Advancements in SGLT2 inhibitors: pharmacokinetics, pharmacodynamics, and clinical efficacy with a focus on pharmacogenomics

Authors

  • Bhagya G Department of Pharmacy Practice, PESU Institute of Pharmacy (Formerly PES College of Pharmacy), PES University, Bangalore, Karnataka, India – 560100
  • Namini M Department of Pharmacy Practice, PESU Institute of Pharmacy (Formerly PES College of Pharmacy), PES University, Bangalore, Karnataka, India – 560100
  • Girish B S a:1:{s:5:"en_US";s:167:"Department of Pharmacy Practice, PESU Institute of Pharmacy (Formerly PES College of Pharmacy), PES University, Electronic City, Bengaluru, Karnataka, India – 560100";} https://orcid.org/0000-0003-1894-7852
  • R Srinivasan Department of Pharmacy Practice, PESU Institute of Pharmacy (Formerly PES College of Pharmacy), PES University, Bangalore, Karnataka, India – 560100

DOI:

https://doi.org/10.56782/pps.274

Keywords:

Diabetes Mellitus, SGLT2 Inhibitors, Pharmacogenomics, Pharmacology, Clinical Practice

Abstract

Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a pivotal advancement in the treatment of type 2 diabetes mellitus (T2DM), offering substantial improvements in glycemic control, cardiovascular protection, and renal outcomes. This review explores the pharmacokinetics, pharmacodynamics, and clinical efficacy of SGLT2 inhibitors, with a particular focus on pharmacogenomics and its impact on individual patient response. Bexagliflozin, a potent SGLT2 inhibitor, exhibits robust glycemic control through selective SGLT2 inhibition, while studies on luseogliflozin, ertugliflozin, tofogliflozin, and remogliflozin have further demonstrated the versatility and safety of this drug class. These inhibitors not only reduce HbA1c but also lower blood pressure, improve renal outcomes, and reduce the risk of major adverse cardiovascular events. Pharmacogenomics has revealed genetic polymorphisms that affect the metabolism and efficacy of SGLT2 inhibitors, guiding more precise therapeutic decisions. Variants in genes like SLC5A2 and CYP enzymes influence drug transport, metabolism, and response, paving the way for personalized treatment approaches. This growing understanding underscores the potential for pharmacogenomics to refine the selection of SGLT2 inhibitors for optimal efficacy and minimal side effects. Despite promising results, further research is needed to fully integrate pharmacogenomics into clinical practice. As personalized medicine continues to evolve, SGLT2 inhibitors, bolstered by pharmacogenomic insights, offer a compelling avenue for enhancing the management of T2DM, ultimately transforming patient care with a more tailored and effective approach.

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References

1. Pradeepa, R.; Mohan, V. Epidemiology of type 2 diabetes in India. Indian J. Ophthalmol. 2021, 69, 2932–2938. DOI: 10.4103/ijo.IJO_1627_21 DOI: https://doi.org/10.4103/ijo.IJO_1627_21

2. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 2015, 3, 866–875. DOI: 10.2337/dc18-1970 DOI: https://doi.org/10.1016/S2213-8587(15)00291-0

3. Kropp, M.; et al. Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications—risks and mitigation. The EPMA J. 2023, 14, 21–42. DOI: 10.1007/s13167-023-00314-8. DOI: https://doi.org/10.1007/s13167-023-00314-8

4. Sherwani, S.I.; Khan, H.A.; Ekhzaimy, A.; Masood, A.; Sakharkar, M.K. Significance of HbA1c Test in Diagnosis and Prognosis of Diabetic Patients. Biomark. Insights 2016, 11, 95–104. DOI: 10.4137/BMI.S38440 DOI: https://doi.org/10.4137/BMI.S38440

5. Ejiri, K.; Miyoshi, T.; Nakamura, K.; Sakuragi, S.; Munemasa, M.; Namba, S.; Takaishi, A.; Ito, H. The effect of luseogliflozin and alpha-glucosidase inhibitor on heart failure with preserved ejection fraction in diabetic patients: rationale and design of the MUSCAT-HF randomised controlled trial. BMJ Open 2019, 9, Art. No: e026590. DOI: 10.1136/bmjopen-2018-026590corr1. DOI: https://doi.org/10.1136/bmjopen-2018-026590

6. Diabetes in India. World Health Organization [Internet]. Available from: https://www.who.int/india/health-topics/mobile-technology-for-preventing-ncds. [Accessed on June 12, 2024].

