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Current Diabetes Reviews

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ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

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Review Article

Empagliflozin-A Sodium Glucose Co-transporter-2 Inhibitor: Overview of its Chemistry, Pharmacology, and Toxicology

Author(s): Jyoti Yadav, Farogh Ahsan*, Prabhudatta Panda, Tarique Mahmood, Vaseem Ahamad Ansari and Arshiya Shamim

Volume 20, Issue 10, 2024

Published on: 23 January, 2024

Article ID: e230124226010 Pages: 23

DOI: 10.2174/0115733998271026231127051545

Price: $65

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Abstract

Background: Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor that has gained significant attention in the treatment of type 2 diabetes mellitus. Understanding its chemistry, pharmacology, and toxicology is crucial for the safe and effective use of this medication.

Objective: This review aims to provide a comprehensive overview of the chemistry, pharmacology, and toxicology of empagliflozin, synthesizing the available literature to present a concise summary of its properties and implications for clinical practice.

Methods: A systematic search of relevant databases was conducted to identify studies and articles related to the chemistry, pharmacology, and toxicology of empagliflozin. Data from preclinical and clinical studies, as well as post-marketing surveillance reports, were reviewed to provide a comprehensive understanding of the topic.

Results: Empagliflozin is a selective SGLT2 inhibitor that works by constraining glucose reabsorption in the kidneys, causing increased urinary glucose elimination. Its unique mechanism of action provides glycemic control, weight reduction, and blood pressure reduction. The drug's chemistry is characterized by its chemical structure, solubility, and stability. Pharmacologically, empagliflozin exhibits favorable pharmacokinetic properties with rapid absorption, extensive protein binding, and renal elimination. Clinical studies have demonstrated its efficacy in improving glycemic control, reducing cardiovascular risks, and preserving renal function. However, adverse effects, for instance, urinary tract infections, genital infections, and diabetic ketoacidosis have been reported. Toxicological studies indicate low potential for organ toxicity, mutagenicity, or carcinogenicity.

Conclusion: Empagliflozin is a promising SGLT2 inhibitor that offers an innovative approach to the treatment of type 2 diabetes mellitus. Its unique action mechanism and favorable pharmacokinetic profile contribute to its efficacy in improving glycemic control and reducing cardiovascular risks. While the drug's safety profile is generally favorable, clinicians should be aware of potential adverse effects and monitor patients closely. More study is required to determine the longterm safety and explore potential benefits in other patient populations. Overall, empagliflozin represents a valuable addition to the armamentarium of antidiabetic medications, offering significant benefits to patients suffering from type 2 diabetes mellitus. This study covers all aspects of empagliflozin, including its history, chemistry, pharmacology, and various clinical studies, case reports, and case series.

Keywords: Empagliflozin, sodium glucose cotransporter 2 inhibitors, SGLT2, diabetes mellitus, clinical trials, pharmacology.

