Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: Evidence to date

Drug Design, Development and Therapy

Volumn 11, Issue , 2017, Pages 2905-2919

  Cinti, Francesca ^a   Moffa, Simona ^a   Impronta, Flavia ^a   Cefalo, Chiara M A ^a   Sun, Vinsin A ^a   Sorice, Gianpio ^a   Mezza, Teresa ^a   Giaccari, Andrea ^a  

^a FONDAZIONE POLICLINICO UNIVERSITARIO A GEMELLI IRCCS   (Italy)

Author keywords

Antidiabetic drugs; Glycemic control; Glycosylated hemoglobin; Precision medicine; Sodium glucose cotransporter 2 inhibitors; Type 1 diabetes mellitus; Type 2 diabetes mel litus; Weight reduction

Indexed keywords

ERTUGLIFLOZIN; GLIMEPIRIDE; HEMOGLOBIN A1C; METFORMIN; SITAGLIPTIN; 5-(4-CHLORO-3-(4-ETHOXYBENZYL)PHENYL)-1-HYDROXYMETHYL-6,8-DIOXABICYCLO(3.2.1)OCTANE-2,3,4-TRIOL; ANTIDIABETIC AGENT; FUSED HETEROCYCLIC RINGS; GLYCOSYLATED HEMOGLOBIN; INSULIN; SLC5A2 PROTEIN, HUMAN; SODIUM GLUCOSE COTRANSPORTER 2;

ACUTE HEART INFARCTION; BLOOD GLUCOSE MONITORING; BLOOD PRESSURE; BODY WEIGHT; CELLULITIS; DEHYDRATION; DIARRHEA; DIZZINESS; DRUG EFFECT; DRUG EFFICACY; DRUG EXCRETION; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; FAINTNESS; GENITAL TRACT INFECTION; HUMAN; HYPOGLYCEMIA; HYPOTENSION; HYPOVOLEMIA; LABORATORY TEST; META ANALYSIS; MONOTHERAPY; MYCOSIS; NON INSULIN DEPENDENT DIABETES MELLITUS; REVIEW; SYSTEMATIC REVIEW; URINARY TRACT INFECTION; ANIMAL; ANTAGONISTS AND INHIBITORS; GLUCOSE BLOOD LEVEL; METABOLISM; ORAL DRUG ADMINISTRATION; PANCREAS ISLET BETA CELL; PATHOPHYSIOLOGY;

ADMINISTRATION, ORAL; ANIMALS; BLOOD GLUCOSE; BLOOD PRESSURE; BODY WEIGHT; BRIDGED BICYCLO COMPOUNDS, HETEROCYCLIC; DIABETES MELLITUS, TYPE 2; GLYCATED HEMOGLOBIN A; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; INSULIN-SECRETING CELLS; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 85031713418     PISSN: None     EISSN: 11778881     Source Type: Journal    
DOI: 10.2147/DDDT.S114932     Document Type: Review

References (76)

1. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136–142.
2. Jiang M, Steyger PS. An evaluation of US patent 2015065565 (A1) for a new class of SGLT2 inhibitors for treatment 1 of type II diabetes mel­litus. Expert Opin Ther Pat. 2015;25(11):1349–1352.
3. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovas­cular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11–26.
4. Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflugers Archiv. 2004;447(5):510–518.
5. Pajor AM, Wright EM. Cloning and functional expression of a mammalian Na+/nucleoside cotransporter. A member of the SGLT family. J Biol Chem. 1992;267(6):3557–3560.
6. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14(1):5–14.
7. Lu Y, Griffen SC, Boulton DW, Leil TA. Use of systems pharmacol­ogy modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans. Front Pharmacol. 2014;5:274.
8. Wang XX, Levi J, Luo Y, et al. SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation and the development of nephropathy in diabetic mice. J Biol Chem. 2017;292(13):5335–5348.
9. Solini A, Rossi C, Mazzanti CM, Proietti A, Koepsell H, Ferrannini E. Sodium-glucose co-transporter (SGLT)2 and SGLT1 renal expression in patients with type 2 diabetes. Diabetes Obes Metab. Epub 2017 Apr 17.
10. Giaccari A, Sorice G, Muscogiuri G. Glucose toxicity: the leading actor in the pathogenesis and clinical history of type 2 diabetes – mechanisms and potentials for treatment. Nutr Metab Cardiovasc Dis. 2009;19(5):365–377.
11. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes. 2003;52(3):581–587.
12. Scheen AJ, Paquot N. Metabolic effects of SGLT-2 inhibitors beyond increased glucosuria: a review of the clinical evidence. Diabetes Metab. 2014;40(6 Suppl 1):S4–S11.
13. Majewski C, Bakris GL. Blood pressure reduction: an added benefit of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes. Diabetes Care. 2015;38(3):429–430.
14. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium-glucose cotransporter 2 inhibition. Dia­betes Care. 2015;38(9):1730–1735.
15. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascu­lar outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.
16. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardio­vascular and renal events in type 2 diabetes. N Engl J Med. Epub 2017 Jun 12.
17. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108–1114.
18. Lopaschuk GD, Verma S. Empagliflozin’s fuel hypothesis: not so soon. Cell Metab. 2016;24(2):200–202.
19. Schnell O, Standl E, Catrinoiu D, et al. Report from the 2nd Cardio­vascular Outcome Trial (CVOT) Summit of the Diabetes and Cardio­vascular Disease (D& CVD) EASD Study Group. Cardiovasc Diabetol. 2017;16(1):35.
20. Raz I. Guideline approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(Suppl 2):S139–S144.
21. Inzucchi SE, Bergenstal RM, Buse JB, et al. 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. 2015;38(1):140–149.
22. Garber AJ, Abrahamson MJ, Barzilay JI, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocri­nology (ACE). Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2016 executive summary. Endocr Pract. 2016;22(1):84–113.
23. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9(1):48–53.
24. 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 Hypertens. 2014;8(4):262.e269–275.e269.
25. Mosley JF 2nd, Smith L, Everton E, Fellner C. Sodium-glucose linked transporter 2 (SGLT2) inhibitors in the management of type-2 diabetes: a drug class overview. P T. 2015;40(7):451–462.
26. Miller ER 3rd, Appel LJ. High prevalence but uncertain clinical sig­nificance of orthostatic hypotension without symptoms. Circulation. 2014;130(20):1772–1774.
27. Sha S, Polidori D, Heise T, et al. Effect of the sodium glucose co transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087–1095.
28. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pres­sure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420–428.
29. Liu XY, Zhang N, Chen R, Zhao JG, 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;29:1295–1303.
30. Cherney DZ, Perkins BA, Soleymanlou N, et al. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int. 2014;86:1057–1058.
31. Kobori H, Nangaku M, Navar LG, et al. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev. 2007;59:251–287.
32. Yoshimoto T, Furuki T, Kobori H, et al. Effects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angio­tensinogen in patients with type 2 diabetes. J Investig Med. Epub 2017 Jun 8.
