The SGLT2 Inhibitor Empagliflozin for the Treatment of Type 2 Diabetes Mellitus: a Bench to Bedside Review

Diabetes Therapy

Volumn 5, Issue 1, 2014, Pages 43-63

  McGill, Janet B ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Add on therapy; Clinical trials; Empagliflozin; Fasting plasma glucose; Glucose excretion; Glycosylated hemoglobin (HbA1c); Sodium glucose co transporter 2 (SGLT2) inhibitor; Type 2 diabetes mellitus (T2DM)

Indexed keywords

DAPAGLIFLOZIN; DIGOXIN; EMPAGLIFLOZIN; HEMOGLOBIN A1C; INCRETIN; METFORMIN; PHLORETIN; PHLORIZIN; RAMIPRIL; SITAGLIPTIN; SULFONYLUREA; VERAPAMIL; WARFARIN;

CONSTIPATION; DEHYDRATION; DIARRHEA; DOSE RESPONSE; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; GENITAL TRACT INFECTION; GLOMERULUS FILTRATION RATE; GLUCOSE BLOOD LEVEL; GLUCOSE TOLERANCE TEST; GLUCOSE URINE LEVEL; GLUCOTOXICITY; GLYCEMIC CONTROL; HEADACHE; HUMAN; HYPERTENSION; HYPOGLYCEMIA; IC50; INSULIN SENSITIVITY; LIVER TOXICITY; NON INSULIN DEPENDENT DIABETES MELLITUS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POLLAKISURIA; PRIORITY JOURNAL; QT INTERVAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHINOPHARYNGITIS; THIRST; URINARY TRACT INFECTION;

EID: 84911440045     PISSN: 18696953     EISSN: 18696961     Source Type: Journal    
DOI: 10.1007/s13300-014-0063-1     Document Type: Review

References (49)

