The journey of Sotagliflozin: from its status as a withdrawn candidate for the treatment of diabetes mellitus, to its repurposing as a groundbreaking drug for the management of heart failure.
Main Article Content
Keywords
Heart Failure, Diabetes Mellitus, Antidiabetic drugs, Pharmacology, therapeutic targets
Abstract
Sotagloflozin is a member of the antidiabetic class of sodium-dependent glucose cotransporter protein inhibitors. It is unique in its class due to its dual inhibitory action, as it can target and inhibit both type 1 and type 2 isoforms of the sodium glucose co-transporter (SGLT). SGLT inhibitors are small-molecule antagonists whose design was inspired by the natural product phlorizin. In May 2023, the United States Food and Drug Administration (U.S. FDA) approved sotagliflozin for the treatment of heart failure. The journey towards the discovery and optimization of this compound, as well as its ultimate repurposing in the setting of heart failure, is intriguing and continues to arouse interest and concern with regard to the safety and applicability of this repositioned candidate. This review offers an in-depth critical report of the journey of this compound, which has been marked by moments of both success and failure, towards its ultimate reproposing and a reported groundbreaking role in the scope of heart failure management.
References
1. Atanasov, A.G., et al., Natural products in drug discovery: advances and opportunities. Nature Reviews Drug Discovery, 2021.
20(3): p. 200-216.
2. Hsia, D.S., O. Grove, and W.T. Cefalu, An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes
mellitus. Curr Opin Endocrinol Diabetes Obes, 2017. 24(1): p. 73-79.
3. Brazy, P.C. and V.W. Dennis, Characteristics of glucose-phlorizin interactions in isolated proximal tubules. American Journal of
Physiology-Renal Physiology, 1978. 234(4): p. F279-F286.
4. De Koninck, L., Ueber das phloridzin (phlorrhizin). Annalen der Pharmacie, 1835. 15(1): p. 75-77.
5. Von Mering, J., Über experimentellen Diabetes. Verh Kongr Inn Med, 1886. 5: p. 185.
6. Jörgens, V., The roots of SGLT inhibition: Laurent-Guillaume de Koninck, Jean Servais Stas and Freiherr Josef von Mering. Acta
Diabetologica, 2019. 56(1): p. 29-31.
7. Mather, A. and C. Pollock, Renal glucose transporters: novel targets for hyperglycemia management. Nature Reviews
Nephrology, 2010. 6(5): p. 307-311.
8. Yamaguchi, K., et al., Pharmacokinetic and pharmacodynamic modeling of the effect of an sodium-glucose cotransporter
inhibitor, phlorizin, on renal glucose transport in rats. Drug Metab Dispos, 2011. 39(10): p. 1801-7.
9. Wright, E.M., D.D. Loo, and B.A. Hirayama, Biology of human sodium glucose transporters. Physiol Rev, 2011. 91(2): p. 733-94.
10. Bakris, G.L., et al., Renal sodium–glucose transport: role in diabetes mellitus and potential clinical implications. Kidney
International, 2009. 75(12): p. 1272-1277.
11. Vrhovac, I., et al., Localizations of Na+-d-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human
small intestine, liver, lung, and heart. Pflügers Archiv - European Journal of Physiology, 2015. 467(9): p. 1881-1898.
12. Hediger, M.A., et al., Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature, 1987. 330(6146): p.
379-81.
13. Kanai, Y., et al., The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive
mechanism for D-glucose. J Clin Invest, 1994. 93(1): p. 397-404.
14. Faham, S., et al., The Crystal Structure of a Sodium Galactose Transporter Reveals Mechanistic Insights into Na+/
Sugar Symport. Science, 2008. 321(5890): p. 810-814.
15. Cui, W., et al., Structures of human SGLT in the occluded state reveal conformational changes during sugar transport. Nature
Communications, 2023. 14(1): p. 2920.
16. Coady, M.J., et al., MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2. J Am Soc Nephrol, 2017. 28(1):
p. 85-93.
