Clinical Therapeutics/Volume ], Number ], 2015

Empagliflozin as Add-on Therapy to Pioglitazone With or Without Metformin in Patients With Type 2 Diabetes Mellitus Christopher S. Kovacs, MD1; Veeraswamy Seshiah, MD, FRCP2; Ludwig Merker, MD3; Anita Vedel Christiansen, MSc, Pharm4; Flavien Roux, MSc5; Afshin Salsali, MD6; Gabriel Kim, MD6; Peter Stella, MD6; Hans-Juergen Woerle, MD6; and Uli C. Broedl, MD6 on behalf of the EMPA-REG EXTEND™ PIO investigators 1

Health Sciences Centre, Memorial University, St. John’s, Newfoundland, Canada; 2Diabetes Care and Research Institute, Chennai, India; 3Diabetes- und Nierenzentrum, Dormagen, Germany; 4Boehringer Ingelheim Danmark A/S Strødamvej 52, Copenhagen, Denmark; 5Boehringer Ingelheim France S.A.S, Reims, France; and 6Boehringer Ingelheim GmbH & Co. KG, Ingelheim, Germany

ABSTRACT Purpose: To investigate the long-term efficacy and safety of empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. Methods: Of 498 patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks in the EMPA-REG PIO™ study, 305 (61.2%) were treated in a double-blind extension trial for Z52 weeks (total duration Z76 weeks). Exploratory end points at week 76 included changes from baseline in glycosylated hemoglobin (HbA1c), weight, and blood pressure assessed using ANCOVA in patients who received Z1 dose of study drug and had a baseline HbA1c measurement in the initial study. Findings: Compared with placebo, adjusted mean (95% CI) changes from baseline in HbA1c level at week 76 were 0.59% (0.79% to 0.40%; P o 0.001) for empagliflozin 10 mg (6.5 [8.6 to 4.4] mmol/mol) and 0.69% (0.88% to 0.50%; P o 0.001) for empagliflozin 25 mg (7.5 [9.6 to 5.4] mmol/mol). Compared with placebo, adjusted mean (95% CI) changes from baseline in weight at week 76 were 2.0 kg (2.7 to 1.2 kg; P o 0.001) and 1.7 kg (2.4 1.0 kg; P o 0.001) for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, only empagliflozin 25 mg led to significant reductions in systolic blood pressure (adjusted mean [95% CI] change: 3.7 mmHg [6.1 to 1.3 mmHg]; P ¼ 0.003) and diastolic blood pressure (adjusted mean [95% CI] change: 2.2 mmHg [3.7 to 0.7 mmHg]; P ¼ 0.004). Sensitivity analyses were consistent with these results for HbA1c level, fasting plasma glucose

] 2015

concentration, and weight, but revealed no significant difference between empagliflozin and placebo in change from baseline in systolic or diastolic blood pressure at week 76. Confirmed hypoglycemic adverse events (glucose r3.9 mmol/L and/or requiring assistance) were reported in 4.2%, 1.8%, and 3.0% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively; 1 patient each taking placebo and empagliflozin 25 mg required assistance. Adverse events consistent with urinary tract infection were reported in 26.7%, 22.4%, and 22.0% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Adverse events consistent with genital infection were reported in 3.0%, 10.3%, and 4.2% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Implications: Empagliflozin 10 mg or 25 mg as add-on therapy to pioglitazone with or without metformin for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo in patients with type 2 diabetes. ClinicalTrials.gov identifier: NCT01210001. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: empagliflozin, glycemic control, metformin, pioglitazone, SGLT2, type 2 diabetes mellitus.

