Advances in Therapy

, Volume 31, Issue 6, pp 621–638 | Cite as

Empagliflozin Monotherapy in Japanese Patients with Type 2 Diabetes Mellitus: a Randomized, 12-Week, Double-Blind, Placebo-Controlled, Phase II Trial

  • Takashi Kadowaki
  • Masakazu Haneda
  • Nobuya Inagaki
  • Yasuo Terauchi
  • Atsushi Taniguchi
  • Kazuki Koiwai
  • Henning Rattunde
  • Hans J. Woerle
  • Uli C. Broedl
Original Research

Abstract

Introduction

This study was designed to determine the efficacy and tolerability of empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus (T2DM).

Methods

Patients with glycosylated hemoglobin (HbA1c) ≥7.0–≤10% were randomized via an interactive web response system, and treated double-blind with empagliflozin 5, 10, 25, 50 mg, or placebo once daily for 12 weeks. The primary endpoint was change from baseline in HbA1c at week 12. Other endpoints included percentage of patients with HbA1c <7.0% and changes from baseline in fasting plasma glucose (FPG), body weight, and systolic blood pressure (SBP) at week 12.

Results

A total of 547 patients were randomized and treated with empagliflozin 5 mg (n = 110), 10 mg (n = 109), 25 mg (n = 109), 50 mg (n = 110), or placebo (n = 109) for 12 weeks. Adjusted mean [95% confidence interval (CI)] differences vs. placebo in changes from baseline in HbA1c were −0.72% (−0.87, −0.57) with empagliflozin 5 mg, −0.70% (−0.85, −0.55) with 10 mg, −0.95% (−1.10, −0.80) with 25 mg, and −0.91 (−1.06, −0.76) with 50 mg (all p < 0.001). More patients with HbA1c ≥7.0% at baseline reached HbA1c <7.0% with empagliflozin (19–33%) than placebo (3%). Compared with placebo, empagliflozin reduced FPG, body weight (p < 0.001 for all doses for both endpoints) and SBP (p = 0.001, p = 0.014 and p = 0.003 for empagliflozin 10, 25, and 50 mg, respectively). Adverse events were reported by 42% of patients receiving placebo and 33–38% of patients receiving empagliflozin. There were few reports of confirmed hypoglycemic adverse events or events consistent with urinary tract infection or genital infection in any treatment group.

Conclusions

Empagliflozin monotherapy for 12 weeks in Japanese patients with T2DM reduced HbA1c, FPG, body weight and SBP, and was well tolerated.

Keywords

Empagliflozin Glycemic control Japanese Monotherapy Sodium glucose cotransporter 2 (SGLT2) Type 2 diabetes mellitus Weight 

Supplementary material

12325_2014_126_MOESM1_ESM.pdf (209 kb)
Supplementary material 1 (PDF 209 kb)
12325_2014_126_MOESM2_ESM.docx (19 kb)
Supplementary material 2 (DOCX 20 kb)