7. Nathan, D.M.; Singer, D.E.; Hurxthal, K.; Goodson, J.D. The clinical information value of the glycosylated hemoglobin assay. N. Engl. J. Med. 1984, 310, 341–346. DOI: 10.1056/NEJM198402093100602 DOI: https://doi.org/10.1056/NEJM198402093100602

8. Frías, J.P.; Guja, C.; Hardy, E.; Ahmed, A.; Dong, F.; Öhman, P.; Jabbour, S.A. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016, 4, 1004–1016. DOI: 10.1016/S2213-8587(16)30267-4

9. Roden, M.; Weng, J.; Eilbracht, J.; Delafont, B.; Kim, G.; Woerle, H.J.; Broedl, U.C.; EMPA-REG MONO trial investigators. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013, 1, 208–219. DOI: 10.1016/S2213-8587(13)70084-6. DOI: https://doi.org/10.1016/S2213-8587(13)70084-6

10. Ejiri, K.; Miyoshi, T.; Nakamura, K.; Sakuragi, S.; Munemasa, M.; Namba, S.; Takaishi, A.; Ito, H. The effect of luseogliflozin and alpha-glucosidase inhibitor on heart failure with preserved ejection fraction in diabetic patients: rationale and design of the MUSCAT-HF randomised controlled trial. BMJ Open 2019, 9, Art. No: e026590. DOI: 10.1136/bmjopen-2018-026590. Erratum in: BMJ Open 2019, 9, e026590corr1. DOI: https://doi.org/10.1136/bmjopen-2018-026590corr1

11. packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Pocock, S.J.; Carson, P.; Januzzi, J.; Verma, S.; Tsutsui, H.; Brueckmann, M.; Jamal, W.; Kimura, K.; Schnee, J.; Zeller, C.; Cotton, D.; Bocchi, E.; Böhm, M.; Choi, D.J.; Chopra, V.; Chuquiure, E.; Giannetti, N.; Janssens, S.; Zhang, J.; Gonzalez Juanatey, J.R.; Kaul, S.; Brunner-La Rocca, H.P.; Merkely, B.; Nicholls, S.J.; Perrone, S.; Pina, I.; Ponikowski, P.; Sattar, N.; Senni, M.; Seronde, M.F.; Spinar, J.; Squire, I.; Taddei, S.; Wanner, C.; Zannad, F.; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N. Engl. J. Med. 2020, 383, 1413–1424. DOI:10.1056/NEJMoa2022190. DOI: https://doi.org/10.1056/NEJMoa2022190

12. Son, S.; Makino, H.; Kasahara, M.; Tanaka, T.; Nishimura, K.; Taneda, S.; Nishimura, T.; Kasama, S.; Ogawa, Y.; Miyamoto, Y.; Hosoda, K. Comparison of efficacy between dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter 2 inhibitor on metabolic risk factors in Japanese patients with type 2 diabetes mellitus: Results from the CANTABILE study. Diabetes Res. Clin. Pract. 2021, 180, Art. No: 109037. DOI: 10.1016/j.diabres.2021.109037 DOI: https://doi.org/10.1016/j.diabres.2021.109037

13. Tye, S.C.; Jongs, N.; Coca, S.G.; Sundström, J.; Arnott, C.; Neal, B.; Perkovic, V.; Mahaffey, K.W.; Vart, P.; Heerspink, H.J.L. Initiation of the SGLT2 inhibitor canagliflozin to prevent kidney and heart failure outcomes guided by HbA1c, albuminuria, and predicted risk of kidney failure. Cardiovasc. Diabetol. 2022, 21, Art. No: 194. DOI: 10.1186/s12933-022-01619-0 DOI: https://doi.org/10.1186/s12933-022-01619-0

14. Kumar, M.; et al. The Bidirectional Link Between Diabetes and Kidney Disease: Mechanisms and Management. Cureus 2023, 15, Art. No: e45615. DOI: 10.7759/cureus.45615. DOI: https://doi.org/10.7759/cureus.45615

15. Charlton, A.; et al. Oxidative Stress and Inflammation in Renal and Cardiovascular Complications of Diabetes. Biology 2020, 10, Art. No: 118. DOI: 10.3390/biology10010018 DOI: https://doi.org/10.3390/biology10010018

16. Marshall, S.M.; Flyvbjerg, A. Prevention and early detection of vascular complications of diabetes. BMJ 2006, 333, 475–480. DOI: 10.1136/bmj.38922.650521.80 DOI: https://doi.org/10.1136/bmj.38922.650521.80

17. Mgbemena, O.; et al. Role of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction: A Review Article. Cureus 2021, 13, Art. No: e19398. DOI: 10.7759/cureus.19398 DOI: https://doi.org/10.7759/cureus.19398

18. Bhattacharya, S.; Rathore, A.; Parwani, D.; Mallick, C.; Asati, V.; Agarwal, S.; Rajoriya, V.; Das, R.; Kashaw, S.K. An exhaustive perspective on structural insights of SGLT2 inhibitors: A novel class of antidiabetic agent. Eur. J. Med. Chem. 2020, 204, Art. No: 112523. DOI: 10.1016/j.ejmech.2020.112523 DOI: https://doi.org/10.1016/j.ejmech.2020.112523

19. Nakka, S.; Guruprasad, L. Structural insights into the active site of human sodium dependent glucose co-transporter 2: homology modelling, molecular docking, and 3D-QSAR studies. Aust. J. Chem. 2012, 65, 1314–1324. DOI: 10.1071/CH12051 DOI: https://doi.org/10.1071/CH12051

20. Srinivas, N.; et al. Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitors: Delving Into the Potential Benefits of Cardiorenal Protection Beyond the Treatment of Type-2 Diabetes Mellitus. Cureus 2021, 13, Art. No: e16868. DOI: 10.7759/cureus.16868 DOI: https://doi.org/10.7759/cureus.16868

21. Dholariya, S.; et al. Bexagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, for improvement of glycemia in type 2 diabetes mellitus: a systematic review and meta-analysis. Expert Opin. Pharmacother. 2023, 24, 2187–2198. DOI: 10.1080/14656566.2023.226985 DOI: https://doi.org/10.1080/14656566.2023.2269854

22. National Center for Biotechnology Information. PubChem Compound Summary Bexagliflozin. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Bexagliflozin. [Accessed on June 14, 2024].