Accepted for publication May 27, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.511 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics

INTRODUCTION Type 2 diabetes mellitus (T2DM) is a chronic disease caused by insulin resistance and progressive β-cell failure.1 Because of the progressive nature of the disease, most patients with T2DM will ultimately require multiple antidiabetes agents to maintain glycemic control.2,3 The sodium glucose cotransporter 2 (SGLT2), located in the proximal tubule, is responsible for reabsorption of most glucose filtered daily by the kidney.4 Empagliflozin is a potent SGLT2 inhibitor5 that has recently been approved in the United States and Europe as a treatment for T2DM. By reducing renal glucose reabsorption, empagliflozin increases urinary glucose excretion and so reduces hyperglycemia.6 In Phase III studies in patients with T2DM, empagliflozin given as monotherapy or as add-on therapy to other antidiabetes therapies consistently reduced glycosylated hemoglobin (HbA1c), weight, and blood pressure (BP) with a low risk of hypoglycemia but an increased risk of events consistent with genital infection.7–12 Pioglitazone, a thiazolidinedione, is an antidiabetes drug that acts by improving insulin sensitivity and reducing hepatic glucose output.13 In addition to improving glycemic control with a low risk of hypoglycemia, pioglitazone has been associated with a reduction in systolic BP (SBP).14 However, pioglitazone is also associated with weight gain, fluid retention leading to edema, and an increased risk of heart failure and bone fractures.13,15 In a Phase III study (EMPA-REG PIO™), empagliflozin given as add-on therapy to pioglitazone with or without metformin for 24 weeks was well tolerated and reduced HbA1c, weight, and BP compared with placebo.7 Reported here are the results of the 52-week extension to this study, EMPA-REG EXTEND™ PIO, undertaken to evaluate the long-term safety, tolerability, and efficacy of empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with T2DM.

PATIENTS AND METHODS In the initial randomized, placebo-controlled, Phase III trial, patients with T2DM who were aged Z18 years (and aged r65 years in India) and had a body mass index (BMI) r45 kg/m2 were eligible for enrollment if they had an HbA1c level Z7% and r10% (Z53 and r86 mmol/mol) despite a diet and exercise regimen and were receiving pioglitazone monotherapy (Z30 mg/day,

2

maximum tolerated dose, or maximum dose according to the local label) or pioglitazone plus metformin (Z1500 mg/day, maximum tolerated dose, or maximum dose according to the local label) at unchanged doses for Z12 weeks before randomization.7 Exclusion criteria included uncontrolled hyperglycemia (plasma glucose 413.3 mmol/L after an overnight fast, confirmed by a second measurement), indication of liver disease, and severe renal impairment (estimated glomerular filtration rate [eGFR] o30 mL/min/1.73 m2).7 Patients were randomized (1:1:1) to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks using a computer-generated random sequence and an interactive voice and web response system. Patients who completed 24 weeks of treatment and who still did not contravene the exclusion criteria for the initial study could elect to continue double-blind treatment for Z52 weeks in an extension study. Patients were required to reconfirm their consent before enrolling in the extension study. Patients continued to receive the treatment they received in the initial 24-week study (Figure 1). Patients who had received antidiabetes rescue medication during the initial 24-week study and were still receiving it at enrollment into the extension study continued to take it. Patients remained in the extension study until the last patient entered had been treated for 76 weeks. Rescue medication could be initiated during the extension study if a patient had a glucose level 410.0 mmol/L after an overnight fast or HbA1c 48% (64 mmol/mol). The choice and dosage of rescue medication were at the discretion of the investigator, according to local prescribing information, but sulfonylureas were the preferred rescue medication for patients taking pioglitazone only, and insulin was the preferred rescue medication for patients taking pioglitazone plus metformin. In cases of hypoglycemia, dose reduction or discontinuation of use of the rescue medication was to be initiated. When hyperglycemia or hypoglycemia could not be controlled, the patient discontinued participation in the trial. The initial study and the extension study were approved by the institutional review boards and independent ethics committees and competent authorities of the participating centers and complied with the Declaration of Helsinki in accordance with the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice.

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C.S. Kovacs et al.