17. Niu, Y., et al., Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter. Nature, 2022. 601(7892): p. 280-
284.
18. Perez, M., et al., MAP17 and SGLT1 protein expression levels as prognostic markers for cervical tumor patient survival. PLoS
One, 2013. 8(2): p. e56169.
19. Silverman, M. and J. Black, High affinity phlorizin receptor sites and their relation to the glucose transport mechanism in the
proximal tubule of dog kidney. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1975. 394(1): p. 10-30.
20. Chasis, H., N. Jolliffe, and H.W. Smith, THE ACTION OF PHLORIZIN ON THE EXCRETION OF GLUCOSE, XYLOSE, SUCROSE,
CREATININE AND UREA BY MAN. J Clin Invest, 1933. 12(6): p. 1083-90.
21. Dimitrakoudis, D., M. Vranic, and A. Klip, Effects of hyperglycemia on glucose transporters of the muscle: use of the renal
glucose reabsorption inhibitor phlorizin to control glycemia. J Am Soc Nephrol, 1992. 3(5): p. 1078-91.
22. Maccari, R. and R. Ottanà, Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future
Perspectives. Journal of Medicinal Chemistry, 2022. 65(16): p. 10848-10881.
23. Oku, A., et al., T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes, 1999. 48(9): p. 1794-1800.
24. Choi, C.-I., Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation
Antihyperglycemic Agents. Molecules, 2016. 21(9): p. 1136.
25. Powell, D.R., et al., Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab, 2013. 304(2):
p. E117-30.
26. Lapuerta, P., et al., Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diabetes and
Vascular Disease Research, 2015. 12(2): p. 101-110.
27. Zambrowicz, B., et al., LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a
randomized, placebo-controlled trial. Clin Pharmacol Ther, 2012. 92(2): p. 158-69.
28. Friesner, R.A., et al., Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−
Ligand Complexes. Journal of Medicinal Chemistry, 2006. 49(21): p. 6177-6196.
29. Hussein, D., In Silico Investigation of the Human GTP Cyclohydrolase 1 Enzyme Reveals the Potential of Drug Repurposing
Approaches towards the Discovery of Effective BH4 Therapeutics. International Journal of Molecular Sciences, 2023. 24(2): p.
1210.
30. Wojcik, C. and B.A. Warden, Mechanisms and Evidence for Heart Failure Benefits from SGLT2 Inhibitors. Current Cardiology
Reports, 2019. 21(10): p. 130.
31. Powell, D.R., et al., LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose
cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J Pharmacol Exp Ther, 2013. 345(2): p. 250-9.
32. Sands, A.T., et al., Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. Diabetes
Care, 2015. 38(7): p. 1181-8.
33. Garg, S.K., et al., Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med, 2017. 377(24): p.
2337-2348.
34. Danne, T., et al., Sotagliflozin Added to Optimized Insulin Therapy Leads to Lower Rates of Clinically Relevant Hypoglycemic
Events at Any HbA1c at 52 Weeks in Adults with Type 1 Diabetes. Diabetes Technol Ther, 2019. 21(9): p. 471-477.
35. Vallianou, N.G., et al., Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor: In the heart of the problem. Metabol Open, 2021. 10:
p. 100089.
36. Packer, M., Sotagliflozin for Heart Failure: What We Know About Trials and Mechanisms. J Card Fail, 2023. 29(11): p. 1586-
1588.
37. Zinman, B., et al., Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med, 2015. 373(22): p.
2117-28.
38. Kosiborod, M., et al., Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors
Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New
Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation, 2017. 136(3): p. 249-259.
39. Mahaffey, K.W., et al., Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS
Program (Canagliflozin Cardiovascular Assessment Study). Circulation, 2018. 137(4): p. 323-334.
40. von Lewinski, D., et al., Functional effects of glucose transporters in human ventricular myocardium. European journal of heart
failure, 2010. 12(2): p. 106-113.
41. Dominguez Rieg, J.A., et al., Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice. Laboratory
Investigation, 2016. 96(1): p. 98-111.