23. Hoy, S.M. Bexagliflozin: First Approval. Drugs 2023, 83, 447–453. DOI: 10.1007/s40265-023-01848-x DOI: https://doi.org/10.1007/s40265-023-01848-x

24. Canagliflozin. PubChem. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Canagliflozin. Accessed December 2, 2024.

25. Dapagliflozin. PubChem. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Dapagliflozin. Accessed December 2, 2024.

26. Empagliflozin. PubChem. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Empagliflozin. Accessed December 2, 2024.

27. Ertugliflozin. PubChem. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Ertugliflozin. Accessed December 2, 2024.

28. Padda, I.S.; Mahtani, A.U.; Parmar, M. Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors. In: StatPearls. Treasure Island (FL): StatPearls Publishing; June 3, 2023. Bookshelf ID: NBK576405

29. Halden, T.A.S.; Kvitne, K.E.; Midtvedt, K.; Rajakumar, L.; Robertsen, I.; Brox, J.; Bollerslev, J.; Hartmann, A.; Åsberg, A.; Jenssen, T. Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus. Diabetes Care 2019, 42, 1067–1074. DOI: 10.2337/dc19-0093 DOI: https://doi.org/10.2337/dc19-0093

30. Barnett, A.H.; Mithal, A.; Manassie, J.; Jones, R.; Rattunde, H.; Woerle, H.J.; Broedl, U.C.; EMPA-REG RENAL trial investigators. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014, 2, 369–384. DOI: 10.1016/S2213-8587(13)70208-0 DOI: https://doi.org/10.1016/S2213-8587(13)70208-0

31. Wilding, J.P.; Woo, V.; Soler, N.G.; Pahor, A.; Sugg, J.; Rohwedder, K.; Parikh, S.; Dapagliflozin 006 Study Group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann. Intern. Med. 2012, 156, 405–415. DOI: 10.7326/0003-4819-156-6-201203200-00003 DOI: https://doi.org/10.7326/0003-4819-156-6-201203200-00003

32. Rosenstock, J.; Jelaska, A.; Frappin, G.; Salsali, A.; Kim, G.; Woerle, H.J.; Broedl, U.C.; EMPA-REG MDI Trial Investigators. 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 2014, 37, 1815–1823. DOI: 10.2337/dc13-3055 DOI: https://doi.org/10.2337/dc13-3055

33. Frías, J.P.; Guja, C.; Hardy, E.; Ahmed, A.; Dong, F.; Öhman, P.; Jabbour, S.A. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016, 4, 1004–1016. DOI: 10.1016/S2213-8587(16)30267-4. Erratum in: Lancet Diabetes Endocrinol. 2017, 5, e8. DOI: https://doi.org/10.1016/S2213-8587(16)30267-4

34. DeFronzo, R.A.; Norton, L.; Abdul-Ghani, M. Renal, Metabolic, and Cardiovascular Considerations of SGLT2 Inhibition. Nat. Rev. Nephrol. 2017, 13(1), 11–26. DOI: 10.1038/nrneph.2016.170 DOI: https://doi.org/10.1038/nrneph.2016.170

35. Nauck, M.A.; Del Prato, S.; Meier, J.J.; Durán-García, S.; Rohwedder, K.; Elze, M.; Parikh, S.J. Dapagliflozin versus Glipizide as Add-on Therapy in Patients with Type 2 Diabetes Who Have Inadequate Glycemic Control with Metformin: A Randomized, 52-Week, Double-Blind, Active-Controlled Noninferiority Trial. Diabetes Care 2011, 34(9), 2015–2022. DOI: 10.2337/dc11-0606 DOI: https://doi.org/10.2337/dc11-0606

36. Tsapas, A.; Karagiannis, T.; Kakotrichi, P.; Avgerinos, I.; Mantsiou, C.; Tousinas, G.; Manolopoulos, A.; Liakos, A.; Malandris, K.; Matthews, D.R.; Bekiari, E. Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes Obes. Metab. 2021, 23(9), 2116–2124. DOI: 10.1111/dom.14451 DOI: https://doi.org/10.1111/dom.14451

37. Tikkanen, I.; Narko, K.; Zeller, C.; Green, A.; Salsali, A.; Broedl, U.C.; Woerle, H.J.; EMPA-REG BP Investigators. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 2015, 38(3), 420–428. DOI: 10.2337/dc14-1096 DOI: https://doi.org/10.2337/dc14-1096

38. Cefalu, W.T.; Leiter, L.A.; de Bruin, T.W.; Gause-Nilsson, I.; Sugg, J.; Parikh, S.J. Dapagliflozin's effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care 2015, 38(7), 1218–1227. DOI: 10.2337/dc14-0315 DOI: https://doi.org/10.2337/dc14-0315