499 Patients randomized

1 Patient not treated

165 Assigned to placebo

165 Assigned to empagliflozin 10 mg

168 Assigned to empagliflozin 25 mg

147 Completed 24-week treatment period in initial study

154 Completed 24-week treatment period in initial study

156 Completed 24-week treatment period in initial study

93 Entered extension study

106 Entered extension study

106 Entered extension study

15 Prematurely discontinued: 13 Withdrew consent 2 Lost to follow-up

78 Completed extension study

13 Prematurely discontinued: 8 Withdrew consent 3 Lost to follow-up 2 Deaths

93 Completed extension study

12 Prematurely discontinued: 7 Withdrew consent 4 Lost to follow-up 1 Death

94 Completed extension study

Figure 1. Study flow. The full analysis set (FAS) was defined as patients who received Z1 dose of study drug and had a baseline HbA1c measurement in the initial study (n ¼ 165 in the placebo group, n ¼ 165 in the empagliflozin 10 mg group, n ¼ 168 in the empagliflozin 25 mg group).

End Points No primary end point was defined for this study because the primary efficacy end point, change from baseline in HbA1c level, was analyzed at week 24 in the initial trial.7 Exploratory efficacy end points at week 76 in the extension study were change from baseline in HbA1c, fasting plasma glucose (FPG), weight, SBP, and diastolic BP (DBP); the use of rescue therapy; and the proportion of patients who were treated in the extension study and had HbA1c levels Z7% (53 mmol/mol) at baseline who achieved HbA1c levels o7% (53 mmol/mol) at week 76. These end points were also analyzed at week 52. Baseline was defined as baseline in the initial study (ie, before administration of study drug). Safety profiles were assessed via reporting of adverse events (AEs; preferred terms coded according to the Medical Dictionary for Drug Regulatory Activities version 16.0). Confirmed hypoglycemic AEs were defined as hypoglycemic AEs with plasma glucose levels r3.9 mmol/L and/or requiring assistance. Events consistent with urinary tract infection, events consistent with genital infection, and events

] 2015

consistent with volume depletion were identified using prospectively defined search categories based on 77, 89, and 8 preferred terms, respectively. Changes from baseline in clinical laboratory values were assessed.

Statistical Analyses No formal sample size calculation was undertaken for the extension study because it was open to all patients who completed 24 weeks of treatment in the initial study and who did not contravene the exclusion criteria. Treatment differences versus placebo were assessed using an analysis of covariance (ANCOVA) model in the full analysis set (FAS) with baseline HbA1c level and the baseline value of the end point in question as linear covariates and baseline eGFR, baseline background medication (pioglitazone alone or pioglitazone plus metformin), and treatment as fixed effects. The FAS comprised patients who received Z1 dose of study drug and had a baseline HbA1c measurement in the initial study. Values observed after initiation of antidiabetes rescue therapy were set to missing. A last observation carried forward (LOCF) approach was used to impute missing data.

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Clinical Therapeutics

Table I. Demographics and baseline characteristics. Data are given as mean (SD), unless otherwise indicated, in the full analysis set (patients who received Z1 dose of study drug and had a baseline HbA1c measurement in the initial study). Placebo (n ¼ 165) Sex Male, no. (%) Age, y Race, no. (%) Asian White Black/African American American Indian/Alaska Native Time since diagnosis of T2DM, Remove indentation before no. (%) r1 year 41 to 5 years 45 to 10 years 410 years Weight, kg Body mass index, kg/m2 HbA1c, % HbA1c, mmol/mol FPG, mmol/L SBP, mmHg DBP, mmHg eGFR, mL/min/1.73 m2 (MDRD)

Empagliflozin 10 mg Empagliflozin 25 mg Total (n ¼ 165) (n ¼ 168) (N ¼ 498)

73 (44.2) 54.6 (10.5)

83 (50.3) 54.7 (9.9)

103 60 1 1

(62.4) (36.4) (0.6) (0.6)

91 69 4 1

(55.2) (41.8) (2.4) (0.6)