42. Cefalo, C.M.A., et al., Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovascular Diabetology,
2019. 18(1): p. 20.
43. Seidelmann, S.B., et al., Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. J Am Coll Cardiol, 2018.
72(15): p. 1763-1773.
44. Bhatt, D.L., et al., Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. New England Journal of Medicine, 2020.
384(2): p. 129-139.
45. Pitt, B., et al., Effect of Sotagliflozin on Early Mortality and Heart Failure-Related Events. JACC: Heart Failure, 2023. 11(8_
Part_1): p. 879-889.
46. Al-Madhagi, H.A., FDA-approved drugs in 2022: A brief outline. Saudi Pharm J, 2023. 31(3): p. 401-409.
47. Davies, M.J., et al., Sotagliflozin Reduces The Risk Of Cardiovascular Events In Patients With Left Ventricular Hypertrophy
Without Hypertension: A Post Hoc Analysis From SCORED. Journal of Cardiac Failure, 2024. 30(1): p. 262.
48. Marwick, T.H., Methods used for the assessment of LV systolic function: common currency or tower of Babel? Heart, 2013.
99(15): p. 1078-1086.
49. Melero-Ferrer, J.L., et al., Novel Imaging Techniques for Heart Failure. Card Fail Rev, 2016. 2(1): p. 27-34.
50. Maron, M.S., et al., Effect of Spironolactone on Myocardial Fibrosis and Other Clinical Variables in Patients with Hypertrophic
Cardiomyopathy. The American Journal of Medicine, 2018. 131(7): p. 837-841.
51. Young, S.L., et al., Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of
Cardiac Pressure Overload. Frontiers in Physiology, 2021. 12.
52. Kim, I., et al., Comparison of the effects of empagliflozin and sotagliflozin on a zebrafish model of diabetic heart failure with reduced ejection fraction. Experimental & Molecular Medicine, 2023. 55(6): p. 1174-1181.
53. Zhong, P., et al., Sotagliflozin attenuates cardiac dysfunction and remodeling in myocardial infarction rats. Heliyon, 2023. 9(11):
p. e22423.
54. Banerjee, S.K., et al., SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovascular Research,
2009. 84(1): p. 111-118.
20(3): p. 200-216.
2. Hsia, D.S., O. Grove, and W.T. Cefalu, An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes
mellitus. Curr Opin Endocrinol Diabetes Obes, 2017. 24(1): p. 73-79.
3. Brazy, P.C. and V.W. Dennis, Characteristics of glucose-phlorizin interactions in isolated proximal tubules. American Journal of
Physiology-Renal Physiology, 1978. 234(4): p. F279-F286.
4. De Koninck, L., Ueber das phloridzin (phlorrhizin). Annalen der Pharmacie, 1835. 15(1): p. 75-77.
5. Von Mering, J., Über experimentellen Diabetes. Verh Kongr Inn Med, 1886. 5: p. 185.
6. Jörgens, V., The roots of SGLT inhibition: Laurent-Guillaume de Koninck, Jean Servais Stas and Freiherr Josef von Mering. Acta
Diabetologica, 2019. 56(1): p. 29-31.
7. Mather, A. and C. Pollock, Renal glucose transporters: novel targets for hyperglycemia management. Nature Reviews
Nephrology, 2010. 6(5): p. 307-311.
8. Yamaguchi, K., et al., Pharmacokinetic and pharmacodynamic modeling of the effect of an sodium-glucose cotransporter
inhibitor, phlorizin, on renal glucose transport in rats. Drug Metab Dispos, 2011. 39(10): p. 1801-7.
9. Wright, E.M., D.D. Loo, and B.A. Hirayama, Biology of human sodium glucose transporters. Physiol Rev, 2011. 91(2): p. 733-94.
10. Bakris, G.L., et al., Renal sodium–glucose transport: role in diabetes mellitus and potential clinical implications. Kidney
International, 2009. 75(12): p. 1272-1277.
