The analysis of a wide spectrum of activity of Sodium-Glucose co-transporter-2 inhibitors. A literature review

Magdalena Kozioł, Danuta Krasowska, Marcin Lewicki, Mateusz Pawlicki, Anna Łopuszyńska, Aleksandra Krasa, Ewa Piekarska



Introduction: The discovery of sodium-glucose co-transporter-2 inhibitors is attributed to phlorizin, which after oral administration caused the excretion of glucose in urine. Later studies showed that this effect was conditioned by SGLT-2 inhibition. However, this substance has not been used in the treatment of diabetes mellitus due to its non-selective action. Beeing also active against SGLT-1 transporters in alimentary tract, it causes osmotic diarrhea, dehydration and eventually malnutrition. Currently in Poland, gliflozins are used only in the treatment of diabetes mellitus, mainly type 2, especially with coexisting obesity and high cardio-vascular risk. However, as many human and animal studies show, the effect of SGLT2 inhibitors can be observed in many systems and organs.

Results: The best known non-anti-diabetic action is the reduction of body fat and protection against fat accumulation following a high-calorie diet. These compounds reduce the production of endogenous fatty acids. Moreover, gliflozines lower the levels of cholesterol, triglycerides, uric acid and aminotransferases. They have a protective effect on the liver because they cause remission of nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD). They lower the cardiovascular risk and have an anti-inflammatory effect. Moreover, they inhibit vascular remodeling and improve hemodynamic conditions.

Conclusions: According to many research, gliflozines have many collateral effects which can be used in the clinic as a treatment of diseases other than diabetes or coexisting with it. Obesity and cardiovascular diseases are among the most important health problems in the modern world. SGLT-2 inhibitors can prevent the above-mentioned diseases and reduce them.


Sodium-glucose co-transporter-2 (SGLT2) inhibitors; obesity; weight loss; mechanisms; kidney.

Full Text:



Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21(1):31-38.

White J.R. Apple trees to sodium glucose co-transporter inhibitors. Clinical Diabetes 2010; 28: 5–10.

Barfuss DW, Schafer JA Differences in active and passive glucose transport along the proximal nephron. Am J Physiol. 1981 Sep; 241(3):F322-32.

Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, Radović N, Jadrijević S, Aleksic I, Walles T, Sauvant C, Sabolić I, Koepsell H Pflugers Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Arch. 2015 Sep; 467(9):1881-98.

Gallo L.A., Wright E.M., Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015;12:78–89.

Błażej Przybysławski, Piotr Karbowiak, Jacek Rzeszotarski, Lech Walasek Sodium-glucose co-transporter-2 (SGLT2) inhibitors: novel oral antidiabetic drugs; Via Medica Diabetologia Kliniczna 2013, tom 2, 5, 191–197

Schernthaner G, Gross JL, Rosenstock J, et al Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glyce mic control with metformin plus sulfonylurea. A 52‐week randomized trial. Diabetes Care 2013; 36: 2508–2515

Leiter LA, Yoon K‐H, Arios P, et al Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double‐blind, phase 3 study. Diabetes Care 2015; 38: 355–364.

Kashiwagi A, Maegawa H. Metabolic and hemodynamic effects of sodium-dependent glucose cotransporter 2 inhibitors on cardio-renal protection in the treatment of patients with type 2 diabetes mellitus. J Diabetes Investig. 2017;8(4):416–427.

Prato SD, Nauck M, Duran‐Garcia S, et al Long‐term glycaemic response and tolerability of dapagliflozin versus a sulfonylurea as add‐on therapy to metformin in patients with type 2 diabetes: 4‐year data. Diabetes Obes Metab 2015; 17: 581–590

H.G. Gunhan, E. Imre, P. Erel, and O. Ustay. Empagliflozin is more effective in reducing microalbuminuria and alt levels compared with dapagliflozin: real life experience; Acta Endocrinol (Buchar). 2020 Jan-Mar; 16(1): 59–67

Kern M, Klöting N, Mark M, Mayoux E, Klein T, Blüher M. The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin. Metabolism. 2016 Feb;65(2):114-23.. Epub 2015 Nov 13.

Wang D, Luo Y, Wang X, et al. The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Renal and Liver Disease in Western Diet Induced Obesity Mice. Int J Mol Sci. 2018;19(1):137. Published 2018 Jan 3.

Orme M, Fenici P, Lomon ID, Wygant G, Townsend R, Roudaut M A systematic review and mixed-treatment comparison of dapagliflozin with existing anti-diabetes treatments for those with type 2 diabetes mellitus inadequately controlled by sulfonylurea monotherapy. Diabetol Metab Syndr. 2014; 6():73.

Jabbour SA, Hardy E, Sugg J, Parikh S; Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study., Study 10 Group. Diabetes Care. 2014; 37(3):740-50.

Bolinder J, Ljunggren Ö, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16(2):159-169.