39. Kohan, D.E.; Fioretto, P.; Tang, W.; List, J.F. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014, 85(4), 962–971. DOI: 10.1038/ki.2013.356 DOI: https://doi.org/10.1038/ki.2013.356

40. Sano, M. Sodium-glucose cotransporter (SGLT)-2 inhibitors alleviate the renal stress responsible for sympathetic activation. Ther. Adv. Cardiovasc. Dis. 2020, 14, Art. No: 1753944720939383. DOI: 10.1177/1753944720939383 DOI: https://doi.org/10.1177/1753944720939383

41. McGuire, D.K.; Shih, W.J.; Cosentino, F.; Charbonnel, B.; Cherney, D.Z.I.; Dagogo-Jack, S.; Pratley, R.; Greenberg, M.; Wang, S.; Huyck, S.; Gantz, I.; Terra, S.G.; Masiukiewicz, U.; Cannon, C.P. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: A meta-analysis. JAMA Cardiol. 2021, 6(2), 148–158. DOI: 10.1001/jamacardio.2020.4511 DOI: https://doi.org/10.1001/jamacardio.2020.4511

42. Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Inzucchi, S.E.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015, 373(22), 2117–2128. DOI: 10.1056/NEJMoa1504720 DOI: https://doi.org/10.1056/NEJMoa1504720

43. Neal, B.; Perkovic, V.; Matthews, D.R. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 2017, 377(21), Art. No: 2099. DOI: 10.1056/NEJMc1712572 DOI: https://doi.org/10.1056/NEJMc1712572

44. Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; Bhatt, D.L.; Leiter, L.A.; McGuire, D.K.; Wilding, J.P.H.; Ruff, C.T.; Gause-Nilsson, I.A.M.; Fredriksson, M.; Johansson, P.A.; Langkilde, A.M.; Sabatine, M.S.; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 2019, 380(4), 347–357. DOI: 10.1056/NEJMoa1812389 DOI: https://doi.org/10.1056/NEJMoa1812389

45. Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Law, G.; Desai, M.; Matthews, D.R.; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 2017, 377(7), 644–657. DOI: 10.1056/NEJMoa1611925 DOI: https://doi.org/10.1056/NEJMoa1611925

46. Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.L.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G.; Bull, S.; Cannon, C.P.; Capuano, G.; Chu, P.L.; de Zeeuw, D.; Greene, T.; Levin, A.; Pollock, C.; Wheeler, D.C.; Yavin, Y.; Zhang, H.; Zinman, B.; Meininger, G.; Brenner, B.M.; Mahaffey, K.W.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 2019, 380(24), 2295–2306. DOI: 10.1056/NEJMoa1811744 DOI: https://doi.org/10.1056/NEJMoa1811744

47. Jardine, M.J.; Zhou, Z.; Mahaffey, K.W.; Oshima, M.; Agarwal, R.; Bakris, G.; Bajaj, H.S.; Bull, S.; Cannon, C.P.; Charytan, D.M.; de Zeeuw, D.; Di Tanna, G.L.; Greene, T.; Heerspink, H.J.L.; Levin, A.; Neal, B.; Pollock, C.; Qiu, R.; Sun, T.; Wheeler, D.C.; Zhang, H.; Zinman, B.; Rosenthal, N.; Perkovic, V.; CREDENCE Study Investigators. Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: A secondary analysis of the CREDENCE randomized trial. J. Am. Soc. Nephrol. 2020, 31(5), 1128–1139. DOI: 10.1681/ASN.2019111168 DOI: https://doi.org/10.1681/ASN.2019111168

48. Cherney, D.Z.I.; Charbonnel, B.; Cosentino, F.; Dagogo-Jack, S.; McGuire, D.K.; Pratley, R.; Shih, W.J.; Frederich, R.; Maldonado, M.; Pong, A.; Cannon, C.P.; VERTIS CV Investigators. Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: An analysis from the randomised VERTIS CV trial. Diabetologia 2021, 64(6), 1256–1267. DOI: 10.1007/s00125-021-05407-5. DOI: https://doi.org/10.1007/s00125-021-05407-5

49. Allegretti, A.S.; Zhang, W.; Zhou, W.; Thurber, T.K.; Rigby, S.P.; Bowman-Stroud, C.; Trescoli, C.; Serusclat, P.; Freeman, M.W.; Halvorsen, Y.C. Safety and effectiveness of bexagliflozin in patients with type 2 diabetes mellitus and stage 3a/3b CKD. Am. J. Kidney Dis. 2019, 74(3), 328–337. DOI: 10.1053/j.ajkd.2019.03.417. DOI: https://doi.org/10.1053/j.ajkd.2019.03.417

50. Mordi, N.A.; Mordi, I.R.; Singh, J.S.; McCrimmon, R.J.; Struthers, A.D.; Lang, C.C. Renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic heart failure: The RECEDE-CHF trial. Circulation 2020, 142(18), 1713–1724. DOI: 10.1161/CIRCULATIONAHA.120.048739 DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.048739

