Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a promising class of medications for type 2 diabetes mellitus (DM2) treatment. This study aims to evaluate the clinical efficacy, safety, and potential benefits of SGLT-2 inhibitors in improving cardiovascular and renal outcomes in DM2 patients. A comprehensive review of clinical trials and studies on SGLT-2 inhibitors was conducted. SGLT-2 inhibitors significantly improve glycemic control, reduce cardiovascular mortality, and lower the risk of renal events in DM2 patients. SGLT-2 inhibitors offer substantial cardio-renal protection in DM2 management, though further research is needed to optimize their use.
KeywordsSGLT-2 InhibitorsType 2 Diabetes MellitusCardiovascular OutcomesRenal ProtectionGlycemic Control
Barnett, A.H., Mithal, A., Manassie, J., Jones, R., Rattunde, H., Woerle, H.J., et al . (2014) Efficacy and Safety of Empagliflozin Added to Existing Antidiabetes Treatment in Patients with Type 2 Diabetes and Chronic Kidney Disease: A Randomized, Double-Blind, Placebo-Controlled Trial. The Lancet Diabetes & Endocrinology , 2, 369-384. https://doi.org/10.1016/s2213-8587(13)70208-0
DeFronzo, R.A., Davidson, J.A. and Del Prato, S. (2011) The Role of the Kidneys in Glucose Homeostasis: A New Path Towards Normalizing Glycaemia. Diabetes , Obesity and Metabolism , 14, 5-14. https://doi.org/10.1111/j.1463-1326.2011.01511.x
Vallon, V. and Thomson, S.C. (2016) Targeting Renal Glucose Reabsorption to Treat Hyperglycaemia: The Pleiotropic Effects of SGLT2 Inhibition. Diabetologia , 60, 215-225. https://doi.org/10.1007/s00125-016-4157-3
Buse, J.B., Wexler, D.J., Tsapas, A., Rossing, P., Mingrone, G., Mathieu, C., et al . (2019) 2019 Update To: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care , 43, 487-493. https://doi.org/10.2337/dci19-0066
Packer, M., Anker, S.D., Butler, J., Filippatos, G., Pocock, S.J., Carson, P., et al . (2020) Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. New England Journal of Medicine , 383, 1413-1424. https://doi.org/10.1056/nejmoa2022190
Heerspink, H.J.L., Stefánsson, B.V., Correa-Rotter, R., Chertow, G.M., Greene, T., Hou, F., et al . (2020) Dapagliflozin in Patients with Chronic Kidney Disease. New England Journal of Medicine , 383, 1436-1446. https://doi.org/10.1056/nejmoa2024816
Neal, B., Perkovic, V., Mahaffey, K.W., de Zeeuw, D., Fulcher, G., Erondu, N., et al . (2017) Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine , 377, 644-657. https://doi.org/10.1056/nejmoa1611925
Gorboulev, V., Schürmann, A., Vallon, V., Kipp, H., Jaschke, A., Klessen, D., et al . (2011) Na + -D-Glucose Cotransporter SGLT1 Is Pivotal for Intestinal Glucose Absorption and Glucose-Dependent Incretin Secretion. Diabetes , 61, 187-196. https://doi.org/10.2337/db11-1029
Wright, E.M., Loo, D.D.F. and Hirayama, B.A. (2011) Biology of Human Sodium Glucose Transporters. Physiological Reviews , 91, 733-794. https://doi.org/10.1152/physrev.00055.2009
Heerspink, H.J.L., Perkins, B.A., Fitchett, D.H., Husain, M. and Cherney, D.Z.I. (2016) Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus. Circulation , 134, 752-772. https://doi.org/10.1161/circulationaha.116.021887
Turk, E. and Wright, E.M. (2004) The Sodium/glucose Cotransport Family SLC5. European Journal of Physiology , 447, 510-518. https://doi.org/10.1007/s00424-003-1063-6
Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., et al . (2015) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine , 373, 2117-2128. https://doi.org/10.1056/nejmoa1504720
Simes, B.C. and MacGregor, G.G. (2019) Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Clinician’s Guide. Diabetes , Metabolic Syndrome and Obesity : Targets and Therapy , 12, 2125-2136. https://doi.org/10.2147/dmso.s212003