Johansson L, Hockings PD, Johnsson E, Dronamraju N, Maaske J, Garcia-Sanchez R, Wilding JPH. Dapagliflozin plus saxagliptin add-on to metformin reduces liver fat and adipose tissue volume in patients with type 2 diabetes. Diabetes Obes Metab. 2020 Feb 18.

Komiya C, Tsuchiya K, Shiba K, 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(3):e0151511.

Jojima T, Tomotsune T, Iijima T, Akimoto K, Suzuki K, Aso Y. Empagliflozin (an SGLT2 inhibitor), 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.

. Sattar N, Fitchett D, Hantel S, George JT, Zinman B. 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.] Diabetologia. 2018 Oct;61(10):2155-2163. Epub 2018 Jul 31

. Eriksson JW, Lundkvist P, Jansson PA, Johansson L, Kvarnström M, Moris L, Miliotis T, Forsberg GB, Risérus U, Lind L, Oscarsson J. 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 Sep;61(9):1923-1934. Epub 2018 Jul 3

Chiang H, Lee JC, Huang HC, Huang H, Liu HK, Huang C. Br J Delayed intervention with a novel SGLT2 inhibitor NGI001 suppresses diet-induced metabolic dysfunction and non-alcoholic fatty liver disease in mice. Pharmacol. 2020 Jan;177(2):239-253.. Epub 2019 Nov 12.

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.

Nick Townsend, Lauren Wilson, Prachi Bhatnagar, Kremlin Wickramasinghe, Mike Rayner, Melanie Nichols, Cardiovascular disease in Europe: epidemiological update 2016, European Heart Journal, Volume 37, Issue 42, 7 November 2016, Pages 3232–3245,

Jokinen E. Obesity and cardiovascular disease. Minerva Pediatr 2015 February;67(1):25-32.

Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11:85–97.

Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014;233:104–112.

Takaoka M, Nagata D, Kihara S, Shimomura I, Kimura Y, Tabata Y, et al. Periadventitial adipose tissue plays a critical role in vascular remodeling. Circ Res. 2009;105:906–911.

Mori Y, Terasaki M, Hiromura M, et al. Luseogliflozin attenuates neointimal hyperplasia after wire injury in high-fat diet-fed mice via inhibition of perivascular adipose tissue remodeling. Cardiovasc Diabetol. 2019;18(1):143.

Verma S., McMurray J.J.V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61:2108–2117.

Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Cardiol. 2017;120:S28–S36.

Butler J, Handelsman Y, Bakris G, Verma S. Use of sodium-glucose co-transporter-2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure. Eur J Heart Fail. 2020;22(4):604-617.

Filippatos T.D., Liontos A., Papakitsou I., Elisaf M.S. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses. Postgrad Med. 2019;131:82–88.

Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors. Predispose to Ketoacidosis. J Clin Endocrinol Metab 2015; 100: 2849–2852

Chino Y, Samukawa Y, Sakai S, et al SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos 2014; 35: 391–404.

List JF, Woo V, Morales E, et al Sodium‐glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009; 32: 650–657

Kashiwagi A, Yoshida S, Nakamura I, et al Efficacy and safety of ipragli‐flozin in Japanese patients with type 2 diabetes stratified by body mass index: a subgroup analysis of five randomized clinical trials. J Diabetes Investig 2016; 7: 544–554

Zinman B., Wanner C., Lachin J.M., for the EMPA-REG OUTCOME Investigators Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.

Neal B., Perkovic V., Mahaffey K.W., for the CANVAS Program Collaborative Group Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657.

Perkovic V., Jardine M.J., Neal B., for CREDENCE Trial Investigators Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306.

Briasoulis A, Al Dhaybi O, Bakris GL. SGLT2 Inhibitors and Mechanisms of Hypertension. Curr Cardiol Rep. 2018;20(1):1

Oliva RV, Bakris GL. Blood pressure effects of sodium‐glucose co‐transport 2 (SGLT2) inhibitors. J Am Soc Hypertens 2014; 8: 330–339

Emdin CA, Rahimi K, Neal B, et al Blood pressure lowering in type 2 diabetes: a systematic review and meta‐analysis. JAMA 2015; 313: 603–615

Lambers Heerspink HJ, de Zeeuw D, Wie L, et al Dapagliflozin a glucose‐regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 2013; 15: 853–862

Baker WL, Smyth LR, Riche DM, et al Effects of sodium‐glucose co‐transporter 2 inhibitors on blood pressure: a systematic review and meta‐analysis. J Am Soc Hypertens 2014; 8: 262–275

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(R) trial. Eur Heart J 2016;37: 1526–1534

Cherney DZ, Perkins BA, Soleymanlou N et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129: 587–597

Sanchez-Nino MD, Bozic M, Cordoba-Lanus E et al. Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy. Am J Physiol Renal Physiol2012; 302: F647–F657

Nakamura N, Matsui T, Ishibashi Y, Yamagishi S Insulin stimulates SGLT2-mediated tubular glucose absorption via oxidative stress generation. Diabetol Metab Syndr. 2015; 7():48.

