Doms № 5 -2022

Metabolic effects of empagliflozine

Kedyk A.V., Kutsyn O. O.


Kedyk A.V.

Uzhorod National Uneversity, Deratment of  Hospital Therapy

Kutsyn O. O.

Uzhorod National Uneversity, Deratment of  Hospital Therapy




Key words: sodium-glucose co-transporter type 2 inhibitors, empagliflozin, type 2 diabetes, cardiovascular diseases, nephroprotection, non-alcoholic fatty liver disease, hyperuricemia.


Potentially beneficial metabolic effects of empagliflozin remain “overshadowed” by the undeniable benefits of this drug in terms of cardio- and renoprotection. Today, there is a large data array (meta-analyses, systematic reviews and separate cohort studies with empagliflozin) that confirm the beneficial effect of this drug on various metabolic processes, which was systematized in this scientific review. It is emphasized that the antihyperglycemic effect of the drug does not depend on the secretion of insulin by β-cells of the pancreas and insulin resistance, it is manifested only in conditions of glucosuria and limited by eGFR. Empagliflozin combines well with all oral and parenteral hypoglycemic drugs; combination with drugs that have a potential risk of hypoglycemia (insulin and sulfonylurea drugs) requires a dose reduction of the latter. The durability of empagliflozin allows to maintain the achieved levels of glycated hemoglobin for a long time and postpone the start of insulin therapy. Weight loss by drug using corrects blood pressure and insulin resistance. In addition to the ability to reduce the level of uric acid and postpone the appointment of antigout drugs, empagliflozin can be considered a drug that has a multi-vector effect on various component of the metabolic syndrome. Promising areas of the drug using are reducing the risk of nephrolithiasis, steatosis and slowing down the progression of liver fibrosis.





  1. Thomas, M.C., Cherney, D.Z.I. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia 61, 2098–2107 (2018).
  2. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017 Feb;60(2):215-225. doi: 10.1007/s00125-016-4157-3.
  3. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014 Feb;124(2):509-14. doi: 10.1172/JCI70704.
  4. van Bommel EJ, Muskiet MH, Tonneijck L, Kramer MH, Nieuwdorp M, van Raalte DH. SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome. Clin J Am Soc Nephrol. 2017 Apr 3;12(4):700-710. doi: 10.2215/CJN.06080616.
  5. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. doi: 10.1172/JCI72227.19
  6. Cherukuri L, Smith MS, Tayek JA. The durability of oral diabetic medications: Time to A1c baseline and a review of common oral medications used by the primary care provider. Endocrinol Diabetes Metab J. 2018 Sep;2(3): Epub 2018 Jul 8.
  7. Vaduganathan M, Inzucchi SE, Sattar N, Fitchett DH, Ofstad AP, Brueckmann M, George JT, Verma S, Mattheus M, Wanner C, Zinman B, Butler J. Effects of empagliflozin on insulin initiation or intensification in patients with type 2 diabetes and cardiovascular disease: Findings from the EMPA-REG OUTCOME trial. Diabetes Obes Metab. 2021 Dec;23(12):2775-2784. doi: 10.1111/dom.14535.
  8. Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR, Frederick DW, Pongratz RL, Zhao X, Moeckel GW, Samuel VT, Whaley JM, Shulman GI, Kibbey RG. SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function. Diabetes. 2011 Mar;60(3):890-8. doi: 10.2337/db10-1328.
  9. Obata A, Kubota N, Kubota T, Iwamoto M, Sato H, Sakurai Y, Takamoto I, Katsuyama H, Suzuki Y, Fukazawa M, Ikeda S, Iwayama K, Tokuyama K, Ueki K, Kadowaki T. Tofogliflozin Improves Insulin Resistance in Skeletal Muscle and Accelerates Lipolysis in Adipose Tissue in Male Mice. Endocrinology. 2016 Mar;157(3):1029-42. doi: 10.1210/en.2015-1588.
