1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2015 年 2 月 5 日 8:30-8:55 ８階 医局 Lewin A, DeFronzo RA, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC. Initial Combination of Empagliflozin and Linagliptin in Subjects With Type 2 Diabetes. Diabetes Care. 2015 Jan 29. pii: dc142365. DOI: 10.2337/dc14-2365 DeFronzo RA, Lewin A, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC. Combination of Empagliflozin and Linagliptin as Second-Line Therapy in Subjects With Type 2 Diabetes Inadequately Controlled on Metformin. Diabetes Care. 2015 Jan 12. pii: dc142364. DOI: 10.2337/dc14-2364

2. 1 National Research Institute, Los Angeles, CA 2 University of Texas Health Sciences, San Antonio, TX 3 Boehringer Ingelheim Ltd., Bracknell, Berkshire, U.K. 4 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 5 Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

3. OBJECTIVE To evaluate the efficacy and safety of empagliflozin/linagliptin in subjects with type 2 diabetes.

4. RESEARCH DESIGN AND METHODS Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 135), empagliflozin 10 mg (n = 134), or linagliptin 5 mg (n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.

7. Treatment and Interventions After a 2-week placebo run-in period, subjects were randomized (1:1:1:1:1) to receive empagliflozin 25 mg/linagliptin 5 mg as a fixed-dose combination (FDC) tablet, empagliflozin 10 mg/linagliptin 5 mg as an FDC tablet, empagliflozin 25 mg, empagliflozin 10 mg, or linagliptin 5 mg for 52 weeks. All study drugs were taken once daily in the morning. Study visits were scheduled at screening, at the start of the placebo run-in, at baseline, and at weeks 6, 12, 18, 24, 32, 40, and 52 of treatment. A follow-up visit occurred 4 weeks after the last dose of study drug for subjects who completed the treatment period or within 7 days after the last administration of study drug for those who discontinued treatment before week 52. Rescue medication was to be initiated if a subject had blood glucose >240 mg/dL after an overnight fast between weeks 1 and 12, blood glucose >200 mg/dL after an overnight fast between weeks 12 and 24, or blood glucose >180 mg/dL or HbA1c >8% (>63.9 mmol/mol) after an overnight fast between weeks 24 and 52. The initiation, choice, and dosage of rescue medication were at the discretion of the investigator, according to local prescribing information, but the use of DPP- 4 inhibitors, GLP-1 analogs, and SGLT2 inhibitors was not permitted. In cases of hypoglycemia, rescue medication was to be reduced in dose or discontinued. If hyper- or hypoglycemia could not be controlled, the subject was discontinued from the trial.

8. Figure 1—Efficacy parameters at week 24. A: Change from baseline in HbA1c at week 24 (ANCOVA using LOCF). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio. A last-observation carried-forward (LOCF)

9. Figure 1—Efficacy parameters at week 24. B: Change from baseline in HbA1c at week 24 in subjects with baseline HbA1c ≥8.5% (≥69 mmol/mol) (ANCOVA, LOCF). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

10. Figure 1—Efficacy parameters at week 24. C: Subjects with HbA1c ≥ 7% (≥ 53 mmol/mol) at baseline who reached HbA1c <7% (<53 mmol/mol) at week 24 (logistic regression). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

11. Figure 1—Efficacy parameters at week 24. D: Change from baseline in FPG at week 24 (ANCOVA, LOCF). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

12. Figure 1—Efficacy parameters at week 24. E: Change from baseline in body weight at week 24 (ANCOVA, LOCF). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

13. Figure 2—Changes in efficacy parameters at week 52. A: HbA1c over 52 weeks (MMRM analysis using observed cases). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio. restricted maximum likelihood (REML)–based mixed model repeated measures (MMRM)

14. Figure 2—Changes in efficacy parameters at week 52. B: Change from baseline in HbA1c at week 52 (ANCOVA using LOCF). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

15. Figure 2—Changes in efficacy parameters at week 52. C: Subjects with HbA1c≥7% (≥53 mmol/mol) who reached HbA1c<7% (<53 mmol/mol) at week 52 (logistic regression). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

16. Figure 2—Changes in efficacy parameters at week 52. D: Change from baseline in body weight at week 52 (ANCOVA, LOCF). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

17. Figure 2—Changes in efficacy parameters at week 52. E: Change from baseline in SBP at week 52 (ANCOVA, LOCF). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

18. Figure 2—Changes in efficacy parameters at week 52 F: Change from baseline in DBP at week 52 (ANCOVA, LOCF). Data are adjusted means ± SE or n (%) in the full analysis set. OR, odds ratio.

22. RESULTS Mean HbA1c at baseline was 7.99–8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg were 21.08 (0.06)% (211.8 [0.7] mmol/mol), 21.24 (0.06)% (213.6 [0.7] mmol/mol), 20.95 (0.06)% (210.4 [0.7] mmol/mol), 20.83 (0.06)% (29.1 [0.7] mmol/mol), and 20.67 (0.06)% (27.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/linagliptin 5 mg compared with linagliptin 5 mg (P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/linagliptin 5 mg compared with the individual components (P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ‡7% (‡53 mmol/mol) reached HbA1c <7% with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg, respectively. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across groups (68.9–81.5%), with no confirmed hypoglycemic AEs.

23. CONCLUSIONS Reductions from baseline in HbA1c with empagliflozin/linagliptin were significantly different versus linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/linagliptin was well tolerated.

