Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) have transformed diabetes management by targeting renal glucose reabsorption. Designed initially as antidiabetic agents, their ability to lower blood glucose levels independently of insulin is well-documented. Beyond glycemic control, emerging research has unveiled their profound cardiorenal benefits. By inhibiting SGLT-2 protein, these drugs enhance glucose excretion in urine, reducing blood glucose levels. This mechanism has translated into significant cardiovascular and renal protection, establishing SGLT-2 inhibitors as pivotal in managing not only diabetes but also cardiovascular and renal diseases. Recent studies have illuminated the broader therapeutic potential of SGLT-2 inhibitors beyond diabetes. Evidence indicates their efficacy in managing heart failure, chronic kidney disease (CKD), and cardiovascular complications in individuals with or without diabetes. This expanded therapeutic landscape has catalyzed a paradigm shift in SGLT-2 inhibitor use, positioning them as key agents in the cardiorenal metabolic continuum. Moreover, their role in the secondary prevention of cardiovascular events and slowing CKD progression in T2DM patients has garnered considerable attention. This consensus-based review aims to offer practical guidance in an algorithmic approach to primary care healthcare professionals to optimize SGLT-2 inhibitors utilization and maximize their benefits. The review seeks to empower clinicians to effectively manage patients who may benefit from SGLT-2 inhibitor therapy by addressing common initiation barriers and optimizing treatment strategies. Additionally, it aims to raise awareness among primary care physicians regarding the multifaceted benefits of these medications and overcome clinical inertia in their adoption into routine clinical practice.
KeywordsSodium-Glucose Cotransporter-2 InhibitorsCardiorenal BenefitsTherapeutic PotentialCardiovascular ProtectionPrimary Care Optimization
Hsia, D.S., Grove, O. and Cefalu, W.T. (2017) An Update on Sodium-Glucose Co-Transporter-2 Inhibitors for the Treatment of Diabetes Mellitus. Current Opinion in Endocrinology , Diabetes & Obesity , 24, 73-79. https://doi.org/10.1097/med.0000000000000311
Evans, M., Morgan, A.R., Bain, S.C., Davies, S., Dashora, U., Sinha, S., et al . (2022) Defining the Role of SGLT2 Inhibitors in Primary Care: Time to Think Differently. Diabetes Therapy , 13, 889-911. https://doi.org/10.1007/s13300-022-01242-y
Mudaliar, S., Polidori, D., Zambrowicz, B. and Henry, R.R. (2015) Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport. Diabetes Care , 38, 2344-2353. https://doi.org/10.2337/dc15-0642
Rotkvić, P.G., Berković, M.C., Bulj, N., Rotkvić, L. and Ćelap, I. (2020) Sodium-glucose Cotransporter 2 Inhibitors’ Mechanisms of Action in Heart Failure. World Journal of Diabetes , 11, 269-279. https://doi.org/10.4239/wjd.v11.i7.269
Liew, A., Lydia, A., Matawaran, B.J., Susantitaphong, P., Tran, H.T.B. and Lim, L.L. (2023) Practical Considerations for the Use of SGLT‐2 Inhibitors in the Asia-Pacific Countries—An Expert Consensus Statement. Nephrology , 28, 415-424. https://doi.org/10.1111/nep.14167
Marassi, M. and Fadini, G.P. (2023) The Cardio-Renal-Metabolic Connection: A Review of the Evidence. Cardiovascular Diabetology , 22, Article No. 195. https://doi.org/10.1186/s12933-023-01937-x
Elserafy, A.S., Reda, A., Farag, E., Mostafa, T., Farag, N., Elbahry, A., et al . (2021) Egyptian Atherosclerosis and Vascular Biology Association Consensus on the Use of Sodium Glucose Cotransporter-2 Inhibitors in Heart Failure with Reduced Ejection Fraction. Clinical Drug Investigation , 41, 1027-1036. https://doi.org/10.1007/s40261-021-01095-6
Heerspink, H.J.L., Karasik, A., Thuresson, M., Melzer-Cohen, C., Chodick, G., Khunti, K., et al . (2020) Kidney Outcomes Associated with Use of SGLT2 Inhibitors in Real-World Clinical Practice (CVD-REAL 3): A Multinational Observational Cohort Study. The Lancet Diabetes & Endocrinology , 8, 27-35. https://doi.org/10.1016/s2213-8587(19)30384-5
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
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
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
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group (2022) KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International , 105, S117-S314.