19 78 42 26 78.1 29.3 8.16 66 8.4 125.7 76.3 85.5

(11.5) (47.3) (25.5) (15.8) (20.1) (5.4) (0.92) (10) (2.2) (12.1) (8.7) (20.1)

29 60 45 31 78.0 29.2 8.07 65 8.4 126.5 77.2 84.3

(17.6) (36.4) (27.3) (18.8) (19.2) (5.6) (0.89) (9.7) (2.1) (13.7) (8.7) (20.9)

85 (50.6) 54.2 (8.9) 94 (56.0) 68 (40.5) 6 (3.6) 0

17 76 48 27 78.9 29.1 8.06 65 8.4 125.9 77.2 87.4

(10.1) (45.2) (28.6) (16.1) (19.9) (5.5) (0.82) (9.0) (2.1) (13.9) (8.0) (24.4)

241 (48.4) 54.5 (9.8) 288 197 11 2

(57.8) (39.6) (2.2) (0.4)

65 214 135 84 78.3 29.2 8.09 65 8.4 126.1 76.9 85.7

(13.1) (43.0) (27.1) (16.9) (19.7) (5.5) (0.88) (9.6) (2.1) (13.2) (8.4) (21.9)

DBP ¼ diastolic blood pressure; eGFR ¼ estimated glomerular filtration rate; FPG ¼ fasting plasma glucose; HbA1c ¼ glycosylated hemoglobin; MDRD ¼ Modification of Diet in Renal Disease; SBP ¼ systolic blood pressure; T2DM ¼ type 2 diabetes mellitus.

The LOCF method was planned because it was assumed that the efficacy of empagliflozin would be lower in patients with missing data at week 76 than in patients with available data; thus, LOCF was considered to provide an acceptably conservative approach. Analysis based on observed cases was planned as a secondary supportive analysis (sensitivity analysis) to illustrate the robustness of the conclusions. Sensitivity analyses were undertaken for changes over time in HbA1c level, FPG, weight, and BP. A restricted maximum likelihood-based mixed model repeated measures (MMRM) approach was used in the FAS and in FAS completers using observed cases. The FAS completers set comprised patients from the FAS who completed a

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mean (SD) of 76 (1) weeks of treatment and had an HbA1c measurement at the week 76 visit. The MMRM analyses included baseline HbA1c level and the baseline value of the end point in question as linear covariates and baseline eGFR, baseline background medication (pioglitazone alone or pioglitazone plus metformin), treatment, visit, and visit by treatment interaction as fixed effects. The use of rescue therapy was assessed using logistic regression in the FAS, including treatment as a factor and baseline HbA1c level as a covariate. The percentage of patients reaching an HbA1c level o7% at week 76 was assessed in patients from the FAS with a baseline HbA1c level Z7% who were treated in the extension trial using a logistic regression model

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C.S. Kovacs et al.

Table II. Summary of efficacy results at week 76. Data are adjusted mean (standard error) based on ANCOVA in the full analysis set (last observation carried forward), unless otherwise indicated. Result

Placebo (n ¼ 165)

8.08 (0.07) HbA1c at week 76, % 65 (0.8) HbA1c at week 76, mmol/mol Change from baseline, % 0.01 (0.07) Change from baseline, mmol/mol 0.2 (0.8) Difference vs placebo, % (95% CI) Difference vs placebo, mmol/mol (95% CI) P 8 (8.9) Patients with HbA1c Z7% (53 mmol/mol) at baseline who achieved HbA1c o7% (53 mmol/mol) at week 76a, no. (%) Odds ratio vs placebo (95% CI) P FPG at week 76, mmol/L 9.0 (0.2) Change from baseline 0.5 (0.2) Difference vs placebo (95% CI) P Weight at week 76, kg 78.8 (0.3) Change from baseline 0.5 (0.3) Difference vs placebo (95% CI) P SBP at week 76, mmHg 126.4 (0.9) Change from baseline 0.3 (0.9) Difference vs placebo (95% CI) P DBP at week 76, mmHg 77.1 (0.5) Change from baseline 0.2 (0.5) Difference vs placebo (95% CI) P 56 (33.9) Patients receiving rescue therapy up to week 76,b no. (%) Odds ratio vs placebo (95% CI) P

