Advances in SGLT2 Inhibitor Therapy: Comparative Evidence for Empagliflozin and Dapagliflozin in Cardio-Renal-Metabolic Disorders
Abstract
Cardiovascular disease, Type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) interact to cause the progressive multisystem condition known as cardio-renal-metabolic (CRM) syndrome. With pleiotropic advantages that go beyond glycaemic control, sodium-glucose cotransporter-2 (SGLT2) inhibitors have completely changed the way CRM is managed. To compile and contrast clinical data on dapagliflozin and empagliflozin throughout the CRM continuum's glycaemic, cardiovascular, renal, and metabolic outcomes. Pharmacokinetic studies, real-world observational cohorts, randomised cardiovascular and renal outcome trials, and regulatory guidelines were all narratively reviewed. A summary was provided of head-to-head meta-analytic data evaluating HbA1c, cardiovascular risk scores, and estimated glomerular filtration rate (eGFR). Regardless of diabetes status, both drugs showed strong, class-consistent benefits, such as decreases in heart failure hospitalisation, cardiovascular events, and CKD progression. HbA1c reduction (SMD −0.10; 95% CI −0.29 to 0.09), cardiovascular risk scores (SMD 0.11; 95% CI −0.08 to 0.31), and renal outcomes by eGFR (SMD 0.11; 95% CI −0.08 to 0.31) did not differ significantly, according to pooled head-to-head analyses. Comparable long-term risks for severe adverse cardiovascular events, acute renal injury, and the progression of chronic kidney disease were established by large real-world registries. Dapagliflozin slightly improved blood pressure and cholesterol, while empagliflozin showed better weight reduction and glycaemic control, though differences were not significant. Empagliflozin and dapagliflozin are interchangeable as a class effect because they offer comparable, clinically significant protection over the CRM spectrum. Instead of assuming molecular superiority, therapeutic selection should be based on patient phenotype and clinical priorities.
Keywords:
Cardio-Renal-Metabolic Syndrome, Dapagliflozin, Empagliflozin, Phenotype-Based Precision Medicine, SGLT2 Inhibitors
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References
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Bonnesen, K., Heide-Jørgensen, U., Christensen, D. H., Christiansen, C. F., Lash, T. L., Hennessy, S., ... & Schmidt, M. (2025). Effectiveness of empagliflozin vs dapagliflozin for kidney outcomes in type 2 diabetes. JAMA Internal Medicine, 185(3), 314-323. https://doi.org/10.1001/jamainternmed.2024.7381
Bonnesen, K., Heide-Jørgensen, U., Christensen, D. H., Lash, T. L., Hennessy, S., Matthews, A., ... & Schmidt, M. (2024). Comparative cardiovascular effectiveness of empagliflozin versus dapagliflozin in adults with treated type 2 diabetes: A target trial emulation. Circulation, 150(18), 1401-1411. https://doi.org/10.1161/CIRCULATIONAHA.124.068613
Brown, E., Rajeev, S. P., Cuthbertson, D. J., & Wilding, J. P. (2019). A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium‐glucose co‐transporter‐2 inhibitors. Diabetes, Obesity and Metabolism, 21, 9-18. https://doi.org/10.1111/dom.13650
Brownlee, M. (2005). The pathobiology of diabetic complications: a unifying mechanism. diabetes, 54(6), 1615. https://doi.org/10.2337/diabetes.54.6.1615
Cai, X., Cao, H., Wang, M., Yu, P., Liang, X., Liang, H., ... & Cai, M. (2025). SGLT2 inhibitor empagliflozin ameliorates tubulointerstitial fibrosis in DKD by downregulating renal tubular PKM2. Cellular and Molecular Life Sciences, 82, 159. https://doi.org/10.1007/s00018-025-05688-8
Cai, X., Yang, W., Gao, X., Chen, Y., Zhou, L., Zhang, S., ... & Ji, L. (2018). The association between the dosage of SGLT2 inhibitor and weight reduction in type 2 diabetes patients: A meta‐analysis. Obesity, 26(1), 70-80. https://doi.org/10.1002/oby.22066
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DeFronzo, R. A., Davidson, J. A., & Prato, S. D. (2012). The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes, Obesity and Metabolism, 14(1), 5-14. https://doi.org/10.1111/j.1463-1326.2011.01511.x
DeFronzo, R. A., Hompesch, M., Kasichayanula, S., Liu, X., Hong, Y., Pfister, M., Morrow, L. A., Leslie, B. R., Boulton, D. W., Ching, A., LaCreta, F. P., & Griffen, S. C. (2013). Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care, 36(10), 3169–3176. https://doi.org/10.2337/dc13-0387
European Medicines Agency. (2026). Forxiga: European Public Assessment Report (EPAR) – Product information. https://www.ema.europa.eu/en/medicines/human/EPAR/forxiga
Forbes, J. M., & Cooper, M. E. (2013). Mechanisms of diabetic complications. Physiological Reviews, 93(1), 137-188. https://doi.org/10.1152/physrev.00045.2011
Ghezzi, C., Loo, D.D.F. & Wright, E.M. (2018). Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2. Diabetologia61, 2087–2097. https://doi.org/10.1007/s00125-018-4656-5