Stumvoll, M., Goldstein, B.J. and van Haeften, T.W. (2005) Type 2 Diabetes: Principles of Pathogenesis and Therapy. The Lancet , 365, 1333-1346. https://doi.org/10.1016/s0140-6736(05)61032-x
Jabbour, S.A., Ibrahim, N.E. and Argyropoulos, C.P. (2022) Physicians’ Considerations and Practice Recommendations Regarding the Use of Sodium-Glucose Cotransporter-2 Inhibitors. Journal of Clinical Medicine , 11, Article 6051. https://doi.org/10.3390/jcm11206051
Sun, H., Saeedi, P., Karuranga, S., Pinkepank, M., Ogurtsova, K., Duncan, B.B., et al . (2022) IDF Diabetes Atlas: Global, Regional and Country-Level Diabetes Prevalence Estimates for 2021 and Projections for 2045. Diabetes Research and Clinical Practice , 183, Article ID: 109119. https://doi.org/10.1016/j.diabres.2021.109119
Groenewegen, A., Rutten, F.H., Mosterd, A. and Hoes, A.W. (2020) Epidemiology of Heart Failure. European Journal of Heart Failure , 22, 1342-1356. https://doi.org/10.1002/ejhf.1858
Bikbov, B., Purcell, C.A., Levey, A.S., Smith, M., Abdoli, A., Abebe, M., et al . (2020) Global, Regional, and National Burden of Chronic Kidney Disease, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017. The Lancet , 395, 709-733. https://doi.org/10.1016/s0140-6736(20)30045-3
Maack, C., Lehrke, M., Backs, J., Heinzel, F.R., Hulot, J., Marx, N., et al . (2018) Heart Failure and Diabetes: Metabolic Alterations and Therapeutic Interventions: A State-of-the-Art Review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology. European Heart Journal , 39, 4243-4254. https://doi.org/10.1093/eurheartj/ehy596
Seferović, P.M. and Paulus, W.J. (2015) Clinical Diabetic Cardiomyopathy: A Two-Faced Disease with Restrictive and Dilated Phenotypes. European Heart Journal , 36, 1718-1727. https://doi.org/10.1093/eurheartj/ehv134
Usman, M.S., Khan, M.S. and Butler, J. (2021) The Interplay between Diabetes, Cardiovascular Disease, and Kidney Disease. ADA Clinical Compendia , 2021, 13-18. https://doi.org/10.2337/db20211-13
Damman, K., Valente, M.A.E., Voors, A.A., O’Connor, C.M., van Veldhuisen, D.J. and Hillege, H.L. (2013) Renal Impairment, Worsening Renal Function, and Outcome in Patients with Heart Failure: An Updated Meta-Analysis. European Heart Journal , 35, 455-469. https://doi.org/10.1093/eurheartj/eht386
Kadowaki, T., Maegawa, H., Watada, H., Yabe, D., Node, K., Murohara, T., et al . (2022) Interconnection between Cardiovascular, Renal and Metabolic Disorders: A Narrative Review with a Focus on Japan. Diabetes , Obesity and Metabolism , 24, 2283-2296. https://doi.org/10.1111/dom.14829
Schechter, M., Melzer Cohen, C., Yanuv, I., Rozenberg, A., Chodick, G., et al . (2022) Epidemiology of the Diabetes-Cardio-Renal Spectrum: A Cross-Sectional Report of 1.4 Million Adults. Cardiovascular Diabetology , 21, Article No. 104. https://doi.org/10.1186/s12933-022-01521-9
Nichols, G.A., Amitay, E.L., Chatterjee, S. and Steubl, D. (2023) The Bidirectional Association of Chronic Kidney Disease, Type 2 Diabetes, Atherosclerotic Cardiovascular Disease, and Heart Failure: The Cardio-Renal-Metabolic Syndrome. Metabolic Syndrome and Related Disorders , 21, 261-266. https://doi.org/10.1089/met.2023.0006
Olufade, T., Jiang, L., Israni, R., Huang, J. and Gosmanov, A.R. (2021) Cardiovascular and Renal Disease Manifestation and Healthcare Resource Utilization in Patients on First‐Line Oral Therapy for Type 2 Diabetes: A Claims‐based Observational Cohort Study. Diabetes , Obesity and Metabolism , 23, 2741-2751. https://doi.org/10.1111/dom.14530