24. Message SGLT-2 阻害薬は２社の販売になっているが、 DPP4 阻害薬との合剤が課題となっている。 Empagliflozin は日本では最後に発売であるが、 １年後には合剤として市場に出してゆくことで活 路を模索してゆくのかもしれない。 Linagliptin と empagliflozin でメトホルミンな しの治療で併用効果を示している。

26. 1 University of Texas Health Science Center, San Antonio, TX 2 National Research Institute, Los Angeles, CA 3 Boehringer Ingelheim, Ltd., Bracknel l, Berkshire, U.K. 4 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 5 Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

27. OBJECTIVE To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin.

28. RESEARCH DESIGN AND METHODS Subjects were randomized to a combination of empagliflozin 25 mg/linagliptin 5mg (n = 137), empagliflozin 10 mg/linagliptin 5mg (n = 136), empagliflozin 25 mg (n = 141), empagliflozin 10 mg (n = 140), or linagliptin 5 mg (n = 132) as add-on to metformin for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.

31. Treatment and Interventions After a 2-week placebo run-in period, subjects were randomized (1:1:1:1:1) to receive empagliflozin 25 mg/linagliptin 5 mg as a fixed-dose combination (FDC) tablet, empagliflozin 10 mg/linagliptin 5 mg as an FDC tablet, empagliflozin 25 mg, empagliflozin 10 mg, or linagliptin 5 mg for 52 weeks. All study drugs were taken once daily in the morning. Study visits were scheduled at screening, at the start of the placebo run-in, at baseline, and at weeks 6, 12, 18, 24, 32, 40, and 52 of treatment. A follow-up visit occurred 4 weeks after the last dose of study drug for subjects who completed the treatment period or within 7 days after the last administration of study drug for those who discontinued treatment before week 52. Rescue medication was to be initiated if a subject had blood glucose >240 mg/dL after an overnight fast between weeks 1 and 12, blood glucose >200 mg/dL after an overnight fast between weeks 12 and 24, or blood glucose >180 mg/dL or HbA1c >8% (>63.9 mmol/mol) after an overnight fast between weeks 24 and 52. The initiation, choice, and dosage of rescue medication were at the discretion of the investigator, according to local prescribing information, but the use of DPP- 4 inhibitors, GLP-1 analogs, and SGLT2 inhibitors was not permitted. In cases of hypoglycemia, rescue medication was to be reduced in dose or discontinued. If hyper- or hypoglycemia could not be controlled, the subject was discontinued from the trial.

32. Figure 1—Efficacy parameters at week 24. A: Change from baseline in HbA1c at week 24 (ANCOVA in FAS using LOCF imputation). Data are adjusted mean ± SE or n (%). OR, odds ratio. Efficacy analyseswere performed on the full analysis set (FAS), which included subjects treated with one ormore doses of study drug who had a baseline and an on-treatment HbA1c measurement. Safety was assessed in the treated set (subjects treated with one or more doses of study drug).

33. Figure 1—Efficacy parameters at week 24. B: Change from baseline in HbA1c at week 24 in subjects with baseline HbA1c ≥8.5% (ANCOVA in FAS [LOCF]). Data are adjusted mean ± SE or n (%). OR, odds ratio.

34. Figure 1—Efficacy parameters at week 24. C: Subjects with HbA1c ≥7% (≥53 mmol/mol) at baseline who reached HbA1c <7% (<53 mmol/mol) at week 24 (logistic regression analysis). Data are adjusted mean ± SE or n (%). OR, odds ratio.

35. Figure 1—Efficacy parameters at week 24 D: Change from baseline in FPG at week 24 (ANCOVA in FAS [LOCF]). Data are adjusted mean ± SE or n (%). OR, odds ratio.

36. Figure 1—Efficacy parameters at week 24. E: Change from baseline in body weight at week 24 (ANCOVA in FAS [LOCF]). Data are adjusted mean ± SE or n (%). OR, odds ratio.

37. Figure 2—Efficacy parameters at week 52. A: HbA1c over 52 weeks (MMRM analysis in the FAS using observed cases). restricted maximum likelihood (REML)–based mixed model repeated measures (MMRM)

38. Figure 2—Efficacy parameters at week 52. B: Subjects with HbA1c ≥7% (≥53 mmol/mol) who reached HbA1c <7% (<53mmol/mol) at week 52 (logistic regression, FAS).

39. Figure 2—Efficacy parameters at week 52. C: Change from baseline in body weight at week 52 (ANCOVA in FAS [LOCF]). OR, odds ratio.

40. Figure 3 Blood pressure at week 52. A: Change from baseline in SBP at week 52 (ANCOVA in FAS using LOCF imputation). Data are adjusted mean ± SE.

41. Figure 3 Blood pressure at week 52. B: Change from baseline in DBP at week 52 (ANCOVA in FAS [LOCF]). Data are adjusted mean ± SE.

45. RESULTS At week 24, reductions in HbA1c (mean baseline 7.90–8.02% [62.8–64.1 mmol/mol]) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin; adjusted mean (SE) changes from baseline were － 1.19% (0.06) ( － 13.1 mmol/mol [0.7]) with empagliflozin 25 mg/linagliptin 5 mg, － 1.08% (0.06) ( － 11.8 mmol/mol [0.7]) with empagliflozin 10 mg/linagliptin 5 mg, － 0.62% (0.06) ( － 6.8 mmol/mol [0.7]) with empagliflozin 25 mg, － 0.66% (0.06) ( － 7.2 mmol/mol [0.7]) with empagliflozin 10 mg, and － 0.70% (0.06) ( － 7.6 mmol/mol [0.7]) with linagliptin 5 mg (P < 0.001 for all comparisons). In these groups, respectively, 61.8, 57.8, 32.6, 28.0, and 36.1% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) had HbA1c <7% (<53 mmol/mol) at week 24. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across treatment arms (68.6–73.0%), with no hypoglycemic AEs requiring assistance.

46. CONCLUSIONS Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated.

47. Message Linagliptin と empagliflozin でメトホルミンに 追加することで併用効果を示している。