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Heerspink, H. J., Stefánsson, B. V., Correa-Rotter, R., Chertow, G. M., Greene, T., Hou, F. F., ... & Wheeler, D. C. (2020). Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine, 383(15), 1436-1446. https://doi.org/10.1056/NEJMoa2024816
Heidenreich, P. A., Bozkurt, B., Aguilar, D., Allen, L. A., Byun, J. J., Colvin, M. M., ... & Yancy, C. W. (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(18), e895-e1032. https://doi.org/10.1161/CIR.0000000000001063
Herrington, W. G., Judge, P. K., Grams, M. E., & Wanner, C. (2026). Chronic kidney disease. The Lancet, 407(10523), 90-104. https://doi.org/10.1016/s0140-6736(25)01942-7
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Jankauskas, S. S., Komici, K., Varzideh, F., Aversa, L. S., Kansakar, U., D’Onghia, M. L., ... & Santulli, G. (2026). Cardiovascular–kidney–metabolic syndrome: A comprehensive review of pathophysiology, epidemiology, diagnosis, and management. Cardiovascular Diabetology, 25, 182. https://doi.org/10.1186/s12933-026-03177-1
Kasichayanula, S., Liu, X., LaCreta, F., Griffen, S. C., & Boulton, D. W. (2014). Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clinical Pharmacokinetics, 53, 17-27. https://doi.org/10.1007/s40262-013-0104-3
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group (2022). KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney International, 102(5S), S1–S127. https://doi.org/10.1016/j.kint.2022.06.008
Kim, J. H., Yoon, Y. C., Kim, Y. H., Park, J. I., Choi, K. U., Nam, J. H., ... & Kim, U. (2024). Cardiovascular outcomes between dapagliflozin versus empagliflozin in patients with diabetes mellitus. Clinical Cardiology, 47(3), e24248. https://doi.org/10.1002/clc.24248
Ku, E. J., Lee, D. H., Jeon, H. J., & Oh, T. K. (2021). Long-term effectiveness and safety of quadruple combination therapy with empagliflozin versus dapagliflozin in patients with type 2 diabetes: 3-year prospective observational study. Diabetes Research and Clinical Practice, 182, 109123. https://doi.org/10.1016/j.diabres.2021.109123
Macha, S., Jungnik, A., Hohl, K., Hobson, D., Salsali, A., &Woerle, H. J. (2013). Effect of food on the pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and assessment of dose proportionality in healthy volunteers. International Journal of Clinical Pharmacology and Therapeutics, 51(11), 873-879. https://doi.org/10.5414/cp201948
Macha, S., Mattheus, M., Halabi, A., Pinnetti, S., Woerle, H. J., & Broedl, U. C. (2014). Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes, Obesity and Metabolism, 16(3), 215–222. https://doi.org/10.1111/dom.12182
Mcdonagh, T. H., & Metra, M. (2023). 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Russian Journal of Cardiology, 28(1), 5168. https://doi.org/10.15829/1560-4071-2023-5168
McMurray, J. J., Solomon, S. D., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Martinez, F. A., ... & Langkilde, A. M. (2019). Dapagliflozin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine, 381(21), 1995-2008. https://doi.org/10.1056/NEJMoa1911303
Mullens, W., Damman, K., Testani, J. M., Martens, P., Mueller, C., Lassus, J., ... & Coats, A. (2020). Evaluation of kidney function throughout the heart failure trajectory–a position statement from the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure, 22(4), 584-603. https://doi.org/10.1002/ejhf.1697
Ndefo, U. A., Anidiobi, N. O., Basheer, E., & Eaton, A. T. (2015). Empagliflozin (Jardiance): A novel SGLT2 inhibitor for the treatment of type-2 diabetes. Pharmacy and Therapeutics, 40(6), 364-368.
Ndumele, C. E., Rangaswami, J., Chow, S. L., Neeland, I. J., Tuttle, K. R., Khan, S. S., ... & American Heart Association. (2023). Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation, 148(20), 1606-1635. https://doi.org/10.1161/CIR.0000000000001184
Neal, B., Perkovic, V., Mahaffey, K. W., De Zeeuw, D., Fulcher, G., Erondu, N., ... & Matthews, D. R. (2017). Canagliflozin and cardiovascular and renal events in type 2 diabetes. New England Journal of Medicine, 377(7), 644-657. https://doi.org/10.1056/NEJMoa1611925
Özgöl, I., Yigit Gencer, E., Yildiz, C., Karabulut, D., Turhan Çağlar, F. N., Bicakhan, B., Yucel, C., Ketenciler, S., Ay, A., & Yigit, Z. (2025). Effects of empagliflozin and dapagliflozin on lipid profiles and atherogenic risk indices in patients with heart failure and a history of CABG: First evidence in the literature. Journal of Clinical Medicine, 14(20), 7395. https://doi.org/10.3390/jcm14207395
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Subramanian, S., Rajendiran, M., Paramasivam, M., Murugesan, I., Palani, S. and Velusamy, S. (2026) “Advances in SGLT2 Inhibitor Therapy: Comparative Evidence for Empagliflozin and Dapagliflozin in Cardio-Renal-Metabolic Disorders”, International Journal of Advancement in Life Sciences Research, 9(4), pp. 56-68. doi: https://doi.org/10.31632/ijalsr.2026.v09i04.004.
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