33. Mascitti V, Maurer TS, Robinson RP, et al. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J Med Chem. 2011;54(8):2952–2960.
34. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: charac­terisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14(1):83–90.
35. Zambrowicz B, Freiman J, Brown PM, 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):158–169.
36. Lapuerta P, Zambrowicz B, Strumph P, Sands A. Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diabetes Vasc Dis Res. 2015;12(2):101–110.
37. Castaneda F, Burse A, Boland W, Kinne RK. Thioglycosides as inhibitors of hSGLT1 and hSGLT2: potential therapeutic agents for the control of hyperglycemia in diabetes. Int J Med Sci. 2007;4(3):131–139.
38. Dash RP, Babu RJ, Srinivas NR. Comparative pharmacokinetics of three SGLT-2 inhibitors sergliflozin, remogliflozin and ertugliflozin: an overview. Xenobiotica. 2016:1–12.
39. Kalgutkar AS, Tugnait M, Zhu T, et al. Preclinical species and human disposition of PF-04971729, a selective inhibitor of the sodium-dependent glucose cotransporter 2 and clinical candidate for the treat­ment of type 2 diabetes mellitus. Drug Metab Dispos. 2011;39(9):1609–1619.
40. Miao Z, Nucci G, Amin N, et al. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab Dispos. 2013;41(2):445–456.
41. Kumar V, Sahasrabudhe V, Matschke K, et al. Lack of a pharmacoki­netic interaction between ertugliflozin and sitagliptin or metformin in healthy subjects. Poster presented at: ASCPT 2016 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics; March 12; 2016; San Diego, CA.
42. Sahasrabudhe V, Terra SG, Fountaine RJ, et al. The effect of renal impairment on the pharmacokinetics and pharmacodynamics of ertug­liflozin in subjects with type 2 diabetes mellitus. Poster presented at: EASD 2015 51st European Association for the Study of Diabetes; September 14; 2015; Stockholm, Sweden.
43. Amin NB, Wang X, Jain SM, Lee DS, Nucci G, Rusnak JM. Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin. Diabetes Obes Metab. 2015;17(6):591–598.
44. Terra SG, Focht K, Davies M, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab. 2017;19(5):721–728.
45. Aronson R, Goldman A, Frias J, et al. Long-term efficacy and safety of ertugliflozin monotherapy in patients with inadequately controlled T2DM despite diet and exercise: the 52-week VERTIS MONO study. Poster presented at: ADA 2017; June 8; 2017; San Diego, CA.
46. Rosenstock J, Frias J, Pall D, et al. Effect of ertugliflozin on glycemic control, body weight, blood pressure (BP), and bone mineral density (BMD) in T2DM inadequately controlled with metformin monotherapy: VERTIS MET Trial. Poster presented at: ADA 2017; June 8; 2017; San Diego, CA.
47. Pratley R, Eldor R, Golm G, et al. Safety and efficacy of ertugliflozin plus sitagliptin versus either treatment alone in subjects with type 2 diabetes inadequately controlled with metformin: the VERTIS FACTO­RIAL trial. Poster presented at: EASD 2016 52nd European Association for the Study of Diabetes; September 15; 2016; Munich, Germany.
48. Pratley R, Raji A, Eldor R, et al. Safety and efficacy of ertugliflozin plus sitagliptin vs. either treatment alone after 52 weeks in subjects with T2DM inadequately controlled on metformin: VERTIS FACTORIAL trial extension. Oral presentation at: ADA 2017; June 9; 2017; San Diego, CA.
49. Lauring B, Miller SS, Krumins T, et al. Safety and efficacy of ertugliflozin in combination with sitagliptin in subjects with T2DM inadequately controlled on diet and exercise: the VERTIS SITA Trial. Poster presented at: ADA 2017; June 8; 2017; San Diego, CA.
50. Lauring B, Eldor R, Liu J, et al. Efficacy and safety of ertugliflozin in subjects with type 2 diabetes mellitus inadequately controlled on the dual combination of metformin and sitagliptin: the VERTIS SITA2 trial. Poster presented at: EASD 2016 52nd European Association for the Study of Diabetes; September 15; 2016; Munich, Germany.
51. Liu J, Eldor R, Dagogo-Jack S, et al. Safety and efficacy of ertugli­flozin after 52 weeks in subjects with T2DM inadequately controlled on metformin and sitagliptin: results from the extension phase of the VERTIS SITA2 Trial. Oral presentation at: ADA 2017; June 9; 2017; San Diego, CA.