[1]
Seferović PM, Petrie MC, Filippatos GS, et al. Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018; 20(5): 853-72.
[http://dx.doi.org/10.1002/ejhf.1170] [PMID: 29520964]
[2]
Abdul-Ghani MA, Norton L, Defronzo RA. Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol -. Ren Physiol 2015; 309(11): F900.
[3]
Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of type 2 diabetes–global burden of disease and forecasted trends. J Epidemiol Glob Health 2019; 10(1): 107-11.
[http://dx.doi.org/10.2991/jegh.k.191028.001] [PMID: 32175717]
[4]
Kahl S, Gancheva S, Straßburger K, et al. Empagliflozin effectively lowers liver fat content in well-controlled type 2 diabetes: A randomized, double-blind, phase 4, placebo-controlled trial. Diabetes Care 2020; 43(2): 298-305.
[http://dx.doi.org/10.2337/dc19-0641] [PMID: 31540903]
[5]
Forycka J, Hajdys J, Krzemińska J, et al. New insights into the use of empagliflozin—a comprehensive review. Biomedicines 2022; 10(12): 3294.
[http://dx.doi.org/10.3390/biomedicines10123294] [PMID: 36552050]
[6]
McGovern A, Feher M, Munro N, de Lusignan S. Sodium-glucose co-transporter 2 (SGLT2) Inhibitor: Comparing trial data and real-world use. Diabetes Ther 2017; 8(2): 365-76.
[http://dx.doi.org/10.1007/s13300-017-0254-7] [PMID: 28324484]
[7]
Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences. Diab Vasc Dis Res 2015; 12(2): 78-89.
[http://dx.doi.org/10.1177/1479164114561992] [PMID: 25616707]
[8]
Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med 2021; 385(16): 1451-61.
[http://dx.doi.org/10.1056/NEJMoa2107038] [PMID: 34449189]
[9]
Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME ® trial. Eur Heart J 2016; 37(19): 1526-34.
[http://dx.doi.org/10.1093/eurheartj/ehv728] [PMID: 26819227]
[10]
Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier gangrene associated with sodium–glucose cotransporter-2 inhibitors. Ann Intern Med 2019; 170(11): 764-9.
[http://dx.doi.org/10.7326/M19-0085] [PMID: 31060053]
[11]
Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375(9733): 2215-22.
[http://dx.doi.org/10.1016/S0140-6736(10)60484-9] [PMID: 20609967]
[12]
Choi CI. Sodium-glucose cotransporter 2 (SGLT2) inhibitors from natural products: Discovery of next-generation antihyperglycemic agents. Molecules 2016; 21(9): 1136.
[http://dx.doi.org/10.3390/molecules21091136] [PMID: 27618891]
[13]
Athawale PR, Kumari N, Dandawate MR, Kashinath K, Srinivasa Reddy D. Synthesis of chiral tetrahydrofuran building blocks from pantolactones: Application in the synthesis of empagliflozin and amprenavir analogs. Eur J Org Chem 2019; 2019(30): 4805-10.
[http://dx.doi.org/10.1002/ejoc.201900718]
[14]
Saha S, Saha S. The comparison of efficacy and safety between different doses of empagliflozin in insulin-treated type 1 diabetes mellitus patients: a systematic review and meta-analysis protocol. J Diabetes Metab Disord 2020; 19(1): 545-50.
[http://dx.doi.org/10.1007/s40200-020-00544-x] [PMID: 32550206]
[15]
Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors. JACC Basic Transl Sci 2020; 5(6): 632-44.
[http://dx.doi.org/10.1016/j.jacbts.2020.02.004] [PMID: 32613148]
[16]
Bayes-Genis A, Iborra-Egea O, Spitaleri G, et al. Decoding empagliflozin’s molecular mechanism of action in heart failure with preserved ejection fraction using artificial intelligence. Sci Rep 2021; 11(1): 12025.
[http://dx.doi.org/10.1038/s41598-021-91546-z] [PMID: 34103605]
[17]
Iborra-Egea O, Santiago-Vacas E, Yurista SR, et al. Unraveling the molecular mechanism of action of empagliflozin in heart failure with reduced ejection fraction with or without diabetes. JACC Basic Transl Sci 2019; 4(7): 831-40.