  10. Merovci A, Abdul-Ghani M, Mari A, Solis-Herrera C, Xiong J, Daniele G, Tripathy D, DeFronzo RA. Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males. J Clin Endocrinol Metab. 2016 Mar;101(3):1249-56. doi: 10.1210/jc.2015-2597.
  11. Meier JJ, Nauck MA. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev. 2005 Mar-Apr;21(2):91-117. doi: 10.1002/dmrr.538.
  12. Singh AK, Singh R. Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. World J Cardiol. 2022 Jun 26;14(6):329-342. doi: 10.4330/wjc.v14.i6.329.
  13. Li D, Shi W, Wang T, Tang H. SGLT2 inhibitor plus DPP-4 inhibitor as combination therapy for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. 2018 Aug;20(8):1972-1976. doi: 10.1111/dom.13294.
  14. Min SH, Yoon JH, Hahn S, Cho YM. 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 Jan;33(1). doi: 10.1002/dmrr.2818.
  15. Yang Y, Zhao C, Ye Y, Yu M, Qu X. Prospect of Sodium-Glucose Co-transporter 2 Inhibitors Combined With Insulin for the Treatment of Type 2 Diabetes. Front Endocrinol (Lausanne). 2020 Apr 15;11:190. doi: 10.3389/fendo.2020.00190.
  16. Lu J, Tang L, Meng H, Zhao J, Liang Y. Effects of sodium-glucose cotransporter (SGLT) inhibitors in addition to insulin therapy on glucose control and safety outcomes in adults with type 1 diabetes: A meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2019 Oct;35(7):e3169. doi: 10.1002/dmrr.3169.
  17. Forst T, Heise T, Plum-Morschel L. Pharmacological Intervention in Type 2 Diabetes Mellitus – A Pathophysiologically Reasoned Approach? Curr Diabetes Rev. 2016;12(4):429-439. doi: 10.2174/1573399812666160613111959.
  18. Liao HW, Wu YL, Sue YM, Lee M, Ovbiagele B. Sodium-glucose cotransporter 2 inhibitor plus pioglitazone vs pioglitazone alone in patients with diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. Endocrinol Diabetes Metab. 2018 Nov 15;2(1):e00050. doi: 10.1002/edm2.50.
  19. Ridderstråle M, Svaerd R, Zeller C, Kim G, Woerle HJ, Broedl UC; EMPA-REG H2H-SU trial investigators. Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control. Cardiovasc Diabetol. 2013 Sep 5;12:129. doi: 10.1186/1475-2840-12-129. PMID: 24007456; PMCID: PMC3844307.
  20. Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC; EMPA-REG H2H-SU trial investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014 Sep;2(9):691-700. doi: 10.1016/S2213-8587(14)70120-2. Epub 2014 Jun 16. Erratum in: Lancet Diabetes Endocrinol. 2015 Sept;3(9):e7. PMID: 24948511.
  21. American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan 1;45(Suppl 1):S144-S174. doi: 10.2337/dc22-S010. Erratum in: Diabetes Care. 2022 Mar 07;: Erratum in: Diabetes Care. 2022 Sep 1;45(9):2178-2181.
  22. American Diabetes Association Professional Practice Committee, Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R, Green J, Huang E, Isaacs D, Kahan S, Leon J, Lyons SK, Peters AL, Prahalad P, Reusch JEB, Young-Hyman D. 11. Chronic Kidney Disease and Risk Management: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan 1;45(Suppl 1):S175-S184. doi: 10.2337/dc22-S011. Erratum in: Diabetes Care. 2022 Mar 1;45(3):758. Erratum in: Diabetes Care. 2022 Sep 1;45(9):2182-2184.
  23. Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1009-22. doi: 10.1152/ajpregu.00809.2010.
  24. Freitas HS, Anhê GF, Melo KF, Okamoto MM, Oliveira-Souza M, Bordin S, Machado UF. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology. 2008 Feb;149(2):717-24. doi: 10.1210/en.2007-1088.
  25. Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014 Jan;306(2):F194-204. doi: 10.1152/ajprenal.00520.2013.