11. Vrhovac, I., et al., Localizations of Na+-d-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human
small intestine, liver, lung, and heart. Pflügers Archiv - European Journal of Physiology, 2015. 467(9): p. 1881-1898.
12. Hediger, M.A., et al., Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature, 1987. 330(6146): p.
379-81.
13. Kanai, Y., et al., The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive
mechanism for D-glucose. J Clin Invest, 1994. 93(1): p. 397-404.
14. Faham, S., et al., The Crystal Structure of a Sodium Galactose Transporter Reveals Mechanistic Insights into Na+/
Sugar Symport. Science, 2008. 321(5890): p. 810-814.
15. Cui, W., et al., Structures of human SGLT in the occluded state reveal conformational changes during sugar transport. Nature
Communications, 2023. 14(1): p. 2920.
16. Coady, M.J., et al., MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2. J Am Soc Nephrol, 2017. 28(1):
p. 85-93.
17. Niu, Y., et al., Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter. Nature, 2022. 601(7892): p. 280-
284.
18. Perez, M., et al., MAP17 and SGLT1 protein expression levels as prognostic markers for cervical tumor patient survival. PLoS
One, 2013. 8(2): p. e56169.
19. Silverman, M. and J. Black, High affinity phlorizin receptor sites and their relation to the glucose transport mechanism in the
proximal tubule of dog kidney. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1975. 394(1): p. 10-30.
20. Chasis, H., N. Jolliffe, and H.W. Smith, THE ACTION OF PHLORIZIN ON THE EXCRETION OF GLUCOSE, XYLOSE, SUCROSE,
CREATININE AND UREA BY MAN. J Clin Invest, 1933. 12(6): p. 1083-90.
21. Dimitrakoudis, D., M. Vranic, and A. Klip, Effects of hyperglycemia on glucose transporters of the muscle: use of the renal
glucose reabsorption inhibitor phlorizin to control glycemia. J Am Soc Nephrol, 1992. 3(5): p. 1078-91.
22. Maccari, R. and R. Ottanà, Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future
Perspectives. Journal of Medicinal Chemistry, 2022. 65(16): p. 10848-10881.
23. Oku, A., et al., T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes, 1999. 48(9): p. 1794-1800.
24. Choi, C.-I., Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation
Antihyperglycemic Agents. Molecules, 2016. 21(9): p. 1136.
25. Powell, D.R., et al., Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab, 2013. 304(2):
p. E117-30.
26. Lapuerta, P., et al., Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diabetes and
Vascular Disease Research, 2015. 12(2): p. 101-110.
27. Zambrowicz, B., et al., LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a
randomized, placebo-controlled trial. Clin Pharmacol Ther, 2012. 92(2): p. 158-69.
28. Friesner, R.A., et al., Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−
Ligand Complexes. Journal of Medicinal Chemistry, 2006. 49(21): p. 6177-6196.
29. Hussein, D., In Silico Investigation of the Human GTP Cyclohydrolase 1 Enzyme Reveals the Potential of Drug Repurposing
Approaches towards the Discovery of Effective BH4 Therapeutics. International Journal of Molecular Sciences, 2023. 24(2): p.
1210.
30. Wojcik, C. and B.A. Warden, Mechanisms and Evidence for Heart Failure Benefits from SGLT2 Inhibitors. Current Cardiology
Reports, 2019. 21(10): p. 130.
31. Powell, D.R., et al., LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose
cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J Pharmacol Exp Ther, 2013. 345(2): p. 250-9.
32. Sands, A.T., et al., Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. Diabetes
Care, 2015. 38(7): p. 1181-8.
33. Garg, S.K., et al., Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med, 2017. 377(24): p.
2337-2348.
34. Danne, T., et al., Sotagliflozin Added to Optimized Insulin Therapy Leads to Lower Rates of Clinically Relevant Hypoglycemic
Events at Any HbA1c at 52 Weeks in Adults with Type 1 Diabetes. Diabetes Technol Ther, 2019. 21(9): p. 471-477.