[http://dx.doi.org/10.1016/j.jacbts.2019.07.010] [PMID: 31998851]
[18]
Requena-Ibáñez JA, Santos-Gallego CG, Rodriguez-Cordero A, et al. Mechanistic insights of empagliflozin in nondiabetic patients with HFrEF. JACC Heart Fail 2021; 9(8): 578-89.
[http://dx.doi.org/10.1016/j.jchf.2021.04.014] [PMID: 34325888]
[19]
Jensen J, Omar M, Kistorp C, et al. Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: A double-blinded, randomized, and placebo-controlled trial. Am Heart J 2020; 228: 47-56.
[http://dx.doi.org/10.1016/j.ahj.2020.07.011] [PMID: 32798787]
[20]
Vallon V. Glucose transporters in the kidney in health and disease. Pflugers Arch 2020; 472(9): 1345-70.
[http://dx.doi.org/10.1007/s00424-020-02361-w] [PMID: 32144488]
[21]
Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 2012; 14(1): 83-90.
[http://dx.doi.org/10.1111/j.1463-1326.2011.01517.x] [PMID: 21985634]
[22]
Norhammar A, Bodegård J, Nyström T, Thuresson M, Nathanson D, Eriksson JW. Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE‐TIMI 58 trial: A nationwide observational study. Diabetes Obes Metab 2019; 21(5): 1136-45.
[http://dx.doi.org/10.1111/dom.13627] [PMID: 30609272]
[23]
Ndefo UA, Anidiobi NO, Basheer E, Eaton AT. Empagliflozin (Jardiance): A novel SGLT2 inhibitor for the treatment of type-2 diabetes. P&T 2015; 40(6): 364-8.
[PMID: 26045645]
[24]
Aragón-Herrera A, Feijóo-Bandín S, Otero Santiago M, et al. Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. Biochem Pharmacol 2019; 170: 113677.
[http://dx.doi.org/10.1016/j.bcp.2019.113677] [PMID: 31647926]
[25]
FDA. Highlights of prescribing information: Jardiance. In: Maryland, USA; 2014.
[26]
Michel MC, Mayoux E, Vallon V. A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans. Naunyn Schmiedebergs Arch Pharmacol 2015; 388(8): 801-16.
[http://dx.doi.org/10.1007/s00210-015-1134-1] [PMID: 26108304]
[27]
Scheen AJ. Cardiovascular effects of new oral glucose-lowering agents. Circ Res 2018; 122(10): 1439-59.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311588] [PMID: 29748368]
[28]
Di Angelantonio E, Kaptoge S, Wormser D, et al. Association of cardiometabolic multimorbidity with mortality. JAMA 2015; 314(1): 52-60.
[http://dx.doi.org/10.1001/jama.2015.7008] [PMID: 26151266]
[29]
Hari Senthil Kumar S, Anandan R, Devaki T, Santhosh Kumar M. Cardioprotective effects of Picrorrhiza kurroa against isoproterenol-induced myocardial stress in rats. Fitoterapia 2001; 72(4): 402-5.
[http://dx.doi.org/10.1016/S0367-326X(01)00264-7] [PMID: 11395263]
[30]
Goerg J, Sommerfeld M, Greiner B, et al. Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a. Int J Mol Sci 2021; 22(11): 5437-46.
[http://dx.doi.org/10.3390/ijms22115437] [PMID: 34063987]
[31]
Féraille E, Doucet A. Sodium-potassium-adenosinetriphosphatase-dependent sodium transport in the kidney: hormonal control. Physiol Rev 2001; 81(1): 345-418.
[http://dx.doi.org/10.1152/physrev.2001.81.1.345] [PMID: 11152761]
[32]
Toto RD. SGLT-2 inhibition: a potential new treatment for diabetic kidney disease? Nephron J 2017; 137(1): 64-7.
[http://dx.doi.org/10.1159/000450895] [PMID: 28743130]
[33]
Ehrenkranz JRL, Lewis NG, Ronald Kahn C, Roth J. Phlorizin: a review. Diabetes Metab Res Rev 2005; 21(1): 31-8.
[http://dx.doi.org/10.1002/dmrr.532] [PMID: 15624123]
[34]
van der Laan JW, Buitenhuis WHW, Wagenaar L, et al. Prediction of the carcinogenic potential of human pharmaceuticals using Repeated dose toxicity data and their pharmacological properties. Front Med (Lausanne) 2016; 3(45): 45.
[http://dx.doi.org/10.3389/fmed.2016.00045] [PMID: 27790617]
[35]
Iijima H, Kifuji T, Maruyama N, Inagaki N. Pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with type 2 diabetes mellitus. Adv Ther 2015; 32(8): 768-82.