  26. Kaur P, Behera BS, Singh S, Munshi A. The pharmacological profile of SGLT2 inhibitors: Focus on mechanistic aspects and pharmacogenomics. Eur J Pharmacol. 2021.5;904:174169. doi: 10.1016/j.ejphar.2021.174169.
  27. Rabizadeh S, Nakhjavani M, Esteghamati A. Cardiovascular and Renal Benefits of SGLT2 Inhibitors: A Narrative Review. Int J Endocrinol Metab. 2019. 22;17(2):e84353. doi: 10.5812/ijem.84353.
  28. Vlotides G, Mertens PR. Sodium-glucose cotransport inhibitors: mechanisms, metabolic effects and implications for the treatment of diabetic patients with chronic kidney disease. Nephrol Dial Transplant. 2015 Aug;30(8):1272-6. doi: 10.1093/ndt/gfu299.
  29. Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA, Koepsell H, Cunard R, Sharma K, Thomson SC, Rieg T. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol. 2013 Jan 15;304(2):F156-67. doi: 10.1152/ajprenal.00409.2012.
  30. Vallon V, Schroth J, Satriano J, Blantz RC, Thomson SC, Rieg T. Adenosine A(1) receptors determine glomerular hyperfiltration and the salt paradox in early streptozotocin diabetes mellitus. Nephron Physiol. 2009;111(3):p30-8. doi: 10.1159/000208211.
  31. Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol. 2012;74:351-75. doi: 10.1146/annurev-physiol-020911-153333.
  32. Tonneijck L, Muskiet MH, Smits MM, van Bommel EJ, Heerspink HJ, van Raalte DH, Joles JA. Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment. J Am Soc Nephrol. 2017 Apr;28(4):1023-1039. doi: 10.1681/ASN.2016060666.
  33. Evans RG, Harrop GK, Ngo JP, Ow CP, O’Connor PM. Basal renal O2 consumption and the efficiency of O2 utilization for Na+ reabsorption. Am J Physiol Renal Physiol. 2014 Mar 1;306(5):F551-60. doi: 10.1152/ajprenal.00473.2013.
  34. Takiyama Y, Haneda M. Hypoxia in diabetic kidneys. Biomed Res Int. 2014;2014:837421. doi: 10.1155/2014/837421.
  35. Layton AT, Laghmani K, Vallon V, Edwards A. Solute transport and oxygen consumption along the nephrons: effects of Na+ transport inhibitors. Am J Physiol Renal Physiol. 2016 Dec 1;311(6):F1217-F1229. doi: 10.1152/ajprenal.00294.2016.
  36. Persson P, Palm F. Hypoxia-inducible factor activation in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2017 Sep;26(5):345-350. doi: 10.1097/MNH.0000000000000341.
  37. García-Pastor C, Benito-Martínez S, Moreno-Manzano V, Fernández-Martínez AB, Lucio-Cazaña FJ. Mechanism and Consequences of The Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose. Sci Rep. 2019 Nov 1;9(1):15868. doi: 10.1038/s41598-019-52310-6.
  38. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol. 2001 Nov;281(5):F887-99. doi: 10.1152/ajprenal.2001.281.5.F887.
  39. Brenner BM. Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int. 1983 Apr;23(4):647-55. doi: 10.1038/ki.1983.72.
  40. DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol. 2021 May;17(5):319-334. doi: 10.1038/s41581-021-00393-8.
  41. Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012 Jan 1;302(1):R75-83. doi: 10.1152/ajpregu.00357.2011.
  42. Terami N, Ogawa D, Tachibana H, Hatanaka T, Wada J, Nakatsuka A, Eguchi J, Horiguchi CS, Nishii N, Yamada H, Takei K, Makino H. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One. 2014 Jun 24;9(6):e100777. doi: 10.1371/journal.pone.0100777.
  43. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014 Feb 4;129(5):587-97. doi: 10.1161/CIRCULATIONAHA.113.005081.
  44. Skrtić M, Yang GK, Perkins BA, Soleymanlou N, Lytvyn Y, von Eynatten M, Woerle HJ, Johansen OE, Broedl UC, Hach T, Silverman M, Cherney DZ. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia. 2014 Dec;57(12):2599-602. doi: 10.1007/s00125-014-3396-4.