Dei Cas, A., Khan, S.S., Butler, J., Mentz, R.J., Bonow, R.O., Avogaro, A., et al . (2015) Impact of Diabetes on Epidemiology, Treatment, and Outcomes of Patients with Heart Failure. JACC : Heart Failure , 3, 136-145. https://doi.org/10.1016/j.jchf.2014.08.004
Kuznik, A., Mardekian, J. and Tarasenko, L. (2013) Evaluation of Cardiovascular Disease Burden and Therapeutic Goal Attainment in US Adults with Chronic Kidney Disease: An Analysis of National Health and Nutritional Examination Survey Data, 2001–2010. BMC Nephrology , 14, Article No. 132. https://doi.org/10.1186/1471-2369-14-132
Nitta, K., Iimuro, S., Imai, E., Matsuo, S., Makino, H., Akizawa, T., et al . (2018) Risk Factors for Increased Left Ventricular Hypertrophy in Patients with Chronic Kidney Disease: Findings from the CKD-JAC Study. Clinical and Experimental Nephrology , 23, 85-98. https://doi.org/10.1007/s10157-018-1605-z
Titze, S., Schmid, M., Kottgen, A., Busch, M., Floege, J., Wanner, C., et al . (2014) Disease Burden and Risk Profile in Referred Patients with Moderate Chronic Kidney Disease: Composition of the German Chronic Kidney Disease (GCKD) Cohort. Nephrology Dialysis Transplantation , 30, 441-451. https://doi.org/10.1093/ndt/gfu294
Go, A.S., Chertow, G.M., Fan, D., McCulloch, C.E. and Hsu, C. (2004) Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization. New England Journal of Medicine , 351, 1296-1305. https://doi.org/10.1056/nejmoa041031
Sarnak, M.J., Levey, A.S., Schoolwerth, A.C., Coresh, J., Culleton, B., Hamm, L.L., et al . (2003) Kidney Disease as a Risk Factor for Development of Cardiovascular Disease. Hypertension , 42, 1050-1065. https://doi.org/10.1161/01.hyp.0000102971.85504.7c
Fried, L.F., Shlipak, M.G., Crump, C., Kronmal, R.A., Bleyer, A.J., Gottdiener, J.S., et al . (2003) Renal Insufficiency as a Predictor of Cardiovascular Outcomes and Mortality in Elderly Individuals. Journal of the American College of Cardiology , 41, 1364-1372. https://doi.org/10.1016/s0735-1097(03)00163-3
George, L.K., Koshy, S.K.G., Molnar, M.Z., Thomas, F., Lu, J.L., Kalantar-Zadeh, K., et al . (2017) Heart Failure Increases the Risk of Adverse Renal Outcomes in Patients with Normal Kidney Function. Circulation : Heart Failure , 10, e003825. https://doi.org/10.1161/circheartfailure.116.003825
Fonseca-Correa, J.I. and Correa-Rotter, R. (2021) Sodium-glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review. Frontiers in Medicine , 8, Article 777861. https://doi.org/10.3389/fmed.2021.777861
DeFronzo, R.A., Eldor, R. and Abdul-Ghani, M. (2013) Pathophysiologic Approach to Therapy in Patients with Newly Diagnosed Type 2 Diabetes. Diabetes Care , 36, S127-S138. https://doi.org/10.2337/dcs13-2011
DeFronzo, R.A. (2009) From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus. Diabetes , 58, 773-795. https://doi.org/10.2337/db09-9028
Schwartz, S.S., Epstein, S., Corkey, B.E., Grant, S.F.A., Gavin, J.R. and Aguilar, R.B. (2016) The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the Β-Cell-Centric Classification Schema. Diabetes Care , 39, 179-186. https://doi.org/10.2337/dc15-1585
Garber, A.J., Handelsman, Y., Grunberger, G., Einhorn, D., Abrahamson, M.J., Barzilay, J.I., et al . (2020) Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2020 Executive Summary. Endocrine Practice , 26, 107-139. https://doi.org/10.4158/cs-2019-0472
Inzucchi, S.E., et al. (2015) Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care , 38, 140-149. https://pubmed.ncbi.nlm.nih.gov/25538310/
American Diabetes Association (2023) Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2024. Diabetes Care , 47, S158-S178.