[http://dx.doi.org/10.1007/s12325-015-0234-0] [PMID: 26280756]
[36]
Tanaka H, Takano K, Iijima H, et al. Factors affecting canagliflozin-induced transient urine volume increase in patients with type 2 diabetes mellitus. Adv Ther 2017; 34(2): 436-51.
[http://dx.doi.org/10.1007/s12325-016-0457-8] [PMID: 27981497]
[37]
Tang J, Ye L, Yan Q, Zhang X, Wang L. Effects of sodium-glucose cotransporter 2 inhibitors on water and sodium metabolism. Front Pharmacol 2022; 13: 800490.
[http://dx.doi.org/10.3389/fphar.2022.800490] [PMID: 35281930]
[38]
Davies MJ, Drexel H, Jornayvaz FR, Pataky Z, Seferović PM, Wanner C. Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes. Cardiovasc Diabetol 2022; 21(1): 144.
[http://dx.doi.org/10.1186/s12933-022-01575-9] [PMID: 35927730]
[39]
Singh A, Agarwal A, Wafford QE, Shah SJ, Huffman M, Khan S. Efficacy and safety of diuretics in heart failure with preserved ejection fraction: a scoping review. Heart 2022; 108(8): 593-605.
[http://dx.doi.org/10.1136/heartjnl-2021-319643] [PMID: 34340995]
[40]
Shepherd PR, Kahn BB. Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N Engl J Med 1999; 341(4): 248-57.
[http://dx.doi.org/10.1056/NEJM199907223410406] [PMID: 10413738]
[41]
Ren JM, Marshall BA, Mueckler MM, McCaleb M, Amatruda JM, Shulman GI. Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice. J Clin Invest 1995; 95(1): 429-32.
[http://dx.doi.org/10.1172/JCI117673] [PMID: 7814644]
[42]
Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 1995; 95(5): 2195-204.
[http://dx.doi.org/10.1172/JCI117909] [PMID: 7537758]
[43]
McCall AL, Cox DJ, Crean J, Gloster M, Kovatchev BP. A novel analytical method for assessing glucose variability: using CGMS in type 1 diabetes mellitus. Diabetes Technol Ther 2006; 8(6): 644-53.
[http://dx.doi.org/10.1089/dia.2006.8.644] [PMID: 17109596]
[44]
Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2014; 37(6): 1650-9.
[http://dx.doi.org/10.2337/dc13-2105] [PMID: 24722494]
[45]
Baghurst PA. Calculating the mean amplitude of glycemic excursion from continuous glucose monitoring data: an automated algorithm. Diabetes Technol Ther 2011; 13(3): 296-302.
[http://dx.doi.org/10.1089/dia.2010.0090] [PMID: 21291334]
[46]
Munir KM, Davis SN. Differential pharmacology and clinical utility of empagliflozin in type 2 diabetes. Clin Pharmacol 2016; 8: 19-34.
[PMID: 27186083]
[47]
Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab 2013; 15(7): 613-21.
[http://dx.doi.org/10.1111/dom.12073] [PMID: 23356556]
[48]
Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta‐analysis. Diabetes Obes Metab 2014; 16(10): 984-93.
[http://dx.doi.org/10.1111/dom.12307] [PMID: 24766495]
[49]
Chu C, Lu YP, Yin L, Hocher B. The SGLT2 Inhibitor Empagliflozin Might Be a New Approach for the Prevention of Acute Kidney Injury. Kidney Blood Press Res 2019; 44(2): 149-57.
[http://dx.doi.org/10.1159/000498963] [PMID: 30939483]
[50]
Boorsma EM, Beusekamp JC, ter Maaten JM, et al. Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure. Eur J Heart Fail 2021; 23(1): 68-78.
[http://dx.doi.org/10.1002/ejhf.2066] [PMID: 33251643]
[51]
Sizar O, Podder V, Talati R. SA Pharmaceutical Journal. In: Tampa, Florida, United States: StatPearls Publishing 2023; pp. 45-7.
[52]
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22): 2117-28.
[http://dx.doi.org/10.1056/NEJMoa1504720] [PMID: 26378978]
[53]
Bailey CJ, Day C. SGLT2 inhibitors: glucuretic treatment for type 2 diabetes. Br J Diabetes Vasc Dis 2010; 10(4): 193-9.
[http://dx.doi.org/10.1177/1474651410377832]
[54]
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377(7): 644-57.
[http://dx.doi.org/10.1056/NEJMoa1611925] [PMID: 28605608]
