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Effect of Empagliflozin on Free Fatty Acids and Ketone Bodies in Japanese Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial

Advances in Therapy volume 36, pages 2769–2782 (2019)Cite this article

Abstract

Introduction

We report a randomized, double-blind, placebo-controlled, 4-week study to investigate the effect of empagliflozin on free fatty acids and blood ketone bodies in Japanese patients with type 2 diabetes mellitus.

Methods

Patients (baseline mean [standard deviation] glycated hemoglobin 7.91% [0.80%]; body mass index 24.3 [3.2] kg/m2) were randomized to empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19), or placebo (n = 21) daily as monotherapy for 28 days. Meal tolerance tests (MTTs; breakfast, lunch, dinner) were performed on day − 1, day 1 (first day of treatment), and day 28. On day 1 and day 28, study drug was administered 1 h before breakfast. Free fatty acids and blood ketone bodies were measured before and 1, 2, and 3 h after each MTT, and the next morning (overnight fast).

Results

Empagliflozin significantly reduced plasma glucose and insulin and reduced body weight vs. placebo. Empagliflozin increased free fatty acids and total ketones bodies at day 1 and day 28. At day 28, the adjusted mean (95% confidence interval) difference vs. placebo in the time-corrected area under curve over 24 h for total ketone bodies was 67.1 (12.3, 121.8) µmol·h/L·h (P = 0.017) with empagliflozin 10 mg and 178.1 (123.9, 232.2) µmol·h/L·h (P < 0.001) with empagliflozin 25 mg. Increases in ketones with empagliflozin vs. placebo peaked just before and declined after meals, with the highest peak before breakfast. Changes in total ketone bodies appeared to be associated with changes in plasma glucose, insulin, and free fatty acids.

Conclusion

Empagliflozin modestly increased free fatty acids and blood ketone bodies after a single dose and 28 days’ treatment. Increases in ketones appeared to be related to the duration of fasting and were most pronounced before breakfast. Increases in ketones appeared to be associated with changes in well-known metabolic determinants of ketone production.

Trial Registration

ClinicalTrials.gov identifier, NCT01947855.

Funding

Boehringer Ingelheim & Eli Lilly and Company.

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Acknowledgements

The authors would like to thank the patients who participated in the study. The authors thank Rabia Ahmad of inVentiv Health, New Jersey, USA; Kohei Inoue; and Lee Ganghyuck of Nippon Boehringer Ingelheim Co. Ltd for providing support with the statistical analyses. The authors thank Atsutaka Yasui of Nippon Boehringer Ingelheim Co. Ltd for support with this manuscript.

Funding

This study was funded by Boehringer Ingelheim & Eli Lilly and Company, who also provided financial support for the article processing charges. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Medical Writing and Editorial Assistance

Medical writing and editing assistance, supported financially by Boehringer Ingelheim, was provided by Elizabeth Ng of FleishmanHillard Fishburn, London, UK, and Radhika Bhatia, PhD, CMPP, of Elevate Scientific Solutions, Horsham, UK, during the preparation of this manuscript. The authors sent the manuscript for accuracy review to the sponsor (Boehringer Ingelheim) on 19 February 2018. The sponsor reviewed and eventually released the manuscript on 24 January 2019, without changes. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Rimei Nishimura has received research support from Japan Diabetes Foundation, Boehringer Ingelheim, Daiichi-Sankyo, and Astellas; has participated in speaker’s bureau/advisory panels for Novo Nordisk, Eli Lilly, Sanofi, Kissei, Astellas, Boehringer Ingelheim, Daiichi-Sankyo, Tanabe-Mitsubishi, Astra Zeneca, Kowa, Ono, Johnson & Johnson, Medtronic, Takeda, and Astellas; and served as a consultant for Boehringer Ingelheim and Eli Lilly. Yuko Tanaka is an employee of Boehringer Ingelheim. Afshin Salsali is an employee of Boehringer Ingelheim. Stefan Kaspers is an employee of Boehringer Ingelheim. Sven Kohler is an employee of Boehringer Ingelheim. Søren S. Lund is an employee of Boehringer Ingelheim and owns shares in Novo Nordisk A/S and shares in dynamically traded investment funds, which may own stocks from pharmaceutical companies. Kosuke Ishida is an employee of Rakuten Medical Japan, K.K. and was an employee of Boehringer Ingelheim at the time the analyses were conducted. Kazuki Koiwai is an employee of Amgen Astellas BioPharma K.K. and was an employee of Boehringer Ingelheim at the time the analyses were conducted.

Compliance with Ethics Guidelines

The clinical trial protocol was approved by the Institutional Review Board of Heishinkai Medical Group Incorporated OPHAC Hospital (Osaka, Japan), and complied with the Declaration of Helsinki in accordance with the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice. All patients provided written informed consent.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author information

Authors and Affiliations

  1. Jikei University School of Medicine, Tokyo, Japan

    Rimei Nishimura

  2. Nippon Boehringer Ingelheim Co. Ltd., Tokyo, Japan

    Yuko Tanaka, Kazuki Koiwai & Kosuke Ishida

  3. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA

    Afshin Salsali

  4. Boehringer Ingelheim International GmbH, Ingelheim, Germany

    Stefan Kaspers, Sven Kohler & Søren S. Lund

Authors
  1. Rimei Nishimura
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Corresponding author

Correspondence to Yuko Tanaka.

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Cite this article

Nishimura, R., Tanaka, Y., Koiwai, K. et al. Effect of Empagliflozin on Free Fatty Acids and Ketone Bodies in Japanese Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial. Adv Ther 36, 2769–2782 (2019). https://doi.org/10.1007/s12325-019-01045-x

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  • DOI: https://doi.org/10.1007/s12325-019-01045-x

Keywords

  • Diabetes
  • Empagliflozin
  • Sodium-glucose co-transporter-2 inhibitor
  • Type 2 diabetes mellitus