  45. Kidokoro K, Cherney DZI, Bozovic A, Nagasu H, Satoh M, Kanda E, Sasaki T, Kashihara N. Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using In Vivo Imaging. Circulation. 2019 Jul 23;140(4):303-315. doi: 10.1161/CIRCULATIONAHA.118.037418.
  46. Corrigendum to “van Bommel EJM, Muskiet MHA, van Baar MJB, et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.” Kidney Int. 2020;97:202-212. Kidney Int. 2020 May;97(5):1061. doi: 10.1016/j.kint.2020.03.009.
  47. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016 Sep 6;134(10):752-72. doi: 10.1161/CIRCULATIONAHA.116.021887.
  48. Wanner C, Heerspink HJL, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, Hantel S, Woerle HJ, Broedl UC, von Eynatten M, Groop PH; EMPA-REG OUTCOME Investigators. Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial. J Am Soc Nephrol. 2018 Nov;29(11):2755-2769. doi: 10.1681/ASN.2018010103.
  49. De Nicola L, Gabbai FB, Garofalo C, Conte G, Minutolo R. Nephroprotection by SGLT2 Inhibition: Back to the Future? J Clin Med. 2020 Jul 15;9(7):2243. doi: 10.3390/jcm9072243.
  50. Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 2018 Jul;94(1):26-39. doi: 10.1016/j.kint.2017.12.027.
  51. Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, Wanner C. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Aug;5(8):610-621. doi: 10.1016/S2213-8587(17)30182-1.
  52. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920.
  53. Giugliano D, De Nicola L, Maiorino MI, Bellastella G, Garofalo C, Chiodini P, Ceriello A, Esposito K. Preventing major adverse cardiovascular events by SGLT-2 inhibition in patients with type 2 diabetes: the role of kidney. Cardiovasc Diabetol. 2020 Mar 19;19(1):35. doi: 10.1186/s12933-020-01010-x.
  54. Steffes MW, Schmidt D, McCrery R, Basgen JM; International Diabetic Nephropathy Study Group. Glomerular cell number in normal subjects and in type 1 diabetic patients. Kidney Int. 2001 Jun;59(6):2104-13. doi: 10.1046/j.1523-1755.2001.00725.x.
  55. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest. 1997 Jan 15;99(2):342-8. doi: 10.1172/JCI119163.
  56. Tanaka S, Tanaka T, Nangaku M. Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol. 2014 Dec 1;307(11):F1187-95. doi: 10.1152/ajprenal.00425.2014.
  57. Hesp AC, Schaub JA, Prasad PV, Vallon V, Laverman GD, Bjornstad P, van Raalte DH. The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors? Kidney Int. 2020 Sep;98(3):579-589. doi: 10.1016/j.kint.2020.02.041.
  58. Ganz MB, Hawkins K, Reilly RF. High glucose induces the activity and expression of Na(+)/H(+) exchange in glomerular mesangial cells. Am J Physiol Renal Physiol. 2000 Jan;278(1):F91-6. doi: 10.1152/ajprenal.2000.278.1.F91.
  59. Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2018 Feb;41(2):356-363. doi: 10.2337/dc17-1096.
  60. Koye DN, Magliano DJ, Nelson RG, Pavkov ME. The Global Epidemiology of Diabetes and Kidney Disease. Adv Chronic Kidney Dis. 2018 Mar;25(2):121-132. doi: 10.1053/j.ackd.2017.10.011.
  61. Maeda S, Matsui T, Takeuchi M, Yamagishi S. Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products-induced tubular cell apoptosis. Diabetes Metab Res Rev. 2013 Jul;29(5):406-12. doi: 10.1002/dmrr.2407.
  62. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744.
  63. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015 Sep;38(9):1730-5. doi: 10.2337/dc15-0355.
  64. Wang H, Yang J, Chen X, Qiu F, Li J. Effects of Sodium-glucose Cotransporter 2 Inhibitor Monotherapy on Weight Changes in Patients With Type 2 Diabetes Mellitus: a Bayesian Network Meta-analysis. Clin Ther. 2019 Feb;41(2):322-334.e11. doi: 10.1016/j.clinthera.2019.01.001.