Tentolouris, A., Vlachakis, P., Tzeravini, E., Eleftheriadou, I. and Tentolouris, N. (2019) SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects. International Journal of Environmental Research and Public Health , 16, Article 2965. https://doi.org/10.3390/ijerph16162965
Nelinson, D.S., Sosa, J.M. and Chilton, R.J. (2021) SGLT2 Inhibitors: A Narrative Review of Efficacy and Safety. Journal of Osteopathic Medicine , 121, 229-239. https://doi.org/10.1515/jom-2020-0153
Giugliano, D., Maiorino, M.I., Bellastella, G. and Esposito, K. (2021) The Residual Cardiorenal Risk in Type 2 Diabetes. Cardiovascular Diabetology , 20, Article No. 36. https://doi.org/10.1186/s12933-021-01229-2
Bain, S., Druyts, E., Balijepalli, C., Baxter, C.A., Currie, C.J., Das, R., et al . (2016) Cardiovascular Events and All‐Cause Mortality Associated with Sulphonylureas Compared with Other Antihyperglycaemic Drugs: A Bayesian Meta‐Analysis of Survival Data. Diabetes , Obesity and Metabolism , 19, 329-335. https://doi.org/10.1111/dom.12821
Mannucci, E., Nreu, B., Montereggi, C., Ragghianti, B., Gallo, M., Giaccari, A., et al . (2021) Cardiovascular Events and All-Cause Mortality in Patients with Type 2 Diabetes Treated with Dipeptidyl Peptidase-4 Inhibitors: An Extensive Meta-Analysis of Randomized Controlled Trials. Nutrition , Metabolism and Cardiovascular Diseases , 31, 2745-2755. https://doi.org/10.1016/j.numecd.2021.06.002
Chaudhury, A., Duvoor, C., Reddy Dendi, V.S., Kraleti, S., Chada, A., Ravilla, R., et al . (2017) Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management. Frontiers in Endocrinology , 8, Article 6. https://doi.org/10.3389/fendo.2017.00006
Häring, H., Merker, L., Seewaldt-Becker, E., Weimer, M., Meinicke, T., Woerle, H.J., et al . (2013) Empagliflozin as Add-On to Metformin Plus Sulfonylurea in Patients with Type 2 Diabetes. Diabetes Care , 36, 3396-3404. https://doi.org/10.2337/dc12-2673
Rosenstock, J., Jelaska, A., Frappin, G., Salsali, A., Kim, G., Woerle, H.J., et al . (2014) Improved Glucose Control with Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia with Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes. Diabetes Care , 37, 1815-1823. https://doi.org/10.2337/dc13-3055
Stenlöf, K., Cefalu, W.T., Kim, K., Jodar, E., Alba, M., Edwards, R., et al . (2013) Long-term Efficacy and Safety of Canagliflozin Monotherapy in Patients with Type 2 Diabetes Inadequately Controlled with Diet and Exercise: Findings from the 52-Week CANTATA-M Study. Current Medical Research and Opinion , 30, 163-175. https://doi.org/10.1185/03007995.2013.850066
Xiong, W., Xiao, M.Y., Zhang, M. and Chang, F. (2016) Efficacy and Safety of Canagliflozin in Patients with Type 2 Diabetes. Medicine , 95, e5473. https://doi.org/10.1097/md.0000000000005473
Neal, B., Perkovic, V., de Zeeuw, D., Mahaffey, K.W., Fulcher, G., Ways, K., et al . (2014) Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium-Glucose Cotransporter 2, When Used in Conjunction with Insulin Therapy in Patients with Type 2 Diabetes. Diabetes Care , 38, 403-411. https://doi.org/10.2337/dc14-1237
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
Bailey, C.J., Gross, J.L., Pieters, A., Bastien, A. and List, J.F. (2010) Effect of Dapagliflozin in Patients with Type 2 Diabetes Who Have Inadequate Glycaemic Control with Metformin: A Randomised, Double-Blind, Placebo-Controlled Trial. The Lancet , 375, 2223-2233. https://doi.org/10.1016/s0140-6736(10)60407-2
Bailey, C.J., Iqbal, N., T'joen, C. and List, J.F. (2012) Dapagliflozin Monotherapy in Drug‐Naïve Patients with Diabetes: A Randomized‐Controlled Trial of Low‐Dose Range. Diabetes , Obesity and Metabolism , 14, 951-959. https://doi.org/10.1111/j.1463-1326.2012.01659.x
Ferrannini, E., Ramos, S.J., Salsali, A., Tang, W. and List, J.F. (2010) Dapagliflozin Monotherapy in Type 2 Diabetic Patients with Inadequate Glycemic Control by Diet and Exercise. Diabetes Care , 33, 2217-2224. https://doi.org/10.2337/dc10-0612
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
Bolinder, J., Ljunggren, Ö., Kullberg, J., Johansson, L., Wilding, J., Langkilde, A.M., et al . (2012) 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. The Journal of Clinical Endocrinology & Metabolism , 97, 1020-1031. https://doi.org/10.1210/jc.2011-2260
Jabbour, S.A., Hardy, E., Sugg, J. and Parikh,, S. (2014) Dapagliflozin Is Effective as Add-On Therapy to Sitagliptin with or without Metformin: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. Diabetes Care , 37, 740-750. https://doi.org/10.2337/dc13-0467