1. Cheng YJ, Imperatore G, Geiss LS, Wang J, Saydah SH, Cowie CC, et al. Secular changes in the age-specific prevalence of diabetes among US adults: 1988–2010. Diabetes Care. 2013;36(9):2690–6.
2. Sherwin R, Jastreboff AM. Year in diabetes 2012: the diabetes tsunami. J Clin Endocrinol Metab. 2012;97(12):4293–301.
3. American Diabetes Association. Economic costs of diabetes in the US in 2012. Diabetes Care. 2013;36(4):1033–46.
4. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19(2):327–36.
5. Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010;95(1):34–42.
6. Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21(1):31–8.
7. Kleinzeller A, Kolínská J, Benes I. Transport of monosaccharides in kidney-cortex cells. Biochem J. 1967;104(3):852–60.
8. Alvarado F, Crane RK. Phlorizin as a competitive inhibitor of the active transport of sugars by hamster small intestine, in vitro. Biochim Biophys Acta. 1962;56:170–2.
9. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987;79(5):1510–5.
10. Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32(4):515–31.
11. Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, 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):158–69.
12. Heise T, Seman L, Macha S, Jones P, Marquart A, Pinnetti S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther. 2013;4(2):331–45.
13. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, 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.
14. Thomas L, Grempler R, Eckhardt M, Himmelsbach F, Sauer A, Klein T, et al. Long-term treatment with empagliflozin, a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats. Diabetes Obes Metab. 2012;14(1):94–6.
15. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.
16. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509–14.
17. Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, et al. Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Drug Dev. 2013;2:152–61.
18. Sarashina A, Koiwai K, Seman LJ, Yamamura N, Taniguchi A, Negishi T, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT 2) inhibitor, in healthy Japanese subjects. Drug Metab Pharmacokinet. 2013;28(3):213–9.
19. Heise T, Seewaldt-Becker E, Macha S, Hantel S, Pinnetti S, Seman L, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(7):613–21.
20. Macha S, Mattheus M, Halabi A, Pinnetti S, Woerle HJ, Broedl UC. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab. 2014;16(3):215–22.
21. Macha S, Rose P, Mattheus M, Cinca R, Pinnetti S, Broedl UC, et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab. 2013 (Epub ahead of print).
22. Center for Drug Evaluation and Research. 2014. Summary review. Available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000SumR.pdf. Accessed February 21 2014.
23. Standards of medical care in diabetes-2014. Diabetes Care. 2014;37(Suppl 1):S14–80.
24. Macha S, Dieterich S, Mattheus M, Seman LJ, Broedl UC, Woerle HJ. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, and metformin following co-administration in healthy volunteers. Int J Clin Pharmacol Ther. 2013;51(2):132–40.
25. Brand T, Macha S, Mattheus M, Pinnetti S, Woerle HJ. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, coadministered with sitagliptin in healthy volunteers. Adv Ther. 2012;29(10):889–99.
26. Macha S, Sennewald R, Rose P, Schoene K, Pinnetti S, Woerle HJ, et al. Lack of clinically relevant drug–drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. Clin Ther. 2013;35(3):226–35.
27. Macha S, Rose P, Mattheus M, Pinnetti S, Woerle HJ. Lack of drug–drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and warfarin in healthy volunteers. Diabetes Obes Metab. 2013;15(4):316–23.
28. Macha S, Mattheus M, Pinnetti S, Woerle HJ, Broedl UC. Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers. Clin Drug Investig. 2013;33(5):351–7.
29. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010;70(1):16–23.
30. Ring A, Brand T, Macha S, Breithaupt-Groegler K, Simons G, Walter B, et al. The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study. Cardiovasc Diabetol. 2013;12(1):70.
31. Food and Drug Administration, US Department of Health and Human Services. Guidance for industry: E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Rockville, MD, 2005.
32. Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(8):721–8.
33. Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, Hach T, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013;15(12):1154–60.
34. 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 3 trial. Lancet Diabetes Endocrinol. 2013;1(3):208–19.
35. Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013;36(11):3396–404.
36. 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. 2013 (Epub ahead of print).
37. Boehringer Ingelheim. Phase III data show investigational compound empagliflozin reduced blood glucose in adults with type 2 diabetes treated with basal insulin. 2013. Available at https://www.boehringer-ingelheim.com/news/news_releases/press_releases/2013/22_june_2013_empagliflozin2.html. Accessed February 17 2013.
38. Häring H-U, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, et al. Empagliflozin as add-on to metformin for 24 weeks improves glycemic control in patients with type 2 diabetes (T2DM) [abstract 1092-P]. Diabetes. 2013;62(Suppl 1):A282.
39. Ridderstråle M, Svaerd R, Zeller C, Kim G, Woerle HJ, Broedl UC. Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control. Cardiovasc Diabetol. 2013;12:129.
40. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al. Empagliflozin in patients with type 2 diabetes mellitus (T2DM) and renal impairment (RI) [abstract 1104-P]. Diabetes. 2013;62(Suppl 1):A286.
41. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin improves blood pressure in patients with type 2 diabetes (T2DM) and hypertension [abstract 942]. Diabetologia. 2013;56(Suppl 1):S377.
42. Inzucchi SE, Zinman B, Lachin JM, Wanner C, Ferrari R, Bluhmki E, et al. Design of the empagliflozin cardiovascular outcome event trial in type 2 diabetes mellitus [abstract 944]. Diabetologia. 2013;56(Suppl 1):S378.
43. NCT01306214. Safety and efficacy of BI 10773 as add-on to insulin regimen in patients with type 2 diabetes mellitus. 2014. Available at http://clinicaltrials.gov/show/NCT01306214. Accessed March 15 2014.
44. NCT01984606. Efficacy and safety of empagliflozin versus sitagliptin in patients with type 2 diabetes. 2014. Available at http://clinicaltrials.gov/ct2/show/NCT01984606?term=NCT01984606&rank=1. Accessed March 15 2014.
45. NCT01719003. Safety and efficacy study of empagliflozin and metformin for 24 weeks in treatment-naive patients with type 2 diabetes. 2014. Available at http://clinicaltrials.gov/ct2/show/NCT01719003?term=NCT01719003&rank=1. Accessed March 15 2014.
46. NCT01778049. Linagliptin as add-on therapy to empagliflozin 10 mg or 25 mg with background metformin in patients with type 2 diabetes. 2014. Available at http://clinicaltrials.gov/ct2/show/NCT01778049?term=NCT01778049&rank=1. Accessed March 15 2014.
47. NCT01422876. Efficacy and safety of empagliflozin/linagliptin fixed-dose combination in treatment-naïve and metformin-treated type 2 diabetes patients. 2014. Available at http://clinicaltrials.gov/ct2/show/NCT01422876?term=NCT01422876&rank=1. Accessed March 15 2014.
48. NCT01734785. Safety and efficacy of the combination of empagliflozin and linagliptin compared to linagliptin alone over 24 weeks in patients with type 2 diabetes. 2014. Available at http://clinicaltrials.gov/ct2/show/NCT01734785?term=NCT01734785&rank=1. Accessed March 15 2014.
49. NCT01368081. Empagliflozin comprehensive add-on study in Japanese subjects with type 2 diabetes mellitus. 2014. Available at http://clinicaltrials.gov/ct2/show/NCT01368081?term=NCT01368081&rank=1. Accessed March 15 2014.