Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial

Abstract

Aims: This phase 2, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin.

Materials and methods: Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%-10.0%, entered a 2-week, open-label, placebo run-in period, followed by a 4-week, double-blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment.

Results: PD: Empagliflozin resulted in a dose-dependent significant increase in 24-hour UGE compared with placebo (UGE placebo-corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose-dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose-dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported.

Conclusions: Based on this short-duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non-Japanese participants.

Keywords: SGLT2 inhibitor; empagliflozin; pharmacodynamics; pharmacokinetics; randomized trial; type 1 diabetes.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Change in UGE and efficacy parameters. A, Mean UGE (±SE) over 28 days. B, Adjusted mean (±SE) change from baseline in HbA1c on Day 28. C, Adjusted mean (±SE) change from baseline in FPG on Day 28. D, Adjusted mean (±SE) change from baseline in recorded insulin dose within Week 4. E, Adjusted mean (±SE) change from baseline in body weight on Day 28. Abbreviations: CI, confidence interval; Empa, empagliflozin; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; h, hours; SE, standard error; UGE, urinary glucose excretion. a % of adjusted mean change from baseline

Figure 2

Change in glucose exposure, glucose variability and time spent with glucose in target range. A, adjusted mean (±SE) change from baseline in MDAUC of glucose within Week 4. B, Adjusted mean (±SE) change from baseline in the IQR of glucose within Week 4. C, Ambulatory glucose profiles (mg/dL) within Week 4. D, Percentage of time with glucose ≤70 mg/dL, >70 to ≤180 mg/dL, and >180 mg/dL at baseline and at Week 4. Abbreviations: P10, 10th percentile; P25, 25th percentile; P75, 75th percentile; P90, 90th percentile

Figure 3

Serum β‐hydroxybutyrate profile. A, Mean (±SD) change from baseline in AUC0‐24h for serum BHB on Day 7. B, Boxplots for serum β‐hydroxybutyrate at baseline and on Day 28 (descriptive statistics). Abbreviations: AUC, area under the concentration‐time curve; BHB, β‐hydroxybutyrate; D, Day; Empa, empagliflozin; P10, 10th percentile; P25, 25th percentile; P75, 75th percentile; P90, 90th percentile; SD, standard deviation