[55]
Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: A potential complication of treatment with sodium–glucose cotransporter 2 inhibition. Diabetes Care 2015; 38(9): 1687-93.
[http://dx.doi.org/10.2337/dc15-0843] [PMID: 26078479]
[56]
Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2016; 101(1): 157-66.
[http://dx.doi.org/10.1210/jc.2015-3167] [PMID: 26580237]
[57]
Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 2015; 38(3): 420-8.
[http://dx.doi.org/10.2337/dc14-1096] [PMID: 25271206]
[58]
Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013; 382(9896): 941-50.
[http://dx.doi.org/10.1016/S0140-6736(13)60683-2] [PMID: 23850055]
[59]
Solini A, Giannini L, Seghieri M, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol 2017; 16(1): 138-49.
[http://dx.doi.org/10.1186/s12933-017-0621-8] [PMID: 29061124]
[60]
Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: A randomised, double-blind, placebo-controlled, phase 3 trial. lancet Diabetes Endocrinol 2013; 1(3): 208-19.
[61]
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375(4): 323-34.
[http://dx.doi.org/10.1056/NEJMoa1515920] [PMID: 27299675]
[62]
Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care 2013; 36(12): 4015-21.
[http://dx.doi.org/10.2337/dc13-0663] [PMID: 24186878]
[63]
Jiang Y, Yang P, Fu L, Sun L, Shen W, Wu Q. Comparative cardiovascular outcomes of SGLT2 inhibitors in type 2 diabetes mellitus: A network meta-analysis of randomized controlled trials. Front Endocrinol 2022; 13: 802992.
[http://dx.doi.org/10.3389/fendo.2022.802992] [PMID: 35370961]
[64]
Srinivas N, Sarnaik MK, Modi S, et al. Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitors: Delving into the potential benefits of cardiorenal protection beyond the treatment of type-2 diabetes mellitus. Cureus 2021; 13(8): e16868-76.
[http://dx.doi.org/10.7759/cureus.16868] [PMID: 34513443]
[65]
Scheen A. Empagliflozin in type 2 diabetes mellitus: Cardiovascular and other clinical considerations. Expert Opin Pharmacother 2015; 16(2): 255-67.
[66]
Zhao Y, Wang L, Yang H. Neuroprotective effect of empagliflozin via reduction of inflammation and oxidative stress in Parkinson’s disease. Cell Mol Neurobiol 2019; 39(6): 839-45.
[PMID: 31065924]
[67]
Verma S, Mazer CD, Al-Omran M, et al. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease. Circulation 2018; 137(4): 405-7.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032031] [PMID: 29133602]
[68]
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): 1801-8.
[http://dx.doi.org/10.2337/dc18-0165] [PMID: 29895557]
[69]
Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 2015; 38(9): 1638-42.
[http://dx.doi.org/10.2337/dc15-1380] [PMID: 26294774]
[70]
Levine MJ. Empagliflozin for type 2 diabetes mellitus: An overview of phase 3 clinical trials. Curr Diabetes Rev 2017; 13(4): 405-23.
[PMID: 27296042]
[71]
Salsali A, Kim G, Woerle HJ, Broedl UC, Hantel S. Cardiovascular safety of empagliflozin in patients with type 2 diabetes: A meta‐analysis of data from randomized placebo‐controlled trials. Diabetes Obes Metab 2016; 18(10): 1034-40.
[http://dx.doi.org/10.1111/dom.12734] [PMID: 27376831]
[72]
Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. lancet Diabetes Endocrinol 2014; 2(5): 369-84.
[73]
Zou CY, Liu XK, Sang YQ, Wang B, Liang J. Effects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes. Medicine 2019; 98(49): e18245.
[http://dx.doi.org/10.1097/MD.0000000000018245] [PMID: 31804352]
[74]
Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation 2018; 137(2): 119-29.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028268] [PMID: 28904068]
[75]