Empagliflozin 10 mg (n ¼ 165)

Empagliflozin 25 mg (n ¼ 168)

7.49 (0.07) 58 (0.8) 0.61 (0.07) 6.7 (0.8) 0.59 (0.79 to 0.40) 6.5 (8.6 to 4.4)

7.39 (0.07) 57 (0.8) 0.70 (0.07) 7.7 (0.8) 0.69 (0.88 to 0.50) 7.5 (9.6 to 5.4)

o0.001 24 (25.3)

o0.001 38 (38.0)

3.50 (1.44 to 8.50) 0.006 7.7 (0.2) 0.8 (0.2) 1.3 (1.7 to 0.8) o0.001 76.9 (0.3) 1.5 (0.3) 2.0 (2.7 to 1.2) o0.001 124.3 (0.9) 1.7 (0.9) 2.0 (4.5 to 0.4) 0.099 75.6 (0.5) 1.3 (0.5) 1.5 (3.0 to 0.0) 0.051 24 (14.5)

6.09 (2.58 to 14.35) o0.001 7.4 (0.2) 1.0 (0.2) 1.5 (2.0 to 1.1) o0.001 77.1 (0.3) 1.2 (0.3) 1.7 (2.4 to 1.0) o0.001 122.7 (0.9) 3.4 (0.9) 3.7 (6.1 to 1.3) 0.003 74.8 (0.5) 2.0 (0.5) 2.2 (3.7 to 0.7) 0.004 24 (14.3)

0.32 (0.18 to 0.56) o0.001

0.32 (0.19 to 0.57) o0.001

DBP ¼ diastolic blood pressure; FPG ¼ fasting plasma glucose; HbA1c ¼ glycosylated hemoglobin; SBP ¼ systolic blood pressure. a Logistic regression analysis in patients in the full analysis set who were treated in the extension study (n ¼ 90 for placebo; n ¼ 95 for empagliflozin 10 mg; n ¼ 100 for empagliflozin 25 mg); noncompleters were considered failures. b Logistic analysis in the full analysis set.

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Clinical Therapeutics

Placebo (n = 165) Empagliflozin 10 mg (n = 165) Empagliflozin 25 mg (n = 168)

8.16

8.06

0.0 –0.01 –0.2 –0.4 –0.6 –0.61 a

–0.8

64

76

Adjusted Mean (95% CI) Difference vs Placebo in Change From Baseline at Week 76

7.6 7.4 7.2 Empagliflozin 10 mg

Placebo

Empagliflozin 25 mg

160 163 163

158 158 162

146 155 159

140 155 155

131 147 156

58 91 97

50 85 91

41 77 84

31 71 78

Baseline Mean 8.4

1.0

b 25.3

15 8.9

5 0

8.4

8.4

0.5 0.5 0.0

Placebo (n = 165) Empagliflozin 10 mg (n = 165)

–0.5

Empagliflozin 25 mg (n = 168)

–1.0

–0.8 a

–1.0 a

–1.5

0

6

12

18

24

30

Week 41

52

64

1.0 Adjusted Mean (SE) Change From Baseline in FPG (mmol/L)

52

7.8

a 38.0

20

10

Week 41

24

Number of patients analyzed

35

25

18

8.0

Adjusted Mean (SE) Change From Baseline in FPG (mmol/L)

Patients With HbA1c ≥7% at Baseline Who Had HbA1c

Empagliflozin as Add-on Therapy to Pioglitazone With or Without Metformin in Patients With Type 2 Diabetes Mellitus.

To investigate the long-term efficacy and safety of empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 ...
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