabetes (T2DM).
        J Diabetes Complications. 2013; 27: 280-286https://doi.org/10.1016/j.jdiacomp.2012.12.004
        • Colosimo S.
        • Ravaioli F.
        • Petroni M.L.
        • Brodosi L.
        • Marchignoli F.
        • Barbanti F.A.
        • et al.
        Effects of antidiabetic agents on steatosis and fibrosis biomarkers in type 2 diabetes: a real-world data analysis.
        Liver Int. 2021; 41: 731-742
        • Leppée M.
        • Boskovic J.
        • Culig J.
        • Eric M.
        Pharmacy claims data as a tool to measure adherence.
        Curr Med Res Opin. 2012; 28: 1389-1393https://doi.org/10.1185/03007995.2012.705781