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SGLT2 Inhibitors for Treating Diabetes

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Essentials of SGLT2 Inhibitors in Diabetes

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Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have a novel therapeutic action compared with the many drugs available to the prescriber to treat type 2 diabetes. The pharmacological action of this drug class is in the kidneys, which play an important role in glucose homeostasis by filtering and reabsorbing glucose in the proximal tubules. On a daily basis, the kidney filters approximately 180 g of glucose. The majority of filtered plasma glucose (80–90 %) is reabsorbed in the early proximal tubule by the high capacity, low affinity SGLT2 [1]. The other 10–20 % is reabsorbed by the low capacity but high-affinity SGLT1 in the more distal portion of the proximal tubule (Fig. 2.1) [2]. This is achieved by cotransporting glucose with sodium via Na+/K+–adenosine triphosphatase pumps. SGLT2 is selectively expressed in the kidney, whereas SGLT1 is also expressed in the gastrointestinal tract where it has a role in the absorption of glucose and galactose [3]. In healthy individuals, virtually all glucose is reabsorbed and the urine is free from glucose.

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References

  1. Liu J, Lee T, DeFronzo R. Why do SGLT2 inhibitors inhibit only 30–50% of renal glucose reabsorption in humans? Diabetes. 2012;16:2199–204.

    Article  Google Scholar 

  2. Chao EC, Henry RR. SGLT2 inhibition – a novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9:551–9.

    Article  CAS  PubMed  Google Scholar 

  3. Hasan F, Alsahi M. Gerich SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res Clin Pract. 2014;104:297–322.

    Article  CAS  PubMed  Google Scholar 

  4. De Nicola L, Gabbai FB, Liberti ME, Sagliocca A, Conte G, Minutolo R. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis. 2014;64:16–24.

    Article  PubMed  Google Scholar 

  5. A study to evaluate the efficacy and safety of Ertugliflozin in participants with type 2 diabetes mellitus and inadequate glycemic control on metformin monotherapy (MK-8835-007). https://clinicaltrials.gov/ct2/show/NCT02033889. Accessed 5 Sept 2016.

  6. Sands AT, Zambrowicz BP, Rosenstock J, Lapuerta P, Bode BW, Garg SK, et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care. 2015;38:1181–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Efficacy, safety, and tolerability study of Sotagliflozin as adjunct therapy in adult patients with type 1 diabetes mellitus who have inadequate glycemic control with insulin therapy (inTandem1). https://clinicaltrials.gov/ct2/show/NCT02384941. Accessed 5 Sept 2016.

  8. Ferranninni E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial. Diabetes Care. 2010;33:2217–24.

    Article  Google Scholar 

  9. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:2223–33.

    Article  CAS  PubMed  Google Scholar 

  10. Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin as add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate control with glimepiride: a randomised, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011;10:928–38.

    Article  Google Scholar 

  12. Jabbour SA, Hardy E, Sugg J, Parikh S, Study 10 Group. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomised, double-blind, placebo-controlled study. Diabetes Care. 2014;37:740–50.

    Article  CAS  PubMed  Google Scholar 

  13. Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, Parikh SJ. 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;34:2015–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, et al; 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;156:405–15.

    Google Scholar 

  15. Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract. 2012;66:446–56.

    Article  CAS  PubMed  Google Scholar 

  16. Stenlof K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15:372–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fulcher G, Matthews DR, Perkovic V, de Zeeuw D, Mahaffey KW, Weiss R, et al. Efficacy and safety of canagliflozin used in conjunction with sulphonylurea in patients with type 2 diabetes mellitus: a randomised control trial. Diabetes Ther. 2015;6:289–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTANA-SU): 52 week results from a randomised, double-blind, Phase III non-inferiority trial. Lancet. 2013;382:941–50.

    Article  CAS  PubMed  Google Scholar 

  19. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, Tong C, Qiu R, Canovatchel W, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background monotherapy: a randomised trial. Diabetologia. 2013;56:2582–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Forst T, Guthrie R, Goldenberg R, Yee J, Vijapurkar U, Meininger G, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metabol. 2014;16:467–77.

    Article  CAS  Google Scholar 

  21. Wilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013;67:1267–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycaemic control with metformin plus sulphonylurea – a 52-week randomised trial. Diabetes Care. 2013;36:2508–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Ways K, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose co-transporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38:403–11.