Nauck, M.A., Del Prato, S., Meier, J.J., Durán-García, S., Rohwedder, K., Elze, M., et al . (2011) Dapagliflozin versus Glipizide as Add-On Therapy in Patients with Type 2 Diabetes Who Have Inadequate Glycemic Control with Metformin. Diabetes Care , 34, 2015-2022. https://doi.org/10.2337/dc11-0606
Rosenstock, J., Vico, M., Wei, L., Salsali, A. and List, J.F. (2012) Effects of Dapagliflozin, an SGLT2 Inhibitor, on Hba1c, Body Weight, and Hypoglycemia Risk in Patients with Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy. Diabetes Care , 35, 1473-1478. https://doi.org/10.2337/dc11-1693
Strojek, K., Yoon, K., Hruba, V., Sugg, J., Langkilde, A.M. and Parikh, S. (2014) Dapagliflozin Added to Glimepiride in Patients with Type 2 Diabetes Mellitus Sustains Glycemic Control and Weight Loss over 48 Weeks: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial. Diabetes Therapy , 5, 267-283. https://doi.org/10.1007/s13300-014-0072-0
Strojek, K., Yoon, K.H., Hruba, V., Elze, M., Langkilde, A.M. and Parikh, S. (2011) Effect of Dapagliflozin in Patients with Type 2 Diabetes Who Have Inadequate Glycaemic Control with Glimepiride: A Randomized, 24-Week, Double-Blind, Placebo-Controlled Trial. Diabetes , Obesity and Metabolism , 13, 928-938. https://doi.org/10.1111/j.1463-1326.2011.01434.x
Roden, M., Weng, J., Eilbracht, J., Delafont, B., Kim, G., Woerle, H.J., et al . (2013) Empagliflozin Monotherapy with Sitagliptin as an Active Comparator in Patients with Type 2 Diabetes: A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. The Lancet Diabetes & Endocrinology , 1, 208-219. https://doi.org/10.1016/s2213-8587(13)70084-6
Wilding, J.P.H. (2012) Long-term Efficacy of Dapagliflozin in Patients with Type 2 Diabetes Mellitus Receiving High Doses of Insulin. Annals of Internal Medicine , 156, 405-415. https://doi.org/10.7326/0003-4819-156-6-201203200-00003
Ridderstråle, M., Andersen, K.R., Zeller, C., Kim, G., Woerle, H.J. and Broedl, U.C. (2014) 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. The Lancet Diabetes & Endocrinology , 2, 691-700. https://doi.org/10.1016/s2213-8587(14)70120-2
Kovacs, C.S., Seshiah, V., Merker, L., Christiansen, A.V., Roux, F., Salsali, A., et al . (2015) Empagliflozin as Add-On Therapy to Pioglitazone with or without Metformin in Patients with Type 2 Diabetes Mellitus. Clinical Therapeutics , 37, 1773-1788.E1. https://doi.org/10.1016/j.clinthera.2015.05.511
Hollander, P., Liu, J., Hill, J., Johnson, J., Jiang, Z.W., Golm, G., et al . (2017) Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study. Diabetes Therapy , 9, 193-207. https://doi.org/10.1007/s13300-017-0354-4
Terra, S.G., Focht, K., Davies, M., Frias, J., Derosa, G., Darekar, A., et al . (2017) Phase III, Efficacy and Safety Study of Ertugliflozin Monotherapy in People with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise Alone. Diabetes , Obesity and Metabolism , 19, 721-728. https://doi.org/10.1111/dom.12888
Rosenstock, J., Frias, J., Páll, D., Charbonnel, B., Pascu, R., Saur, D., et al . (2017) Effect of Ertugliflozin on Glucose Control, Body Weight, Blood Pressure and Bone Density in Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Monotherapy (VERTIS MET). Diabetes , Obesity and Metabolism , 20, 520-529. https://doi.org/10.1111/dom.13103
Dagogo‐Jack, S., Liu, J., Eldor, R., Amorin, G., Johnson, J., Hille, D., et al . (2017) Efficacy and Safety of the Addition of Ertugliflozin in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin and Sitagliptin: The VERTIS SITA2 Placebo‐Controlled Randomized Study. Diabetes , Obesity and Metabolism , 20, 530-540. https://doi.org/10.1111/dom.13116
Miller, S., Krumins, T., Zhou, H., Huyck, S., Johnson, J., Golm, G., et al . (2018) Ertugliflozin and Sitagliptin Co-Initiation in Patients with Type 2 Diabetes: The VERTIS SITA Randomized Study. Diabetes Therapy , 9, 253-268. https://doi.org/10.1007/s13300-017-0358-0
Pratley, R.E., Eldor, R., Raji, A., Golm, G., Huyck, S.B., Qiu, Y., et al . (2018) Ertugliflozin plus Sitagliptin versus Either Individual Agent over 52 Weeks in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin: The VERTIS FACTORIAL Randomized Trial. Diabetes , Obesity and Metabolism , 20, 1111-1120. https://doi.org/10.1111/dom.13194
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
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
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