35. Vallianou, N.G., et al., Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor: In the heart of the problem. Metabol Open, 2021. 10:
p. 100089.
36. Packer, M., Sotagliflozin for Heart Failure: What We Know About Trials and Mechanisms. J Card Fail, 2023. 29(11): p. 1586-
1588.
37. Zinman, B., et al., Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med, 2015. 373(22): p.
2117-28.
38. Kosiborod, M., et al., Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors
Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New
Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation, 2017. 136(3): p. 249-259.
39. Mahaffey, K.W., et al., Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS
Program (Canagliflozin Cardiovascular Assessment Study). Circulation, 2018. 137(4): p. 323-334.
40. von Lewinski, D., et al., Functional effects of glucose transporters in human ventricular myocardium. European journal of heart
failure, 2010. 12(2): p. 106-113.
41. Dominguez Rieg, J.A., et al., Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice. Laboratory
Investigation, 2016. 96(1): p. 98-111.
42. Cefalo, C.M.A., et al., Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovascular Diabetology,
2019. 18(1): p. 20.
43. Seidelmann, S.B., et al., Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. J Am Coll Cardiol, 2018.
72(15): p. 1763-1773.
44. Bhatt, D.L., et al., Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. New England Journal of Medicine, 2020.
384(2): p. 129-139.
45. Pitt, B., et al., Effect of Sotagliflozin on Early Mortality and Heart Failure-Related Events. JACC: Heart Failure, 2023. 11(8_
Part_1): p. 879-889.
46. Al-Madhagi, H.A., FDA-approved drugs in 2022: A brief outline. Saudi Pharm J, 2023. 31(3): p. 401-409.
47. Davies, M.J., et al., Sotagliflozin Reduces The Risk Of Cardiovascular Events In Patients With Left Ventricular Hypertrophy
Without Hypertension: A Post Hoc Analysis From SCORED. Journal of Cardiac Failure, 2024. 30(1): p. 262.
48. Marwick, T.H., Methods used for the assessment of LV systolic function: common currency or tower of Babel? Heart, 2013.
99(15): p. 1078-1086.
49. Melero-Ferrer, J.L., et al., Novel Imaging Techniques for Heart Failure. Card Fail Rev, 2016. 2(1): p. 27-34.
50. Maron, M.S., et al., Effect of Spironolactone on Myocardial Fibrosis and Other Clinical Variables in Patients with Hypertrophic
Cardiomyopathy. The American Journal of Medicine, 2018. 131(7): p. 837-841.
51. Young, S.L., et al., Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of
Cardiac Pressure Overload. Frontiers in Physiology, 2021. 12.
52. Kim, I., et al., Comparison of the effects of empagliflozin and sotagliflozin on a zebrafish model of diabetic heart failure with reduced ejection fraction. Experimental & Molecular Medicine, 2023. 55(6): p. 1174-1181.
53. Zhong, P., et al., Sotagliflozin attenuates cardiac dysfunction and remodeling in myocardial infarction rats. Heliyon, 2023. 9(11):
p. e22423.
54. Banerjee, S.K., et al., SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovascular Research,
2009. 84(1): p. 111-118.
Article Sidebar
Published
Oct 8, 2025
Article Details
How to Cite
1.
The journey of Sotagliflozin: from its status as a withdrawn candidate for the treatment of diabetes mellitus, to its repurposing as a groundbreaking drug for the management of heart failure. Pharm Pract (Granada) [Internet]. 2025 Oct. 8 [cited 2025 Oct. 22];23(3):1-10. Available from: https://pharmacypractice.org/index.php/pp/article/view/3265
Section
Review
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
How to Cite
1.
The journey of Sotagliflozin: from its status as a withdrawn candidate for the treatment of diabetes mellitus, to its repurposing as a groundbreaking drug for the management of heart failure. Pharm Pract (Granada) [Internet]. 2025 Oct. 8 [cited 2025 Oct. 22];23(3):1-10. Available from: https://pharmacypractice.org/index.php/pp/article/view/3265