52. Hollander P, Liu J, Hill J, et al. Safety and efficacy of ertugliflozin compared to glimepiride in patients with type 2 diabetes inadequately controlled on metformin: the VERTIS SU trial. Poster presentation at: EASD 2017; Lisbon, Portugal.
53. Rajeev SP, Cuthbertson DJ, Wilding JP. Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition. Diabetes Obes Metab. 2016;18(2):125–134.
54. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32(4):650–657.
55. Bolinder J, Ljunggren O, Johansson L, et al. 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 Obes Metab. 2014;16(2):159–169.
56. Yang XP, Lai D, Zhong XY, Shen HP, Huang YL. Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis. Eur J Clin Pharmacol. 2014;70(10):1149–1158.
57. Zhang M, Zhang L, Wu B, Song H, An Z, Li S. Dapagliflozin treat­ment for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Metabol Res Rev. 2014;30(3):204–221.
58. Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(10):984–993.
59. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagli­flozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382(9896):941–950.
60. Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012;35(7):1473–1478.
61. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56(12):2582–2592.
62. Chao EC, Henry RR. SGLT2 inhibition – a novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9(7):551–559.
63. Liu J, Li L, Li S, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017;7(1):2824.
64. Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and car­diovascular risk: proposed pathways and review of ongoing outcome trials. Diabetes Vasc Dis Res. 2015;12(2):90–100.
65. Dawed AY, Zhou K, Pearson ER. Pharmacogenetics in type 2 diabetes: influence on response to oral hypoglycemic agents. Pharmgenom Pers Med. 2016;9:17–29.
66. Lyssenko V, Bianchi C, Del Prato S. Personalized therapy by phenotype and genotype. Diabetes Care. 2016;39(Suppl 2):S127–S136.
67. Abdul-Ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17(3):268–275.
68. Terra SG, Focht K, Davies M, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab. 2017;19(5):721–728.
69. Aronson R, Goldman A, Frias J, et al. Long-term efficacy and safety of ertugliflozin monotherapy in patients with inadequately controlled T2DM despite diet and exercise: the 52-week VERTIS MONO study. Poster presented at: ADA 2017; June 8; 2017; San Diego, CA.
70. Rosenstock J, Frias J, Pall D, et al. Effect of ertugliflozin on glycemic control, body weight, blood pressure (BP), and bone mineral density (BMD) in T2DM inadequately controlled with metformin monotherapy: VERTIS MET Trial. Poster presented at: ADA 2017; June 8; 2017; San Diego, CA.
71. Pratley R, Eldor R, Golm G, et al. Safety and efficacy of ertugliflozin plus sitagliptin versus either treatment alone in subjects with type 2 diabetes inadequately controlled with metformin: the VERTIS FACTORIAL trial. Poster presented at: EASD 2016 52nd European Association for the Study of Diabetes; September 15; 2016; Munich, Germany.
72. Pratley R, Raji A, Eldor R, et al. Safety and efficacy of ertugliflozin plus sitagliptin vs. either treatment alone after 52 weeks in subjects with T2DM inadequately controlled on metformin: VERTIS FACTORIAL trial extension. Oral presentation at: ADA 2017; June 9; 2017; San Diego, CA.
73. Lauring B, Miller SS, Krumins T, et al. Safety and efficacy of ertugliflozin in combination with sitagliptin in subjects with T2DM inadequately controlled on diet and exercise: the VERTIS SITA Trial. Poster presented at: ADA 2017; June 8; 2017; San Diego, CA.
74. Lauring B, Eldor R, Liu J, et al. Efficacy and safety of ertugliflozin in subjects with type 2 diabetes mellitus inadequately controlled on the dual combination of metformin and sitagliptin: the VERTIS SITA2 trial. Poster presented at: EASD 2016 52nd European Association for the Study of Diabetes; September 15; 2016; Munich, Germany.
75. Liu J, Eldor R, Dagogo-Jack S, et al. Safety and efficacy of ertugliflozin after 52 weeks in subjects with T2DM inadequately controlled on metformin and sitagliptin: results from the extension phase of the VERTIS SITA2 Trial. Oral presentation at: ADA 2017; June 9; 2017; San Diego, CA.
76. Hollander P, Liu J, Hill J, et al. Safety and efficacy of ertugliflozin compared to glimepiride in patients with type 2 diabetes inadequately controlled on metformin: the VERTIS SU trial. Poster presentation at: EASD 2017; Lisbon, Portugal.