Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin

David Polidori, Hiroaki Iijima, Maki Goda, Nobuko Maruyama, Nobuya Inagaki, Peter A Crawford, David Polidori, Hiroaki Iijima, Maki Goda, Nobuko Maruyama, Nobuya Inagaki, Peter A Crawford

Abstract

Sodium glucose co-transporter 2 (SGLT2) inhibitors have been associated with increased serum ketone body levels in patients with type 2 diabetes mellitus (T2DM). In the present analysis we evaluated serum ketone body levels and variability in 1278 Japanese patients with T2DM treated with canagliflozin 100 or 200 mg. Similar mean increases in ketone body concentrations of ~2-fold were seen with both canagliflozin doses. The median (interquartile range) percent change from baseline was 62% (0;180) for acetoacetate and 78% (2;236) for β-hydroxybutyrate. Approximately two-thirds of the variability in each ketone measure was attributed to intra-subject variability. Intra-subject variability was higher for serum ketones than other metabolites. Patients in the lowest response tertile exhibited no increase in ketones. Those in the highest response tertile tended to be male and have higher fasting plasma glucose levels, lower insulin levels, and longer T2DM duration at baseline. Moreover, changes in serum ketones were not fully explained by changes in plasma fatty acids, suggesting downstream effects of SGLT2 inhibition on hepatic metabolism that favour ketogenesis. In summary, increases in serum ketone bodies with canagliflozin were greater and more variable than changes in other metabolic measures in Japanese patients with T2DM.

Keywords: SGLT2 inhibitor; canagliflozin; type 2 diabetes.

Conflict of interest statement

D.P. is a full‐time employee of Janssen Research & Development, LLC. H.I., M.G. and N.M. are full‐time employees of Mitsubishi Tanabe Pharma Corporation. N.I. has received consulting fees and/or speakers bureau fees from Astellas Pharma Inc., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd, Sanofi K.K. and Takeda Pharmaceutical Co., Ltd; has received research support from AstraZeneca K.K., Daiichi Sankyo Co., Ltd, Eli Lilly Japan K.K., MSD K.K. and Mitsubishi Tanabe Pharma Corporation; and received scholarship grants from Astellas Pharma Inc., AstraZeneca K.K., Daiichi Sankyo Co., Ltd, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd, Kyowa Hakko Kirin Co., Ltd, MSD K.K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd, Novartis Pharma K.K., Novo Nordisk Pharma Ltd, Ono Pharmaceutical Co., Ltd, Pfizer Japan Inc., Sanwa Kagaku Kenkyusho Co., Ltd, Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd, Takeda Pharmaceutical Co., Ltd, and Taisho Toyama Pharmaceutical Co., Ltd. P.A.C. has no relevant disclosures.

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

Figures

Figure 1
Figure 1
A, Serum ketone body concentrations (top) and change from baseline values (bottom) and B, change from baseline for ketone bodies, divided into tertiles of response. Values shown are median (interquartile range). AcAc, acetoacetate; BHB, β‐hydroxybutyrate

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