Cosentino, F., Grant, P.J., Aboyans, V., Bailey, C.J., Ceriello, A., Delgado, V., et al . (2019) 2019 ESC Guidelines on Diabetes, Pre-Diabetes, and Cardiovascular Diseases Developed in Collaboration with the EASD. European Heart Journal , 41, 255-323. https://doi.org/10.1093/eurheartj/ehz486
Wiviott, S.D., Raz, I., Bonaca, M.P., Mosenzon, O., Kato, E.T., Cahn, A., et al . (2019) Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine , 380, 347-357. https://doi.org/10.1056/nejmoa1812389
Cannon, C.P., Pratley, R., Dagogo-Jack, S., Mancuso, J., Huyck, S., Masiukiewicz, U., et al . (2020) Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. New England Journal of Medicine , 383, 1425-1435. https://doi.org/10.1056/nejmoa2004967
Gupta, M., Rao, S., Manek, G., Fonarow, G.C. and Ghosh, R.K. (2021) The Role of Dapagliflozin in the Management of Heart Failure: An Update on the Emerging Evidence. Therapeutics and Clinical Risk Management , 17, 823-830. https://doi.org/10.2147/tcrm.s275076
Ge, Z., Li, A., McNamara, J., dos Remedios, C. and Lal, S. (2019) Pathogenesis and Pathophysiology of Heart Failure with Reduced Ejection Fraction: Translation to Human Studies. Heart Failure Reviews , 24, 743-758. https://doi.org/10.1007/s10741-019-09806-0
Roger, V.L. (2021) Epidemiology of Heart Failure. Circulation Research , 128, 1421-1434. https://doi.org/10.1161/circresaha.121.318172
Bendary, A., Hassanein, M., Bendary, M., Smman, A., Hassanin, A. and Elwany, M. (2023) The Predictive Value of Precipitating Factors on Clinical Outcomes in Hospitalized Patients with Decompensated Heart Failure: Insights from the Egyptian Cohort in the European Society of Cardiology Heart Failure Long-Term Registry. The Egyptian Heart Journal , 75, Article No. 16. https://doi.org/10.1186/s43044-023-00342-9
Liang, M., Bian, B. and Yang, Q. (2022) Characteristics and Long‐term Prognosis of Patients with Reduced, Mid‐range, and Preserved Ejection Fraction: A Systemic Review and Meta‐Analysis. Clinical Cardiology , 45, 5-17. https://doi.org/10.1002/clc.23754
Bhatt, D.L., Szarek, M., Steg, P.G., Cannon, C.P., Leiter, L.A., McGuire, D.K., et al . (2021) Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. New England Journal of Medicine , 384, 117-128. https://doi.org/10.1056/nejmoa2030183
Voors, A.A., Angermann, C.E., Teerlink, J.R., Collins, S.P., Kosiborod, M., Biegus, J., et al . (2022) The SGLT2 Inhibitor Empagliflozin in Patients Hospitalized for Acute Heart Failure: A Multinational Randomized Trial. Nature Medicine , 28, 568-574. https://doi.org/10.1038/s41591-021-01659-1
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
Bhatt, D.L., Szarek, M., Steg, P.G., Cannon, C.P., Leiter, L.A., McGuire, D.K., et al . (2021) Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. New England Journal of Medicine , 384, 117-128. https://doi.org/10.1056/nejmoa2030183
Heidenreich, P.A., Bozkurt, B., Aguilar, D., Allen, L.A., Byun, J.J., Colvin, M.M., et al . (2022) 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation , 145, e895-e1032. https://doi.org/10.1161/cir.0000000000001063
McDonagh, T.A., Metra, M., Adamo, M., Gardner, R.S., Baumbach, A., Böhm, M., et al . (2021) 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. European Heart Journal , 42, 3599-3726. https://doi.org/10.1093/eurheartj/ehab368
Isaza, N., Calvachi, P., Raber, I., Liu, C., Bellows, B.K., Hernandez, I., et al . (2021) Cost-effectiveness of Dapagliflozin for the Treatment of Heart Failure with Reduced Ejection Fraction. JAMA Network Open , 4, e2114501. https://doi.org/10.1001/jamanetworkopen.2021.14501
Tafazzoli, A., Reifsnider, O.S., Bellanca, L., Ishak, J., Carrasco, M., Rakonczai, P., et al . (2022) A European Multinational Cost-Effectiveness Analysis of Empagliflozin in Heart Failure with Reduced Ejection Fraction. The European Journal of Health Economics , 24, 1441-1454. https://doi.org/10.1007/s10198-022-01555-6
Reifsnider, O.S., Kansal, A.R., Franke, J., Lee, J., George, J.T., Brueckmann, M., et al . (2020) Cost‐effectiveness of Empagliflozin in the UK in an EMPA‐REG OUTCOME Subgroup with Type 2 Diabetes and Heart Failure. ESC Heart Failure , 7, 3910-3918. https://doi.org/10.1002/ehf2.12985
Qin, L., Darlington, O., Miller, R., Mellstrom, C. and Mcewan, P. (2021) Budget Impact Evaluation of the DAPA-HF Trial: Is Dapagliflozin Cost-Saving for the Treatment of Heart Failure with Reduced Ejection Fraction? European Journal of Heart Failure , 23, 305-305.