  65. Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S. 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 Mar;97(3):1020-31. doi: 10.1210/jc.2011-2260.
  66. Zheng R, Zhou D, Zhu Y. The long-term prognosis of cardiovascular disease and all-cause mortality for metabolically healthy obesity: a systematic review and meta-analysis. J Epidemiol Community Health. 2016 Oct;70(10):1024-31. doi: 10.1136/jech-2015-206948.
  67. Foster MC, Hwang SJ, Larson MG, Lichtman JH, Parikh NI, Vasan RS, Levy D, Fox CS. Overweight, obesity, and the development of stage 3 CKD: the Framingham Heart Study. Am J Kidney Dis. 2008 Jul;52(1):39-48. doi: 10.1053/j.ajkd.2008.03.003.
  68. Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS. Body mass index and risk for end-stage renal disease. Ann Intern Med. 2006 Jan 3;144(1):21-8. doi: 10.7326/0003-4819-144-1-200601030-00006.
  69. Kimura Y, Tsukui D, Kono H. Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis. Int J Mol Sci. 2021 Nov 17;22(22):12394. doi: 10.3390/ijms222212394.
  70. Goldberg A, Garcia-Arroyo F, Sasai F, Rodriguez-Iturbe B, Sanchez-Lozada LG, Lanaspa MA, Johnson RJ. Mini Review: Reappraisal of Uric Acid in Chronic Kidney Disease. Am J Nephrol. 2021;52(10-11):837-844. doi: 10.1159/000519491.
  71. F. Cicero, M. Rosticci, M. Bove et al. Serum uric acid change and modification of blood pressure and fasting plasma glucose in an overall healthy population sample: data from the Brisighella heart study. Annals of Medicine. 2017; 49 (4):275–282.
  72. Muscelli, A. Natali, S. Bianchi et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. American Journal of Hypertension. 1996; 9(8):746–752.
  73. Zhou, Y. Wang, F. Lian et al. Physical exercises and weight loss in obese patients help to improve uric acid. Oncotarget. 2017; 8(55):94893–94899.
  74. Chino, Y. Samukawa, S. Sakai et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharmaceutics & Drug Disposition. 2014; 35(7):391–404.
  75. M. Nielsen, E. M. Bartels, M. Henriksen et al. Weight loss for overweight and obese individuals with gout: a systematic review of longitudinal studies. Annals of the Rheumatic Diseases. 2017; 76(11):1870–1882.
  76. Ferreira JP, Inzucchi SE, Mattheus M, Meinicke T, Steubl D, Wanner C, Zinman B. Empagliflozin and uric acid metabolism in diabetes: A post hoc analysis of the EMPA-REG OUTCOME trial. Diabetes Obes Metab. 2022 Jan;24(1):135-141. doi: 10.1111/dom.14559.
  77. Zhao, L. Xu, D. Tian et al., “Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level:A meta‐analysis of randomized controlled trials,” Diabetes, Obesity and Metabolism, vol. 20, no. 2, pp. 458–462, 2018.
  78. Xin, Y. Guo, Y. Li, Y. Ma, L. Li,H. Jiang. Effects of sodium glucose cotransporter-2 inhibitors on serum uric acid in type 2 diabetes mellitus: a systematic review with an indirect comparison meta-analysis. Saudi Journal of Biological Sciences. 2019; 26(2): 421–426.
  79. Akbari A, Rafiee M, Sathyapalan T, Sahebkar A. Impacts of Sodium/Glucose Cotransporter-2 Inhibitors on Circulating Uric Acid Concentrations: A Systematic Review and Meta-Analysis. J Diabetes Res. 2022 Feb 17;2022:7520632. doi: 10.1155/2022/7520632
  80. Kristensen KB, Henriksen DP, Hallas J, Pottegård A, Lund LC. Sodium-glucose cotransporter 2 inhibitors and risk of nephrolithiasis. Diabetologia. 2021 Jul;64(7):1563-1571. doi: 10.1007/s00125-021-05424-4.