Wang XX, Levi J, Luo Y, et al. SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice. J Biol Chem. 2017;292(13):5335-5348.

Drug Safety and Availability (2016) FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR),

Nadkarni GN, Ferrandino R, Chang A, Surapaneni A, Chauhan K, Poojary P, Saha A, Ferket B, Grams ME, Coca SG Acute Kidney Injury in Patients on SGLT2 Inhibitors: A Propensity-Matched Analysis Diabetes Care. 2017 Nov; 40(11):1479-1485.

Taylor R. Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause. Diabetologia. 2008;51:1781–1789.

Wild SH, Walker JJ, Morling JR, et al. Cardiovascular disease, cancer, and mortality among people with type 2 diabetes and alcoholic or nonalcoholic fatty liver disease hospital admission. Diabetes Care. 2018;41:341–347.

Mauer S. M. (1994) Structural-functional correlations of diabetic nephropathy. Kidney Int. 45, 612–622

Qian Y, Feldman E, Pennathur S, Kretzler M, Brosius FC 3rd. From fibrosis to sclerosis: mechanisms of glomerulosclerosis in diabetic nephropathy. Diabetes. 2008;57(6):1439-1445.

Rosolowsky E. T., Skupien J., Smiles A. M., Niewczas M., Roshan B., Stanton R., Eckfeldt J. H., Warram J. H., and Krolewski A. S. (2011) Risk for ESRD in type 1 diabetes remains high despite renoprotection. J. Am. Soc. Nephrol. 22, 545–553

Ferreira-Hermosillo A, Molina-Ayala MA, Molina-Guerrero D, et al. Efficacy of the treatment with dapagliflozin and metformin compared to metformin monotherapy for weight loss in patients with class III obesity: a randomized controlled trial. Trials. 2020;21(1):186.

Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM

Journal of Education, Health and Sport formerly Journal of Health Sciences

Declaration on the original version.

Editors indicates that the main version of the magazine is to issue a "electronic".

The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019.

1223 Journal of Education, Health and Sport eISSN 2391-8306 7

ISSN 2391-8306 formerly ISSN: 1429-9623 / 2300-665X

Archives 2011 - 2014

PBN 2011 - 2014

POL-index 2011 - 2014

BASE 2011 - 2014

Indexed in Bases, Bazy indeksacyjne: ERIH Plus, Worldcat, PBN/POL-Index, ICI Journals Master List, Directory of Open Access Journals (DOAJ), ZBD, Ulrich's periodicals, Google Scholar, Polska Bibliografia Lekarska, EuroPub database, NLM Catalog Result - NCBI, BASE, Russian Sciences Index, Arianta.

US NLM = 101679844

101679844 - NLM Catalog Result - NCBI

Find a library that holds this journal:


PBN Poland



Redaction, Publisher and Editorial Office

Publisher and Editorial Office
Department of Physical Culture,
Faculty of Earth Sciences and Spatial Management,
Nicolaus Copernicus University in Toruń, Poland
Address: Str. Lwowska 1, 87-100 Toruń, Poland

  Open Access ISSN 2391-8306 formerly ISSN: 1429-9623 / 2300-665X

The journal has been approved for inclusion in ERIH PLUS.

The ERIH PLUS listing of the journal is available at

Indexed in Index Copernicus Journals Master List.,p24782242,3.html

ICV 2018 = 95.95 ICV 2017 = 91.30 ICV 2016 = 84.69 ICV 2015 = 93.34 ICV 2014 = 89.51 Standardized Value: 8.27 ICV 2013: 7.32 ICV 2012: 6.41 ICV 20115.48

RG Journal Impact: 0.18 *

*This value is calculated using ResearchGate data and is based on average citation counts from work published in this journal. The data used in the calculation may not be exhaustive.

RG Journal impact history

2020Available summer 2021
2018 / 20190.18

RG Journal impact over time

RG Journal impact

Indexed in Polish Scholarly Bibliography (PBN) (PBN Polska Bibliografia Naukowa) (

is a portal of the Polish Ministry of Science and Higher Education, collecting information on publications of Polish scientists and on Polish and foreign scholarly journals. Polish Scholarly Bibliograhpy is a part of POL-on - System of Information on Higher Education. It is operated by the Interdisciplinary Centre for Mathematical and Computational Modelling, University of Warsaw.

Indexed in Russian Sciences Index Российский индекс научного цитирования (РИНЦ)

Indexed in Arianta Polish scientific and professional electronic journals Aneta Drabek i Arkadiusz Pulikowski


Partnerzy platformy czasopism