Abdelhamid, M., Kandil, H., Hassanin, M., Shaheen, S., Sobhy, M., ElEtreby, A., et al . (2022) Egyptian Expert Opinion for the Use of Sodium‐Glucose Cotransporter‐2 Inhibitors in Patients with Heart Failure with Reduced Ejection Fraction. ESC Heart Failure , 9, 800-811. https://doi.org/10.1002/ehf2.13811
Honigberg, M.C., Vardeny, O. and Vaduganathan, M. (2020) Practical Considerations for the Use of Sodium-Glucose Co-Transporter 2 Inhibitors in Heart Failure. Circulation : Heart Failure , 13, e006623. https://doi.org/10.1161/circheartfailure.119.006623
Verma, S. and McMurray, J.J.V. (2018) SGLT2 Inhibitors and Mechanisms of Cardiovascular Benefit: A State-of-the-Art Review. Diabetologia , 61, 2108-2117. https://doi.org/10.1007/s00125-018-4670-7
Kittleson, M.M., Panjrath, G.S., Amancherla, K., Davis, L.L., Deswal, A., Dixon, D.L., et al . (2023) 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure with Preserved Ejection Fraction. Journal of the American College of Cardiology , 81, 1835-1878. https://doi.org/10.1016/j.jacc.2023.03.393
Cleland, J.G.F. (2006) The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) Study. European Heart Journal , 27, 2338-2345. https://doi.org/10.1093/eurheartj/ehl250
Yusuf, S., Pfeffer, M.A., Swedberg, K., Granger, C.B., Held, P., McMurray, J.J., et al . (2003) Effects of Candesartan in Patients with Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction: The Charm-Preserved Trial. The Lancet , 362, 777-781. https://doi.org/10.1016/s0140-6736(03)14285-7
Massie, B.M., Carson, P.E., McMurray, J.J., Komajda, M., McKelvie, R., Zile, M.R., et al . (2008) Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction. New England Journal of Medicine , 359, 2456-2467. https://doi.org/10.1056/nejmoa0805450
Pitt, B., Pfeffer, M.A., Assmann, S.F., Boineau, R., Anand, I.S., Claggett, B., et al . (2014) Spironolactone for Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine , 370, 1383-1392. https://doi.org/10.1056/nejmoa1313731
Ahmed, A., Rich, M.W., Fleg, J.L., Zile, M.R., Young, J.B., Kitzman, D.W., et al . (2006) Effects of Digoxin on Morbidity and Mortality in Diastolic Heart Failure. Circulation , 114, 397-403. https://doi.org/10.1161/circulationaha.106.628347
Solomon, S.D., McMurray, J.J.V., Anand, I.S., Ge, J., Lam, C.S.P., Maggioni, A.P., et al . (2019) Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine , 381, 1609-1620. https://doi.org/10.1056/nejmoa1908655
Solomon, S.D., Claggett, B., Lewis, E.F., Desai, A., Anand, I., Sweitzer, N.K., et al . (2015) Influence of Ejection Fraction on Outcomes and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction. European Heart Journal , 37, 455-462. https://doi.org/10.1093/eurheartj/ehv464
Hogg, K. and McMurray, J. (2006) The Treatment of Heart Failure with Preserved Ejection Fraction (“Diastolic Heart Failure”). Heart Failure Reviews , 11, 141-146. https://doi.org/10.1007/s10741-006-9488-6
Solomon, S.D., Vaduganathan, M., L. Claggett, B., Packer, M., Zile, M., Swedberg, K., et al . (2020) Sacubitril/Valsartan across the Spectrum of Ejection Fraction in Heart Failure. Circulation , 141, 352-361. https://doi.org/10.1161/circulationaha.119.044586
Anker, S.D., Butler, J., Filippatos, G., Ferreira, J.P., Bocchi, E., Böhm, M., et al . (2021) Empagliflozin in Heart Failure with a Preserved Ejection Fraction. New England Journal of Medicine , 385, 1451-1461. https://doi.org/10.1056/nejmoa2107038
Solomon, S.D., McMurray, J.J.V., Claggett, B., de Boer, R.A., DeMets, D., Hernandez, A.F., et al . (2022) Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. New England Journal of Medicine , 387, 1089-1098. https://doi.org/10.1056/nejmoa2206286