Xu L, Nagata N, Chen G, et al. Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet. BMJ Open Diabetes Res Care 2019; 7(1): e000783.
[http://dx.doi.org/10.1136/bmjdrc-2019-000783] [PMID: 31749970]
[76]
Yoon KH, Nishimura R, Lee J, et al. Efficacy and safety of empagliflozin in patients with type 2 diabetes from Asian countries: Pooled data from four phase III trials. Diabetes Obes Metab 2016; 18(10): 1045-9.
[http://dx.doi.org/10.1111/dom.12699] [PMID: 27265507]
[77]
Colbert GB, Madariaga HM, Gaddy A, Elrggal ME, Lerma EV. Empagliflozin in adults with chronic kidney disease (CKD): Current evidence and place in therapy. Ther Clin Risk Manag 2023; 19: 133-42.
[http://dx.doi.org/10.2147/TCRM.S398163] [PMID: 36756278]
[78]
Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: Possible mechanism and contributing factors. J Diabetes Investig 2016; 7(2): 135-8.
[http://dx.doi.org/10.1111/jdi.12401] [PMID: 27042263]
[79]
Ali K, Mohammed SR, Deonarine R, et al. Sodium-Glucose Co-transporter-2 inhibitor-induced pruritus: Itching for answers. Cureus 2021; 13(8): e17573-87.
[http://dx.doi.org/10.7759/cureus.17573] [PMID: 34646628]
[80]
Altowayan WM. Empagliflozin induced euglycemic diabetic ketoacidosis. A case reports. Ann Med Surg 2022; 84: 104879.
[http://dx.doi.org/10.1016/j.amsu.2022.104879] [PMID: 36582864]
[81]
Hassani-Ardakania K, Lipman ML, Laporta D, Yu OHY OH Y. A case of severe acute kidney injury exacerbated by canagliflozin in a patient with type 2 diabetes. Case Rep Endocrinol 2019; 2019: 1-4.
[http://dx.doi.org/10.1155/2019/8639629] [PMID: 31275667]
[82]
Shiba T, Ishii S, Okamura T, Mitsuyoshi R, Pfarr E, Koiwai K. Efficacy and safety of empagliflozin in Japanese patients with type 2 diabetes mellitus: A sub-analysis by body mass index and age of pooled data from three clinical trials. Diabetes Res Clin Pract 2017; 131: 169-78.
[http://dx.doi.org/10.1016/j.diabres.2017.07.004] [PMID: 28753486]
[83]
Foster P, Jha P, Pandit S. Empagliflozin-induced pancreatitis: A case report pattern. Cureus 2022; 14(5): e25189-96.
[PMID: 35747024]
[84]
Antunes M, de León AC, Pizzol D, et al. Empagliflozin use and fournier’s gangrene: Case report and systematic literature review. Surgeries 2021; 2(2): 174-9.
[http://dx.doi.org/10.3390/surgeries2020018]
[85]
To D, Bradshaw S, Lipson J. Case report of empagliflozin-induced cutaneous polyarteritis nodosa. J Cutan Med Surg 2018; 22(5): 516-8.
[http://dx.doi.org/10.1177/1203475418760457] [PMID: 29457486]
[86]
Pai RPR, Kangath RV. Bilateral gangrene of fingers in a patient on empagliflozin: First case report. World J Diabetes 2019; 10(2): 133-6.
[http://dx.doi.org/10.4239/wjd.v10.i2.133] [PMID: 30788049]
[87]
Gao F, Hall S, Bach LA. Myopathy secondary to empagliflozin therapy in type 2 diabetes. Endocrinol Diabetes Metab Case Rep 2020; 2020(1): 1-4.
[http://dx.doi.org/10.1530/EDM-20-0017] [PMID: 32478668]
[88]
Suvarna V, Gupta S, Shaikh S, Joshi P, Bhure S. Long-term efficacy and safety of empagliflozin monotherapy in drug-naïve patients with type 2 diabetes in Indian subgroup: Results from a 76-week extension trial of phase iii, double-blind, randomized study. Indian J Endocrinol Metab 2017; 21(2): 286-92.
[http://dx.doi.org/10.4103/ijem.IJEM_517_16] [PMID: 28459027]
[89]
Cherney DZI, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 2014; 13(1): 28.
[http://dx.doi.org/10.1186/1475-2840-13-28] [PMID: 24475922]
[90]
Tanaka A, Shimabukuro M, Machii N, et al. Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type 2 diabetes and established cardiovascular diseases: The placebo‐controlled double‐blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized trial. J Diabetes Investig 2020; 11(6): 1551-63.
[http://dx.doi.org/10.1111/jdi.13289] [PMID: 32537887]