References

  1. 1.
    Neville SE, Boye KS, Montgomery WS, Iwamoto K, Okamura M, Hayes RP. Diabetes in Japan: a review of disease burden and approaches to treatment. Diabetes Metab Res Rev. 2009;25:705–16.PubMedCrossRefGoogle Scholar
  2. 2.
    Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87:4–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047–53.PubMedCrossRefGoogle Scholar
  4. 4.
    Kawamori R. Diabetes trends in Japan. Diabetes Metab Res Rev. 2002;18(Suppl 3):S9–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Kobayashi M, Yamazaki K, Hirao K, et al. The status of diabetes control and antidiabetic drug therapy in Japan—a cross-sectional survey of 17,000 patients with diabetes mellitus (JDDM 1). Diabetes Res Clin Pract. 2006;73:198–204.PubMedCrossRefGoogle Scholar
  6. 6.
    Arai K, Matoba K, Hirao K, et al. Present status of sulfonylurea treatment for type 2 diabetes in Japan: second report of a cross-sectional survey of 15,652 patients. Endocr J. 2010;57:499–507.PubMedCrossRefGoogle Scholar
  7. 7.
    Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Japan Diabetes Society. Treatment guide for diabetes 2012–2013. http://www.jds.or.jp/modules/en/index.php?content_id=1. Accessed 17 Feb 2014.
  9. 9.
    Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27:136–42.PubMedCrossRefGoogle Scholar
  10. 10.
    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;14:5–14.PubMedCrossRefGoogle Scholar
  11. 11.
    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;14:83–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Sarashina A, Koiwai K, Seman LJ, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects. Drug Metab Pharmacokinet. 2013;28:213–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Seman L, Macha S, Nehmiz G, et al. Empagliflozin (BI 10773), a potent and selective SGLT-2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Drug Dev. 2013;2:152–61.CrossRefGoogle Scholar
  14. 14.
    Heise T, Seewaldt-Becker E, Macha S, 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;15:613–21.PubMedCrossRefGoogle Scholar
  15. 15.
    Kanada S, Koiwai K, Taniguchi A, Sarashina A, Seman L, Woerle HJ. Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks’ treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2013;4:613–7.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    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;15:721–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenstock J, Seman LJ, Jelaska A, 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;15:1154–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care. 2013;36:4015–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Häring HU, Merker L, Seewaldt-Becker E, 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;36:3396–404.PubMedCrossRefGoogle Scholar
  20. 20.
    Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014;37:1650–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Roden M, Weng J, Eilbracht J, 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;1:208–19.PubMedCrossRefGoogle Scholar
  22. 22.
    Rosenstock J, Jelaska A, Wang F, Kim G, Broedl U, Woerle H-J. Empagliflozin as add-on to basal insulin for 78 weeks improves glycemic control with weight loss in insulin-treated type 2 diabetes (T2DM). Diabetes. 2013;62 (Suppl 1):A285 (1102-P).Google Scholar
  23. 23.
    Kovacs CS, Seshiah V, Swallow R, 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.CrossRefGoogle Scholar
  24. 24.
    Matsuo S, Imai E, Horio M, et al. Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.PubMedCrossRefGoogle Scholar
  25. 25.
    Kawasaki R, Tanaka S, Tanaka S, et al. Incidence and progression of diabetic retinopathy in Japanese adults with type 2 diabetes: 8 year follow-up study of the Japan Diabetes Complications Study (JDCS). Diabetologia. 2011;54:2288–94.PubMedCrossRefGoogle Scholar
  26. 26.
    Hardy E, Salsali A, Hruba V, et al. Efficacy increases with increasing baseline HbA1c category with dapagliflozin therapy. Diabetes. 2012;61 (Suppl 1):A23 (82-OR).Google Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    Ferrannini 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 3 trial. Diabetes Care. 2010;33:2217–24.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36:2508–15.PubMedCrossRefGoogle Scholar
  30. 30.
    Stenlof K, Cefalu WT, Kim KA, 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.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011;13:928–38.PubMedCrossRefGoogle Scholar
  32. 32.
    Sone H, Tanaka S, Iimuro S, et al. Waist circumference as a cardiovascular and metabolic risk in Japanese patients with type 2 diabetes. Obesity (Silver Spring). 2009;17:585–92.CrossRefGoogle Scholar
  33. 33.
    Sone H, Tanaka S, Iimuro S, et al. Components of metabolic syndrome and their combinations as predictors of cardiovascular disease in Japanese patients with type 2 diabetes. Implications for improved definition. Analysis from Japan Diabetes Complications Study (JDCS). J Atheroscler Thromb. 2009;16:380–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Inagaki N, Kondo K, Yoshinari T, Maruyama N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab. 2013;15:1136–45.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Kaku K, Inoue S, Matsuoka O, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2013;15:432–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Healthcare 2014

Authors and Affiliations

  • Takashi Kadowaki
    • 2
  • Masakazu Haneda
    • 3
  • Nobuya Inagaki
    • 4
  • Yasuo Terauchi
    • 5
  • Atsushi Taniguchi
    • 1
  • Kazuki Koiwai
    • 1
  • Henning Rattunde
    • 6
  • Hans J. Woerle
    • 6
  • Uli C. Broedl
    • 6
  1. 1.Clinical Development and Medical Affairs TA-DiabetesNippon Boehringer Ingelheim Co., Ltd.TokyoJapan
  2. 2.Department of Diabetes and Metabolic Diseases, Graduate School of MedicineThe University of TokyoTokyoJapan
  3. 3.Department of MedicineAsahikawa Medical UniversityAsahikawaJapan
  4. 4.Department of Diabetes, Endocrinology and Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
  5. 5.Department of Endocrinology and Metabolism, Graduate School of MedicineYokohama City UniversityYokohamaJapan
  6. 6.Boehringer Ingelheim Pharma GmbH & Co. KGIngelheimGermany

Personalised recommendations