    Article  CAS  PubMed  Google Scholar 

  24. Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase III trial. Lancet Diabetes Endocrinol. 2013;1:208–19.

    Article  CAS  PubMed  Google Scholar 

  25. Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, et al; EMPA-REG MET Trial Investigators. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled trial. Diabetes Care. 2014;37:1650–9.

    Google Scholar 

  26. Ridderstrale M, Andersen KR, Zeller C, Kim G, Woerle HJ. Broedl UC; EMPA-REG H2H-SU trial investigators. 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 III trial. Lancet Diabetes Endocrinol. 2014;2:691–700.

    Article  PubMed  Google Scholar 

  27. Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, et al. Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes: a 24-week, randomised, double-blind, placebo-controlled trial. Diabetes Care. 2013;36:3396–404.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16:147–58.

    Article  CAS  PubMed  Google Scholar 

  29. Rosenstock J, Jelaska A, Zeller C, Kim G, Broedl UC, Woerle HJ; EMPA-REG BASAL Trial Investigators. Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2015;17:936–48.

    Google Scholar 

  30. Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, et al; EMPA-REG MDI Trial Investigators. Improved glucose control with weight loss, lower insulin doses and no increased hypoglycaemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014;1815–23.

    Google Scholar 

  31. Long-term safety study of Canagliflozin (TA-7284) in combination with GLP-1 analogue in patients with type 2 diabetes mellitus. https://clinicaltrials.gov/ct2/show/NCT02227849. Accessed 5 Sept 2016.

  32. Sha S, Polidori D, Farrell K, Ghosh A, Natarajan J, Vaccaro N, et al. Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomised, double-blind, crossover study. Diabetes Obes Metab. 2015;17:188–97.

    Article  CAS  PubMed  Google Scholar 

  33. Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycaemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–31.

    Article  CAS  PubMed  Google Scholar 

  34. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium-glucose transporter 2 inhibition. Diabetes Care. 2015;38:1730–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014;8:1335–80.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sjöström CD, Sugg J, Ptaszynska A, Parikh S. Pilot analysis of the effect of the SGLT2 inhibitor dapagliflozin on blood pressure in patients with type 2 diabetes mellitus: a pooled analysis of placebo controlled trials. Eur Heart J. 2012;33(Suppl):S680.

    Google Scholar 

  37. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypert. 2014;8:262–75.

    Article  CAS  Google Scholar 

  38. Hach T, Lambers Heerspink HJ, Pfarr E, Lund S, Ley L, Broedl UC, et al. The sodium glucose co-transporter-2 (SGLT2) inhibitor empagliflozin lowers blood pressure independent of weight or HbA1c change. Diabetologia. 2012;55 Suppl 1:S317. Abstract 770.

    Google Scholar 

  39. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38:420–8.

    Article  CAS  PubMed  Google Scholar 

  40. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262–74.

    Article  PubMed  Google Scholar 

  41. Gray LJ, Dales L, Brady EM, Khunti K, Hanif W, Davies MJ. Safety and effectiveness of non-insulin glucose-lowering agents in the treatment of people with type 2 diabetes who observe Ramadan: a systematic review and meta-analysis. Diabetes Obes Metab. 2015;17:639–48.

    Article  CAS  PubMed  Google Scholar 

  42. Kasichayanula S, Liu X, Pe Benito M. The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol. 2013;76:432–44.

    Article  CAS  PubMed  Google Scholar 

  43. Food and Drug Assocation (FDA). FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. FDA drug safety communication. www.fda.gov/Drugs/DrugSafety/ucm461449.htm. Accessed 5 Sept 2016.

  44. Rosenstock J, Ferrannini E. Euglycaemic diabetic ketoacidosis: a predictable, detectable, and preventable concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–42.

    Article  CAS  PubMed  Google Scholar 

  45. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38:1680–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Glasgow Royal Infirmary, Glasgow, UK

    Gerard McKay MD

  2. Specialty Trainee, Royal Alexandria Hospital, Paisley, UK

    Rachel Livingstone MD

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McKay, G., Livingstone, R. (2017). SGLT2 Inhibitors for Treating Diabetes. In: Essentials of SGLT2 Inhibitors in Diabetes. Adis, Cham. https://doi.org/10.1007/978-3-319-43296-0_2

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  • DOI: https://doi.org/10.1007/978-3-319-43296-0_2

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