Scheen, A.J. (2015) Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease. Clinical Pharmacokinetics , 54, 691-708. https://doi.org/10.1007/s40262-015-0264-4
Bailey, C.J., Gross, J.L., Hennicken, D., Iqbal, N., Mansfield, T.A. and List, J.F. (2013) Dapagliflozin Add-On to Metformin in Type 2 Diabetes Inadequately Controlled with Metformin: A Randomized, Double-Blind, Placebo-Controlled 102-Week Trial. BMC Medicine , 11, Article No. 43. https://doi.org/10.1186/1741-7015-11-43
Rosenstock, J., Aggarwal, N., Polidori, D., Zhao, Y., Arbit, D., Usiskin, K., et al . (2012) Dose-Ranging Effects of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-On to Metformin in Subjects with Type 2 Diabetes. Diabetes Care , 35, 1232-1238. https://doi.org/10.2337/dc11-1926
Budoff, M.J., Davis, T.M.E., Palmer, A.G., Frederich, R., Lawrence, D.E., Liu, J., et al . (2021) Efficacy and Safety of Ertugliflozin in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea: A Sub-Study of VERTIS CV. Diabetes Therapy , 12, 1279-1297. https://doi.org/10.1007/s13300-021-01033-x
Kashiwagi, A., Kazuta, K., Goto, K., Yoshida, S., Ueyama, E. and Utsuno, A. (2014) Ipragliflozin in Combination with Metformin for the Treatment of Japanese Patients with Type 2 Diabetes: illuminate, a Randomized, Double-Blind, Placebo-Controlled Study. Diabetes , Obesity and Metabolism , 17, 304-308. https://doi.org/10.1111/dom.12331
Terauchi, Y., Tamura, M., Senda, M., Gunji, R. and Kaku, K. (2017) Efficacy and Safety of Tofogliflozin in Japanese Patients with Type 2 Diabetes Mellitus with Inadequate Glycaemic Control on Insulin Therapy (J-Step/Ins): Results of a 16-Week Randomized, Double-Blind, Placebo-Controlled Multicentre Trial. Diabetes , Obesity and Metabolism , 19, 1397-1407. https://doi.org/10.1111/dom.12957
Bhatt, D.L., Szarek, M., Pitt, B., Cannon, C.P., Leiter, L.A., McGuire, D.K., et al . (2021) Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. New England Journal of Medicine , 384, 129-139. https://doi.org/10.1056/nejmoa2030186
McMurray, J.J.V., Solomon, S.D., Inzucchi, S.E., Køber, L., Kosiborod, M.N., Martinez, F.A., et al . (2019) Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New England Journal of Medicine , 381, 1995-2008. https://doi.org/10.1056/nejmoa1911303
Perkovic, V., Jardine, M.J., Neal, B., Bompoint, S., Heerspink, H.J.L., Charytan, D.M., et al . (2019) Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine , 380, 2295-2306. https://doi.org/10.1056/nejmoa1811744
Wei, R., Wang, W., Pan, Q. and Guo, L. (2022) Effects of SGLT-2 Inhibitors on Vascular Endothelial Function and Arterial Stiffness in Subjects with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Frontiers in Endocrinology , 13, Article 826604. https://doi.org/10.3389/fendo.2022.826604
Fioretto, P., Zambon, A., Rossato, M., Busetto, L. and Vettor, R. (2016) SGLT2 Inhibitors and the Diabetic Kidney. Diabetes Care , 39, S165-S171. https://doi.org/10.2337/dcs15-3006
Shiva, S. (2010) Mitochondria as Metabolizers and Targets of Nitrite. Nitric Oxide , 22, 64-74. https://doi.org/10.1016/j.niox.2009.09.002
Wanner, C., Inzucchi, S.E., Lachin, J.M., Fitchett, D., von Eynatten, M., Mattheus, M., et al . (2016) Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. New England Journal of Medicine , 375, 323-334. https://doi.org/10.1056/nejmoa1515920
Bolinder, J., Ljunggren, Ö., Johansson, L., Wilding, J., Langkilde, A.M., Sjöström, C.D., et al . (2013) 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 , Obesity and Metabolism , 16, 159-169. https://doi.org/10.1111/dom.12189
Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., et al . (2014) Metabolic Response to Sodium-Glucose Cotransporter 2 Inhibition in Type 2 Diabetic Patients. Journal of Clinical Investigation , 124, 499-508. https://doi.org/10.1172/jci72227
Winiarska, A., Knysak, M., Nabrdalik, K., Gumprecht, J. and Stompór, T. (2021) Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists. International Journal of Molecular Sciences , 22, Article 10822. https://doi.org/10.3390/ijms221910822
Ferrannini, E. and Solini, A. (2012) SGLT2 Inhibition in Diabetes Mellitus: Rationale and Clinical Prospects. Nature Reviews Endocrinology , 8, 495-502. https://doi.org/10.1038/nrendo.2011.243
Ferrannini, G., Hach, T., Crowe, S., Sanghvi, A., Hall, K.D. and Ferrannini, E. (2015) Energy Balance after Sodium–Glucose Cotransporter 2 Inhibition. Diabetes Care , 38, 1730-1735. https://doi.org/10.2337/dc15-0355
Zelniker, T.A., Wiviott, S.D., Raz, I., Im, K., Goodrich, E.L., Bonaca, M.P., et al . (2019) SGLT2 Inhibitors for Primary and Secondary Prevention of Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Cardiovascular Outcome Trials. The Lancet , 393, 31-39. https://doi.org/10.1016/s0140-6736(18)32590-x
Giacco, F. and Brownlee, M. (2010) Oxidative Stress and Diabetic Complications. Circulation Research , 107, 1058-1070. https://doi.org/10.1161/circresaha.110.223545
Hess, D.A., Terenzi, D.C., Trac, J.Z., Quan, A., Mason, T., Al-Omran, M., et al . (2019) SGLT2 Inhibition with Empagliflozin Increases Circulating Provascular Progenitor Cells in People with Type 2 Diabetes Mellitus. Cell Metabolism , 30, 609-613. https://doi.org/10.1016/j.cmet.2019.08.015
Sun, X., Han, F., Lu, Q., Li, X., Ren, D., Zhang, J., et al . (2020) Empagliflozin Ameliorates Obesity-Related Cardiac Dysfunction by Regulating Sestrin2-Mediated AMPK-mTOR Signaling and Redox Homeostasis in High-Fat Diet-Induced Obese Mice. Diabetes , 69, 1292-1305. https://doi.org/10.2337/db19-0991
Laurent, S., Boutouyrie, P., Asmar, R., Gautier, I., Laloux, B., Guize, L., et al . (2001) Aortic Stiffness Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Hypertensive Patients. Hypertension , 37, 1236-1241. https://doi.org/10.1161/01.hyp.37.5.1236
Joubert, M., Jagu, B., Montaigne, D., Marechal, X., Tesse, A., Ayer, A., et al . (2017) The Sodium–Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model. Diabetes , 66, 1030-1040. https://doi.org/10.2337/db16-0733
Mudaliar, S., Alloju, S. and Henry, R.R. (2016) Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis. Diabetes Care , 39, 1115-1122. https://doi.org/10.2337/dc16-0542
Inzucchi, S.E., Zinman, B., Fitchett, D., Wanner, C., Ferrannini, E., Schumacher, M., et al . (2017) How Does Empagliflozin Reduce Cardiovascular Mortality? Insights from a Mediation Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care , 41, 356-363. https://doi.org/10.2337/dc17-1096
Liang, B., Zhao, Y. and Gu, N. (2020) Empagliflozin Improves Cardiac Function in Heart Failure with Reduced Ejection Fraction Independent of Loading Conditions. Cardiovascular Diabetology , 19, Article No. 29. https://doi.org/10.1186/s12933-020-01004-9
Dekkers, C.C.J., Petrykiv, S., Laverman, G.D., Cherney, D.Z., Gansevoort, R.T. and Heerspink, H.J.L. (2018) Effects of the SGLT-2 Inhibitor Dapagliflozin on Glomerular and Tubular Injury Markers. Diabetes , Obesity and Metabolism , 20, 1988-1993. https://doi.org/10.1111/dom.13301
Hatanaka, T., Ogawa, D., Tachibana, H., Eguchi, J., Inoue, T., Yamada, H., et al . (2016) Inhibition of SGLT2 Alleviates Diabetic Nephropathy by Suppressing High Glucose-Induced Oxidative Stress in Type 1 Diabetic Mice. Pharmacology Research & Perspecti ves , 4, e00239. https://doi.org/10.1002/prp2.239