  81. Balasubramanian P, Wanner C, Ferreira JP, Ofstad AP, Elsaesser A, Zinman B, Inzucchi SE. Empagliflozin and Decreased Risk of Nephrolithiasis: A Potential New Role for SGLT2 Inhibition? J Clin Endocrinol Metab. 2022 Jun 16;107(7):e3003-e3007. doi: 10.1210/clinem/dgac154
  82. Wiederkehr MR, Moe OW. Uric Acid Nephrolithiasis: A Systemic Metabolic Disorder. Clin Rev Bone Miner Metab. 2011 Dec;9(3-4):207-217. doi: 10.1007/s12018-011-9106-6. PMID: 25045326;
  83. Schietzel S, Bally L, Cereghetti G, Faller N, Moor MB, Vogt B, Rintelen F, Trelle S, Fuster D. Impact of the SGLT2 inhibitor empagliflozin on urinary supersaturations in kidney stone formers (SWEETSTONE trial): protocol for a randomised, double-blind, placebo-controlled cross-over trial. BMJ Open. 2022 Mar 14;12(3):e059073. doi: 10.1136/bmjopen-2021-059073.
  84. 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 Feb 12;100(6):e24593. doi: 10.1097/MD.0000000000024593.
  85. 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 Nov;14(11):1113-1121. doi: 10.1080/17425255.2018.1541348.
  86. Gohari, S., Reshadmanesh, T., Khodabandehloo, H. et al. Study rationale and design of a study of EMPAgliflozin’s effects in patients with type 2 diabetes mellitus and Coronary ARtery disease: the EMPA-CARD randomized controlled trial. BMC Cardiovasc Disord 21, 318 (2021). org/10.1186/s12872-021-02131-1
  87. Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw,W.; Law, G.; Desai, M.; Matthews, D.R.; et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017; 377:644–657.
  88. Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes
  89. Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019, 380, 347–357.
  90. van Sloten TT, Sedaghat S, Carnethon MR, Launer LJ, Stehouwer CDA. Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. Lancet Diabetes Endocrinol. 2020 Apr;8(4):325-336. doi: 10.1016/S2213-8587(19)30405-X.
  91. Zhang J, Chen C, Hua S, Liao H, Wang M, Xiong Y, Cao F. An updated meta-analysis of cohort studies: diabetes and risk of Alzheimer’s disease. Diabetes Research and Clinical Practice 2017 41–47. (
  92. Amin EF, Rifaai RA, Abdel-Latif RG. Empagliflozin attenuates transient cerebral ischemia/reperfusion injury in hyperglycemic rats via repressing oxidative-inflammatory-apoptotic pathway. Fundam Clin Pharmacol. 2020 Oct;34(5):548-558. doi: 10.1111/fcp.12548.
  93. Hierro-Bujalance C, Infante-Garcia C, Del Marco A, Herrera M, Carranza-Naval MJ, Suarez J, Alves-Martinez P, Lubian-Lopez S, Garcia-Alloza M. Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes. Alzheimers Res Ther. 2020 Apr 7;12(1):40. doi: 10.1186/s13195-020-00607-4.
  94. Bathina S., Das U.N. Brain-derived neurotrophic factor and its clinical Implications. Arch. Med. Sci. 2015;11:1164–1178. doi: 10.5114/aoms.2015.56342.
  95. Poppe R., Karbach U., Gambaryan S., Wiesinger H., Lutzenburg M., Kraemer M., Witte O.W., Koepsell H. Expression of the Na+-D-glucose cotransporter SGLT1 in neurons. J. Neurochem. 1997;69:84–94. doi: 10.1046/j.1471-4159.1997.69010084.x.
  96. Koepsell H. Glucose transporters in brain in health and disease. Pflugers Arch. Eur. J. Physiol. 2020;472:1299–1343. doi: 10.1007/s00424-020-02441-x.
  97. Wium-Andersen IK, Osler M, Jørgensen MB, Rungby J, Wium-Andersen MK. Antidiabetic medication and risk of dementia in patients with type 2 diabetes: a nested case-control study. Eur J Endocrinol. 2019 Nov;181(5):499-507. doi: 10.1530/EJE-19-0259.