Nassif, M.E., Windsor, S.L., Borlaug, B.A., Kitzman, D.W., Shah, S.J., Tang, F., et al . (2021) The SGLT2 Inhibitor Dapagliflozin in Heart Failure with Preserved Ejection Fraction: A Multicenter Randomized Trial. Nature Medicine , 27, 1954-1960. https://doi.org/10.1038/s41591-021-01536-x
McDonagh, T.A., Metra, M., Adamo, M., Gardner, R.S., Baumbach, A., Böhm, M., et al . (2023) 2023 Focused Update of the 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. European Heart Journal , 44, 3627-3639. https://doi.org/10.1093/eurheartj/ehad195
Hill, N.R., Fatoba, S.T., Oke, J.L., Hirst, J.A., O’Callaghan, C.A., Lasserson, D.S., et al . (2016) Global Prevalence of Chronic Kidney Disease—A Systematic Review and Meta-analysis. PLOS ONE , 11, e0158765. https://doi.org/10.1371/journal.pone.0158765
Hoogeveen, E.K. (2022) The Epidemiology of Diabetic Kidney Disease. Kidney and Dialysis , 2, 433-442. https://doi.org/10.3390/kidneydial2030038
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
Mosenzon, O., Wiviott, S.D., Cahn, A., Rozenberg, A., Yanuv, I., Goodrich, E.L., et al . (2019) Effects of Dapagliflozin on Development and Progression of Kidney Disease in Patients with Type 2 Diabetes: An Analysis from the DECLARE-TIMI 58 Randomised Trial. The Lancet Diabetes & Endocrinology , 7, 606-617. https://doi.org/10.1016/s2213-8587(19)30180-9
Kluger, A.Y., Tecson, K.M., Barbin, C.M., Lee, A.Y., Lerma, E.V., Rosol, Z.P., et al . (2018) Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review. Reviews in Cardiovascular Medicine , 19, 41-49. https://doi.org/10.31083/j.rcm.2018.02.907
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 Randomised, Placebo-Controlled Trial. The Lancet Diabetes & Endocrinology , 5, 610-621. https://doi.org/10.1016/s2213-8587(17)30182-1
Cherney, D.Z.I., Dagogo‐Jack, S., McGuire, D.K., Cosentino, F., Pratley, R., Shih, W.J., et al . (2021) Kidney Outcomes Using a Sustained ≥ 40% Decline in EGFR: A Meta‐Analysis of SGLT2 Inhibitor Trials. Clinical Cardiology , 44, 1139-1143. https://doi.org/10.1002/clc.23665
Cherney, D.Z.I., McGuire, D.K., Charbonnel, B., Cosentino, F., Pratley, R., Dagogo-Jack, S., et al . (2021) Gradient of Risk and Associations with Cardiovascular Efficacy of Ertugliflozin by Measures of Kidney Function. Circulation , 143, 602-605. https://doi.org/10.1161/circulationaha.120.051901
Meraz-Muñoz, A.Y., Weinstein, J. and Wald, R. (2021) EGFR Decline after SGLT2 Inhibitor Initiation: The Tortoise and the Hare Reimagined. Kidney 360, 2, 1042-1047. https://doi.org/10.34067/kid.0001172021
Sridhar, V.S., Tuttle, K.R. and Cherney, D.Z.I. (2020) We Can Finally Stop Worrying about SGLT2 Inhibitors and Acute Kidney Injury. American Journal of Kidney Diseases , 76, 454-456. https://doi.org/10.1053/j.ajkd.2020.05.014
Yau, K., Dharia, A., Alrowiyti, I. and Cherney, D.Z.I. (2022) Prescribing SGLT2 Inhibitors in Patients with CKD: Expanding Indications and Practical Considerations. Kidney International Reports , 7, 1463-1476. https://doi.org/10.1016/j.ekir.2022.04.094
Vardeny, O. and Vaduganathan, M. (2019) Practical Guide to Prescribing Sodium-Glucose Cotransporter 2 Inhibitors for Cardiologists. JACC : Heart Failure , 7, 169-172. https://doi.org/10.1016/j.jchf.2018.11.013
Roy, A., Maiti, A., Sinha, A., Baidya, A., Basu, A.K., Sarkar, D., et al . (2020) Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement. Diabetes Therapy , 11, 2791-2827. https://doi.org/10.1007/s13300-020-00921-y
Donnan, J.R., Grandy, C.A., Chibrikov, E., Marra, C.A., Aubrey-Bassler, K., Johnston, K., et al . (2019) Comparative Safety of the Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A Systematic Review and Meta-Analysis. BMJ Open , 9, e022577. https://doi.org/10.1136/bmjopen-2018-022577