Kong, S.H., Koo, B.K. and Moon, M.K. (2019) Effects of Dapagliflozin on Endothelial Function, Renal Injury Markers, and Glycemic Control in Drug-Naïve Patients with Type 2 Diabetes Mellitus. Diabetes & Metabolism Journal , 43, 711-717. https://doi.org/10.4093/dmj.2018.0208
Iskander, C., Cherney, D.Z., Clemens, K.K., Dixon, S.N., Harel, Z., Jeyakumar, N., et al . (2020) Use of Sodium–Glucose Cotransporter-2 Inhibitors and Risk of Acute Kidney Injury in Older Adults with Diabetes: A Population-Based Cohort Study. Canadian Medical Association Journal , 192, E351-E360. https://doi.org/10.1503/cmaj.191283
Heerspink, H.J.L., Kosiborod, M., Inzucchi, S.E. and Cherney, D.Z.I. (2018) Renoprotective Effects of Sodium-Glucose Cotransporter-2 Inhibitors. Kidney International , 94, 26-39. https://doi.org/10.1016/j.kint.2017.12.027
Abdul-Ghani, M.A., Norton, L. and DeFronzo, R.A. (2015) Renal Sodium-Glucose Cotransporter Inhibition in the Management of Type 2 Diabetes Mellitus. American Journal of Physiology-Renal Physiology , 309, F889-F900. https://doi.org/10.1152/ajprenal.00267.2015
Fioretto, P., Del Prato, S., Buse, J.B., Goldenberg, R., Giorgino, F., Reyner, D., et al . (2018) Efficacy and Safety of Dapagliflozin in Patients with Type 2 Diabetes and Moderate Renal Impairment (Chronic Kidney Disease Stage 3A): The DERIVE Study. Diabetes , Obesity and Metabolism , 20, 2532-2540. https://doi.org/10.1111/dom.13413
Itani, T. and Ishihara, T. (2018) Efficacy of Canagliflozin against Nonalcoholic Fatty Liver Disease: A Prospective Cohort Study. Obesity Science & Practice , 4, 477-482. https://doi.org/10.1002/osp4.294
Xing, B., Zhao, Y., Dong, B., Zhou, Y., Lv, W. and Zhao, W. (2020) Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Journal of D iabetes Investigation , 11, 1238-1247. https://doi.org/10.1111/jdi.13237
Danne, T., Cariou, B., Banks, P., Brandle, M., Brath, H., Franek, E., et al . (2018) HbA 1c and Hypoglycemia Reductions at 24 and 52 Weeks with Sotagliflozin in Combination with Insulin in Adults with Type 1 Diabetes: The European Intandem2 Study. Diabetes Care , 41, 1981-1990. https://doi.org/10.2337/dc18-0342
Furtado, R.H.M., Bonaca, M.P., Raz, I., Zelniker, T.A., Mosenzon, O., Cahn, A., et al . (2019) Dapagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Previous Myocardial Infarction. Circulation , 139, 2516-2527. https://doi.org/10.1161/circulationaha.119.039996
Mancia, G., Cannon, C.P., Tikkanen, I., Zeller, C., Ley, L., Woerle, H.J., et al . (2016) Impact of Empagliflozin on Blood Pressure in Patients with Type 2 Diabetes Mellitus and Hypertension by Background Antihypertensive Medication. Hypertension , 68, 1355-1364. https://doi.org/10.1161/hypertensionaha.116.07703
Cherney, D.Z.I., Zinman, B., Inzucchi, S.E., Koitka-Weber, A., Mattheus, M., von Eynatten, M., et al . (2017) 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 Randomized, Placebo-Controlled Trial. The Lancet Diabetes & Endocrinology , 5, 610-621. https://doi.org/10.1016/s2213-8587(17)30182-1
Wilding, J.P.H., Woo, V., Rohwedder, K., Sugg, J. and Parikh, S. (2013) Dapagliflozin in Patients with Type 2 Diabetes Receiving High Doses of Insulin: Efficacy and Safety over 2 Years. Diabetes , Obesity and Metabolism , 16, 124-136. https://doi.org/10.1111/dom.12187
Leiter, L.A., Cefalu, W.T., de Bruin, T.W.A., Gause-Nilsson, I., Sugg, J. and Parikh, S.J. (2014) Dapagliflozin Added to Usual Care in Individuals with Type 2 Diabetes Mellitus with Preexisting Cardiovascular Disease: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study with a 28-Week Extension. Journal of the American Geriatrics Society , 62, 1252-1262. https://doi.org/10.1111/jgs.12881