51. Halvorsen, Y.-D.; Yuan-Di, C. A 24-week, randomized, double-blind, active-controlled clinical trial comparing bexagliflozin with sitagliptin as an adjunct to metformin for the treatment of type 2 diabetes in adults. Diabetes Obes. Metab. 2019, 21(10), 2248–2256. DOI: 10.1080/00498254.2019

52. Dindere, M.E. New FDA-approved SGLT2 inhibitor bexagliflozin for type 2 diabetes therapy. Discoveries Rep. 2023, 6, Art. No: e41. DOI: 10.15190/drep.2023.4

53. Halvorsen, Y.-D.; Yuan-Di, C. A 96-week, multinational, randomized, double-blind, parallel-group, clinical trial evaluating the safety and effectiveness of bexagliflozin as a monotherapy for adults with type 2 diabetes. Diabetes Obes. Metab. 2019, 21(11), 2496–2504. DOI:10.1111/dom.13801 DOI: https://doi.org/10.1111/dom.13833

54. Zhang, W.; Li, X.; Ding, H.; Lu, Y.; Stilwell, G.E.; Halvorsen, Y.D.; Welihinda, A. Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys, and humans. Xenobiotica 2020, 50(5), 559–569. DOI: 10.1080/00498254.2019.1654634

55. Bexagliflozin (Brenzavvy): Advancing diabetes management with SGLT-2 inhibition. PharmacyTimes.com. Available from: https://www.pharmacytimes.com/view/bexagliflozin-brenzavvy-advancing-diabetes-management-with-sglt-2-inhibition13. [Accessed on July 3, 2024].

56. Brenzavvy prescribing information. Available from: https://brenzavvy.com/wp-content/uploads/2023/03/Brenzavvy-PrescribingInformation-PI-001-07.pd. [Accessed July 3, 2024].

57. Azzam, O.; Carnagarin, R.; Lugo-Gavidia, L.M.; Nolde, J.; Matthews, V.B.; Schlaich, M.P. Bexagliflozin for type 2 diabetes: An overview of the data. Expert Opin. Pharmacother. 2021, 22(16), 2095–2103. DOI: 10.1080/14656566.2021.1959915 DOI: https://doi.org/10.1080/14656566.2021.1959915

58. Rendell, M.S. Albiglutide: A unique GLP-1 receptor agonist. Expert Opin. Biol. Ther. 2016, 16(12), 1557–1569. DOI: 10.1080/14712598.2016.1240780 DOI: https://doi.org/10.1080/14712598.2016.1240780

59. Liu, X.Y.; Zhang, N.; Chen, R.; Zhao, J.G.; Yu, P. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: A meta-analysis of randomized controlled trials for 1 to 2 years. J. Diabetes Complications 2015, 29(8), 1295–1303. DOI: 10.1016/j.jdiacomp.2015.07.011. DOI: https://doi.org/10.1016/j.jdiacomp.2015.07.011

60. Palmer, S.C.; Tendal, B.; Mustafa, R.A.; Vandvik, P.O.; Li, S.; Hao, Q.; Tunnicliffe, D.; Ruospo, M.; Natale, P.; Saglimbene, V.; Nicolucci, A.; Johnson, D.W.; Tonelli, M.; Rossi, M.C.; Badve, S.V.; Cho, Y.; Nadeau-Fredette, A.C.; Burke, M.; Faruque, L.I.; Lloyd, A.; Ahmad, N.; Liu, Y.; Tiv, S.; Millard, T.; Gagliardi, L.; Kolanu, N.; Barmanray, R.D.; McMorrow, R.; Raygoza Cortez, A.K.; White, H.; Chen, X.; Zhou, X.; Liu, J.; Rodríguez, A.F.; González-Colmenero, A.D.; Wang, Y.; Li, L.; Sutanto, S.; Solis, R.C.; Díaz González-Colmenero, F.; Rodriguez-Gutierrez, R.; Walsh, M.; Guyatt, G.; Strippoli, G.F.M. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials. BMJ 2021, 372, Art. No: m4573. DOI: 10.1136/bmj.m4573. DOI: https://doi.org/10.1136/bmj.m4573

61. Li, D.; Wu, T.; Wang, T.; Wei, H.; Wang, A.; Tang, H.; Song, Y. Effects of sodium-glucose cotransporter 2 inhibitors on risk of dyslipidemia among patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Pharmacoepidemiol. Drug Saf. 2020, 29(5), 582–590. DOI: 10.1002/pds.4985 DOI: https://doi.org/10.1002/pds.4985

62. Halvorsen, Y.D.; Lock, J.P.; Zhou, W.; Zhu, F.; Freeman, M.W. A 24-week, randomized, double-blind, active-controlled clinical trial comparing bexagliflozin with sitagliptin as an adjunct to metformin for the treatment of type 2 diabetes in adults. Diabetes Obes. Metab. 2019, 21(10), 2248–2256. DOI: 10.1111/dom.13801 DOI: https://doi.org/10.1111/dom.13801

63. Pasqualotto, E.; Hu, B.; Haynes, J.R.; Shapiro, A.; Davis, J. The use of SGLT-2 inhibitors in managing comorbidities in diabetes: A comprehensive review. Expert Opin. Pharmacother. 2020, 21(18), 2073–2081. DOI: 10.1080/14656566.2020.1825232

64. McCormack, P.L. Liraglutide: A review of its use in the management of type 2 diabetes. Drugs 2010, 70(2), 229–248. DOI: 10.2165/11201060-000000000-00000 DOI: https://doi.org/10.2165/11201060-000000000-00000

65. Sussman, S.K.; Turgiss, J.; Solanki, S.; Mandal, A. The efficacy of combining SGLT2 inhibitors with GLP-1 receptor agonists in treating type 2 diabetes. Clin. Endocrinol. 2021, 94(5), 732–741.