  98. Pasquale Mone, Angela Lombardi, Jessica Gambardella, Antonella Pansini, Gaetano Macina, Maria Morgante, Salvatore Frullone, Gaetano Santulli; Empagliflozin Improves Cognitive Impairment in Frail Older Adults With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction. Diabetes Care 1 May 2022; 45 (5): 1247–1251.
  99. Zhou B, Shi Y, Fu R, Ni H, Gu L, Si Y, Zhang M, Jiang K, Shen J, Li X, Sun X. Relationship Between SGLT-2i and Ocular Diseases in Patients With Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne). 2022 May 26;13:907340. doi:10.3389/fendo.2022.907340.
  100. Sano M, Goto S. Possible Mechanism of Hematocrit Elevation by Sodium Glucose Cotransporter 2 Inhibitors and Associated Beneficial Renal and Cardiovascular Effects. Circulation. 2019 Apr 23;139(17):1985-1987. doi: 10.1161/CIRCULATIONAHA.118.038881.
  101. Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased Hematocrit During Sodium-Glucose Cotransporter 2 Inhibitor Therapy Indicates Recovery of Tubulointerstitial Function in Diabetic Kidneys. J Clin Med Res. 2016 Dec;8(12):844-847. doi: 10.14740/jocmr2760w. 
  102. Thiele K, Rau M, Hartmann NK, Möllmann J, Jankowski J, Böhm M, Keszei AP, Marx N, Lehrke M. Effects of empagliflozin on erythropoiesis in patients with type 2 diabetes: Data from a randomized, placebo-controlled study. Diabetes Obes Metab. 2021 Dec;23(12):2814-2818. doi: 10.1111/dom.14517
  103. Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol. 2006 Aug;291(2):F271-81. doi: 10.1152/ajprenal.00071.2006.
  104. Takaori K, Nakamura J, Yamamoto S, Nakata H, Sato Y, Takase M, Nameta M, Yamamoto T, Economides AN, Kohno K, Haga H, Sharma K, Yanagita M. Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis. J Am Soc Nephrol. 2016 Aug;27(8):2393-406. doi: 10.1681/ASN.2015060647.
  105. Symeonidis A, Kouraklis-Symeonidis A, Psiroyiannis A, Leotsinidis M, Kyriazopoulou V, Vassilakos P, Vagenakis A, Zoumbos N. Inappropriately low erythropoietin response for the degree of anemia in patients with noninsulin-dependent diabetes mellitus. Ann Hematol. 2006 Feb;85(2):79-85. doi: 10.1007/s00277-005-1102-9.
  106. Oshima M, Neuen BL, Jardine MJ, Bakris G, Edwards R, Levin A, Mahaffey KW, Neal B, Pollock C, Rosenthal N, Wada T, Wheeler DC, Perkovic V, Heerspink HJL. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol. 2020 Nov;8(11):903-914. doi: 10.1016/S2213-8587(20)30300-4.
  107. Yanai H, Katsuyayama H. A Possible Mechanism for Renoprotective Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Elevation of Erythropoietin Production. J Clin Med Res. 2017 Feb;9(2):178-179. doi: 10.14740/jocmr2857w.
  108. Mazer CD, Hare GMT, Connelly PW, Gilbert RE, Shehata N, Quan A, Teoh H, Leiter LA, Zinman B, Jüni P, Zuo F, Mistry N, Thorpe KE, Goldenberg RM, Yan AT, Connelly KA, Verma S. Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease. Circulation. 2020 Feb 25;141(8):704-707. doi: 10.1161/CIRCULATIONAHA.119.044235.
  109. Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H, Zuo F, Quan A, Farkouh ME, Fitchett DH, Goodman SG, Goldenberg RM, Al-Omran M, Gilbert RE, Bhatt DL, Leiter LA, Jüni P, Zinman B, Connelly KA. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation. 2019 Nov 19;140(21):1693-1702. doi: 10.1161/CIRCULATIONAHA.119.042375.