[91]
Sone H, Kaneko T, Shiki K, et al. Efficacy and safety of empagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled trial. Diabetes Obes Metab 2020; 22(3): 417-26.
[http://dx.doi.org/10.1111/dom.13909] [PMID: 31692244]
[92]
Søfteland E, Meier JJ, Vangen B, Toorawa R, Maldonado-Lutomirsky M, Broedl UC. Empagliflozin as add-on therapy in patients with type 2 diabetes inadequately controlled with linagliptin and metformin: A 24-week randomized, double-blind, parallel-group trial. Diabetes Care 2017; 40(2): 201-9.
[http://dx.doi.org/10.2337/dc16-1347] [PMID: 27913576]
[93]
Kovacs CS, Seshiah V, Merker L, et al. Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. Clin Ther 2015; 37(8): 1773-1788.e1.
[http://dx.doi.org/10.1016/j.clinthera.2015.05.511] [PMID: 26138864]
[94]
Rosenstock J, Jelaska A, Zeller C, Kim G, Broedl UC, Woerle HJ. Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: A 78‐week randomized, double‐blind, placebo‐controlled trial. Diabetes Obes Metab 2015; 17(10): 936-48.
[http://dx.doi.org/10.1111/dom.12503] [PMID: 26040302]
[95]
Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: A 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2013; 36(11): 3396-404.
[http://dx.doi.org/10.2337/dc12-2673] [PMID: 23963895]
[96]
Zhang Y, Liu X, Zhang H, Wang X. Efficacy and safety of empagliflozin on nonalcoholic fatty liver disease: A systematic review and meta-analysis. Front Endocrinol 2022; 13: 836455-63.
[http://dx.doi.org/10.3389/fendo.2022.836455] [PMID: 35282455]
[97]
Attallah N, Yassine L. Use of empagliflozin in recipients of kidney transplant: A report of 8 cases. Transplant Proc 2019; 51(10): 3275-80.
[http://dx.doi.org/10.1016/j.transproceed.2019.05.023] [PMID: 31732204]
[98]
Osman AT, Sharkawi SMZ, Hassan MIA, Abo-youssef AM, Hemeida RAM. Empagliflozin and neohesperidin protect against methotrexate-induced renal toxicity via suppression of oxidative stress and inflammation in male rats. Food Chem Toxicol 2021; 155: 112406.
[http://dx.doi.org/10.1016/j.fct.2021.112406] [PMID: 34256053]
[99]
Kim G, Gerich J, Salsali A, et al. Empagliflozin (EMPA) increases genital infections but not Urinary Tract Infections (UTIs) in pooled data from four pivotal phase III trials. Diabetol Und Stoffwechsel 2014; 9(01): 140-7.
[100]
Taub ME, Ludwig-Schwellinger E, Ishiguro N, et al. Sex-, species-, and tissue-specific metabolism of empagliflozin in male mouse kidney forms an unstable hemiacetal metabolite (m466/2) that degrades to 4-hydroxycrotonaldehyde, a reactive and cytotoxic species. Chem Res Toxicol 2015; 28(1): 103-15.
[http://dx.doi.org/10.1021/tx500380t] [PMID: 25489797]
[101]
Chawla G, Chaudhary KK. A complete review of empagliflozin: Most specific and potent SGLT2 inhibitor used for the treatment of type 2 diabetes mellitus. Diabetes Metab Syndr 2019; 13(3): 2001-8.
[http://dx.doi.org/10.1016/j.dsx.2019.04.035] [PMID: 31235127]
[102]
Chauhan S, Manov A, Dhillon GS, Shah P. Empagliflozin-Associated euglycemic diabetic ketoacidosis in a patient with type 2 diabetes mellitus. Cureus 2023; 15(1): 33892-903.
[103]
Li X, Zhang Q, Zhou X, et al. The different hypoglycemic effects between East Asian and non-Asian type 2 diabetes patients when treated with SGLT-2 inhibitors as an add-on treatment for metformin: A systematic review and meta-analysis of randomized controlled trials. Aging 2021; 13(9): 12748-65.
[http://dx.doi.org/10.18632/aging.202945] [PMID: 33973870]
[104]
McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes. JAMA Cardiol 2021; 6(2): 148-58.
[http://dx.doi.org/10.1001/jamacardio.2020.4511] [PMID: 33031522]

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