66. Ben, D.; Long, W.; Garcia, F.J.; Chen, M.; Wilson, J.W.; Nixon, J.A.; Wright, R.D. The synergistic effects of combining liraglutide with SGLT-2 inhibitors for the treatment of cardiovascular diseases in type 2 diabetes. J. Clin. Pharmacol. 2021, 61(3), 347–354. DOI: 10.1039/c6cs00765a DOI: https://doi.org/10.1039/C6CS00765A

67. Douros, A.; Sharif, S.; Jampani, A.; Brar, R.; Lipka, S.; Nevalainen, K.; Woo, V.; El-Haschimi, A. Bexagliflozin: A comprehensive pharmacological and clinical review of a new SGLT-2 inhibitor. Am. J. Pharm. Educ. 2023, 87(1), 3–16. DOI: 10.1111/dom.13893 DOI: https://doi.org/10.1111/dom.13893

68. Duca, F.A.; Ranganathan, S.; Zeleznik, J.; Nolan, K.; Patel, M.; Vance, S.R. Combining sodium-glucose co-transporter inhibitors with GLP-1 receptor agonists for optimal diabetic care. Diabetes Metab. Res. Rev. 2021, 37(8), 415–428. DOI: 10.1038/nm.3787 DOI: https://doi.org/10.1038/nm.3787

69. Lacy, C.F.; Armstrong, L.L.; Goldman, M.P.; Lance, L.L. Drug Information Handbook, 26th ed.; Lexi-Comp: Hudson, OH, USA, 2020; pp. 1247–1248..

70. Mitchell, H.; O'Connor, A.; Kheradmand, M. The dual benefit of combination therapy with SGLT2 inhibitors and GLP-1 receptor agonists. Diabetes Metab. Syndr. Obes. 2021, 14, 1211–1221

71. Liu, L.; Shi, F.H.; Xu, H.; Wu, Y.; Gu, Z.C.; Lin, H.W. Efficacy and Safety of Ertugliflozin in Type 2 Diabetes: A Systematic Review and Meta-Analysis. Front Pharmacol. 2022, 12, Art. No: 752440. DOI: 10.3389/fphar.2021.752440 DOI: https://doi.org/10.3389/fphar.2021.752440

72. Cannon, C.P.; Pratley, R.; Dagogo-Jack, S.; Mancuso, J.; Huyck, S.; Masiukiewicz, U.; Charbonnel, B.; Frederich, R.; Gallo, S.; Cosentino, F.; Shih, W.J.; Gantz, I.; Terra, S.G.; Cherney, D.Z.I.; McGuire, D.K.; VERTIS CV Investigators. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N. Engl. J. Med. 2020, 383(15), 1425–1435. DOI: 10.1056/NEJMoa2004967 DOI: https://doi.org/10.1056/NEJMoa2004967

73. Poole, R.M.; Prossler, J.E. Tofogliflozin: First Global Approval. Drugs 2014, 74(8), 939–944. DOI: 10.1007/s40265-014-0229-1 DOI: https://doi.org/10.1007/s40265-014-0229-1

74. Katakami, N.; Mita, T.; Yoshii, H.; Shiraiwa, T.; Yasuda, T.; Okada, Y.; Torimoto, K.; Umayahara, Y.; Kaneto, H.; Osonoi, T.; Yamamoto, T.; Kuribayashi, N.; Maeda, K.; Yokoyama, H.; Kosugi, K.; Ohtoshi, K.; Hayashi, I.; Sumitani, S.; Tsugawa, M.; Ryomoto, K.; Taki, H.; Nakamura, T.; Kawashima, S.; Sato, Y.; Watada, H.; Shimomura, I; UTOPIA Study Investigators. The Influence of Tofogliflozin on Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus. Diabetes Ther. 2021, 12(9), 2499–2515. DOI: 10.1007/s13300-021-01125-8 DOI: https://doi.org/10.1007/s13300-021-01125-8

75. Yoneda, M.; Honda, Y.; Ogawa, Y.; Kessoku, T.; Kobayashi, T.; Imajo, K.; Ozaki, A.; Nogami, A.; Taguri, M.; Yamanaka, T.; Kirikoshi, H.; Iwasaki, T.; Kurihashi, T.; Saito, S.; Nakajima, A. Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): a randomized prospective open-label controlled trial. BMJ Open Diabetes Res. Care 2021, 9, Art. No: e001990. DOI: 10.1136/bmjopen-2020-001990 DOI: https://doi.org/10.1136/bmjdrc-2020-001990