  110. Fitchett D, Inzucchi SE, Zinman B, Wanner C, Schumacher M, Schmoor C, Ohneberg K, Ofstad AP, Salsali A, George JT, Hantel S, Bluhmki E, Lachin JM, Zannad F. Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial. ESC Heart Fail. 2021 Dec;8(6):4517-4527. doi: 10.1002/ehf2.13615.
  111. Severson TJ, Besur S, Bonkovsky HL. Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review. World J Gastroenterol. 2016 Aug 7;22(29):6742-56. doi: 10.3748/wjg.v22.i29.6742.
  112. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005 Jan;42(1):132-8. doi: 10.1016/j.jhep.2004.09.012.
  113. Pappachan JM, Antonio FA, Edavalath M, Mukherjee A. Non-alcoholic fatty liver disease: a diabetologist’s perspective. Endocrine. 2014 Apr;45(3):344-53. doi: 10.1007/s12020-013-0087-8.
  114. Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F. Pathophysiology of Non Alcoholic Fatty Liver Disease. Int J Mol Sci. 2016 Dec 11;17(12):2082. doi: 10.3390/ijms17122082.
  115. Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Schattenberg JM, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis. Gut. 2022 Jan;71(1):156-162. doi: 10.1136/gutjnl-2020-323082.
  116. Taylor RS, Taylor RJ, Bayliss S, Hagström H, Nasr P, Schattenberg JM, Ishigami M, Toyoda H, Wai-Sun Wong V, Peleg N, Shlomai A, Sebastiani G, Seko Y, Bhala N, Younossi ZM, Anstee QM, McPherson S, Newsome PN. Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Gastroenterology. 2020 May;158(6):1611-1625.e12. doi: 10.1053/j.gastro.2020.01.043.
  117. Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology. 2018;155(2):443-457.e17. doi:10.1053/j.gastro.2018.04.034
  118. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010 Sep 30;363(14):1341-50. doi: 10.1056/NEJMra0912063.
  119. Kahl S, Straßburger K, Nowotny B, et al. Comparison of liver fat indices for the diagnosis of hepatic steatosis and insulin resistance. PLoS One. 2014;9(4):e94059. doi:10.1371/journal.pone.0094059
  120. EASL-EASD-EASO. Clinical practice guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 2016;59(6):1121-1140. doi:10.1007/s00125-016-3902-y
  121. Fedchuk L, Nascimbeni F, Pais R, Charlotte F, Housset C, Ratziu V. Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2014;40(10):1209-1222. doi:10.1111/apt.12963
  122. Kahl S, Ofstad AP, Zinman B, Wanner C, Schüler E, Sattar N, Inzucchi SE, Roden M. Effects of empagliflozin on markers of liver steatosis and fibrosis and their relationship to cardiorenal outcomes. Diabetes Obes Metab. 2022 Jun;24(6):1061-1071. doi: 10.1111/dom.14670.
  123. Sattar N. Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME® trial / N. Sattar, D. Fitchett, S. Hantel et al. // Diabetologia. – 2018. – Vol. 61(10). – P. 2155-2163. doi: 10.1007/s00125-018-4702-3.
  124. Chehrehgosha H. Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial / H. Chehrehgosha, M. R. Sohrabi, F. Ismail-Beigi et al. // Diabetes Ther. – 2021. – Vol. 12(3). – P. 843-861. doi: 10.1007/s13300-021-01011-3.
  125. Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus. Dig Dis Sci. 2020 Feb;65(2):623-631. doi: 10.1007/s10620-019-5477-1.
  126. Kuchay M. S. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial) / M. S. Kuchay, S. Krishan, S. K. Mishra et al. / Diabetes Care. 2018 Aug;41(8):1801-1808. doi: 10.2337/dc18-0165.
  127. Taheri, M. Malek, F. Ismail-Beigi et al. Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial. Adv Ther.2020; 37(11):4697-4708. doi:10.1007/s12325-020-01498-5.
  128. Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, Kashyap S, Mechanick JI, Mouzaki M, Nadolsky K, Rinella ME, Vos MB, Younossi Z. 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(5):528-562. doi: 10.1016/j.eprac.2022.03.010.