76. Mohan, V.; Mithal, A.; Joshi, S.R.; Aravind, S.R.; Chowdhury, S. Remogliflozin Etabonate in the Treatment of Type 2 Diabetes: Design, Development, and Place in Therapy. Drug Des. Devel. Ther. 2020, 14, 2487–2501. DOI: 10.2147/DDDT.S276960. DOI: https://doi.org/10.2147/DDDT.S221093

77. Dharmalingam, M.; Aravind, S.R.; Thacker, H.; Paramesh, S.; Mohan, B.; Chawla, M.; Asirvatham, A.; Goyal, R.; Shembalkar, J.; Balamurugan, R.; Kadam, P.; Alva, H.; Kodgule, R.; Tandon, M.; Vaidyanathan, S.; Pendse, A.; Gaikwad, R.; Katare, S.; Suryawanshi, S.; Barkate, H. Efficacy and Safety of Remogliflozin Etabonate, a New Sodium Glucose Co-Transporter-2 Inhibitor, in Patients with Type 2 Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Active-Controlled Trial. Drugs 2020, 80, 587–600. DOI: 10.1007/s11095-020-02748-3. DOI: https://doi.org/10.1007/s40265-020-01285-0

78. Klen, J.; Dolžan, V. Treatment response to SGLT2 inhibitors: from clinical characteristics to genetic variations. Int. J. Mol. Sci. 2021, 22, Art. No: 9800. DOI: 10.3390/ijms22189800.

79. Valaiyapathi, B.; Gower, B.; Ashraf, A.P. Pathophysiology of type 2 diabetes in children and adolescents. Curr. Diabetes Rev. 2020, 16, 220–229. DOI: 10.2174/1573399816666200603122037. DOI: https://doi.org/10.2174/1573399814666180608074510

80. Van Niekerk, I. PPARγ gene polymorphisms in black South African females with Type 2 Diabetes Mellitus. Master Thesis, University of the Free State, 2015. Available at: http://hdl.handle.net/11660/857

81. Galiero, R.; Caturano, A.; Vetrano, E.; Monda, M.; Marfella, R.; Sardu, C.; Salvatore, T.; Rinaldi, L.; Sasso, F.C. Precision Medicine in Type 2 Diabetes Mellitus: Utility and Limitations. Diabetes Metab. Syndr. Obes. 2023, 16, 3669–3689. DOI: 10.2147/DMSO.S416185 DOI: https://doi.org/10.2147/DMSO.S390752

82. Srinivasan, S.; Yee, S.W.; Giacomini, K.M. Pharmacogenetics of antidiabetic drugs. Adv. Pharmacol. 2018, 83, 361–389. DOI: 10.1016/bs.apha.2018.07.004 DOI: https://doi.org/10.1016/bs.apha.2018.04.005

83. Lapham, K.; Callegari, E.; Cianfrogna, J.; Lin, J.; Niosi, M.; Orozco, C.C.; Sharma, R.; Goosen, T.C. In vitro characterization of ertugliflozin metabolism by UDP-glucuronosyltransferase and cytochrome P450 enzymes. Drug Metab. Dispos. 2020, 48, 1350–1363. DOI: 10.1124/dmd.120.000207 DOI: https://doi.org/10.1124/dmd.120.000171

84. Hashiba, S.; Nakano, M.; Yokoseki, I.; Takahashi, E.; Kondo, M.; Jimbo, Y.; Ishiguro, N.; Arakawa, H.; Fukami, T.; Nakajima, M. Cytochrome P450 and UDP-glucuronosyltransferase expressions, activities, and induction abilities in 3D-cultured human renal proximal tubule epithelial cells. Drug Metab. Dispos. 2024, 52, 949–956. DOI: 10.1124/dmd.124.000435 DOI: https://doi.org/10.1124/dmd.124.001685

85. Zhang, W.; Li, X.; Ding, H.; Lu, Y.; Stilwell, G.E.; Halvorsen, Y.D.; Welihinda, A. Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys, and humans. Xenobiotica 2020, 50, 559–569. DOI: 10.1080/00498254.2019.1677040 DOI: https://doi.org/10.1080/00498254.2019.1654634

86. Bassett, R.L.; Gallo, G.; Le, K.P.; Volino, L.R. Bexagliflozin: a comprehensive review of a recently approved SGLT2 inhibitor for the treatment of type 2 diabetes mellitus. Med. Chem. Res. 2024, 33, 1–4. DOI: 10.1007/s00044-024-03099-7 DOI: https://doi.org/10.1007/s00044-024-03274-4

87. Marin, J.J.G.; Serrano, M.A.; Monte, M.J.; Sanchez-Martin, A.; Temprano, A.G.; Briz, O.; Romero, M.R. Role of Genetic Variations in the Hepatic Handling of Drugs. Int. J. Mol. Sci. 2020, 21, Art. No: 2884. DOI: 10.3390/ijms21082884 DOI: https://doi.org/10.3390/ijms21082884

88. Chakraborty, C.; Hsu, M.J.; Agoramoorthy, G. Drug metabolizing enzymes in type II diabetes and their pharmacogenetics during therapy of anti-diabetes drugs. Curr. Drug Metab. 2015, 16, 864–876. DOI: 10.2174/1389200216666151020143439 DOI: https://doi.org/10.2174/138920021610151210183821

89. Saiti, A.; Giannopoulos-Dimitriou, A.; Kazakos, I.; Galatou, E.; Vizirianakis, I.S. Systems Pharmacology and Network Analysis to Advance Pharmacogenomics and Precision Medicine Decisions in Type-2 Diabetes Therapy. Future Pharmacol. 2023, 3, 329–363. DOI: 10.3390/fphar3010025 DOI: https://doi.org/10.3390/futurepharmacol3010021

90. Fu, Y.; Breljak, D.; Onishi, A.; Batz, F.; Patel, R.; Huang, W.; Song, P.; Freeman, B.; Mayoux, E.; Koepsell, H.; Anzai, N. Organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin. Am. J. Physiol. Renal Physiol. 2018, 315, F386–F394. DOI: 10.1152/ajprenal.00016.2018 DOI: https://doi.org/10.1152/ajprenal.00503.2017

91. Stöllberger, C.; Finsterer, J.; Schneider, B. Adverse events and drug–drug interactions of sodium glucose co-transporter 2 inhibitors in patients treated for heart failure. Expert Rev. Cardiovasc. Ther. 2023, 21, 803–816. DOI: 10.1080/14779072.2023.2294607 DOI: https://doi.org/10.1080/14779072.2023.2273900

92. Klen, J.; Dolžan, V. Treatment response to SGLT2 inhibitors: from clinical characteristics to genetic variations. Int. J. Mol. Sci. 2021, 22, Art. No: 9800. DOI: 10.3390/ijms22189800 DOI: https://doi.org/10.3390/ijms22189800

93. El-Remessy, A.B. Diabetic Ketoacidosis Management: Updates and Challenges for Specific Patient Population. Endocrines 2022, 3, 801–812. DOI: 10.3390/endocrines3040055 DOI: https://doi.org/10.3390/endocrines3040066

94. Redondo, M.J.; Oram, R.A.; Steck, A.K. Genetic risk scores for type 1 diabetes prediction and diagnosis. Curr. Diabetes Rep. 2017, 17(12), Art. No: 129. DOI: 10.1007/s11892-017-0961-5 DOI: https://doi.org/10.1007/s11892-017-0961-5

95. Fodor, A.; Cozma, A.; Suharoschi, R.; Sitar-Taut, A.; Roman, G. Clinical and genetic predictors of diabetes drug’s response. Drug Metab. Rev. 2019, 51, 408–427. DOI: 10.1080/03602532.2019.1677817 DOI: https://doi.org/10.1080/03602532.2019.1656226

96. Williams, D.M.; Jones, H.; Stephens, J.W. Personalized type 2 diabetes management: an update on recent advances and recommendations. Diabetes Metab. Syndr. Obes. 2022, 15, 281–295. DOI: 10.2147/DMSO.S300931 DOI: https://doi.org/10.2147/DMSO.S331654

97. Eichler, H.G.; Abadie, E.; Breckenridge, A.; Flamion, B.; Gustafsson, L.L.; Leufkens, H.; Rowland, M.; Schneider, C.K.; Bloechl-Daum, B. Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response. Nat. Rev. Drug Discov. 2011, 10, 495–506. DOI: 10.1038/nrd3450 DOI: https://doi.org/10.1038/nrd3501

98. Jarrar, Y.; Lee, S.J. The functionality of UDP-glucuronosyltransferase genetic variants and their association with drug responses and human diseases. J. Pers. Med. 2021, 11, Art. No: 554. DOI: 10.3390/jpm11070554 DOI: https://doi.org/10.3390/jpm11060554

99. Kaur, P.; Behera, B.S.; Singh, S.; Munshi, A. The pharmacological profile of SGLT2 inhibitors: Focus on mechanistic aspects and pharmacogenomics. Eur. J. Pharmacol. 2021, 904, Art. No: 174169. DOI: 10.1016/j.ejphar.2021.174169 DOI: https://doi.org/10.1016/j.ejphar.2021.174169

100. Zhao, M.; Ma, J.; Li, M.; Zhang, Y.; Jiang, B.; Zhao, X.; Huai, C.; Shen, L.; Zhang, N.; He, L.; Qin, S. Cytochrome P450 Enzymes and Drug Metabolism in Humans. Int. J. Mol. Sci. 2021, 22, Art. No: 12808. DOI: 10.3390/ijms222312808 DOI: https://doi.org/10.3390/ijms222312808

101. Francke, S.; Mamidi, R.N.; Solanki, B.; et al. In vitro metabolism of canagliflozin in human liver, kidney, intestine microsomes, and recombinant uridine diphosphate glucuronosyltransferases (UGT) and the effect of genetic variability of UGT enzymes on the pharmacokinetics of canagliflozin in humans. J. Clin. Pharmacol. 2015, 55, 1061–1072. DOI: 10.1002/jcph.506 DOI: https://doi.org/10.1002/jcph.506

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2025-03-27

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Advancements in SGLT2 inhibitors: pharmacokinetics, pharmacodynamics, and clinical efficacy with a focus on pharmacogenomics. (2025). Prospects in Pharmaceutical Sciences, 23(1), 116-128. https://doi.org/10.56782/pps.274

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