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

• Published in: Diabetes, obesity & metabolism Vol. 20; no. 5; pp. 1321 - 1326
• Main Authors: Polidori, David, Iijima, Hiroaki, Goda, Maki, Maruyama, Nobuko, Inagaki, Nobuya, Crawford, Peter A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2018; Wiley Subscription Services, Inc
• Subjects: 3-Hydroxybutyric Acid - blood; Acetoacetates - blood; Antidiabetics; Biological Variation, Population - drug effects; Blood Glucose - analysis; Brief Report; Brief Reports; canagliflozin; Canagliflozin - administration & dosage; Canagliflozin - adverse effects; Canagliflozin - therapeutic use; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetic Ketoacidosis - chemically induced; Diabetic Ketoacidosis - physiopathology; Diabetic Ketoacidosis - prevention & control; Dose-Response Relationship, Drug; Fatty acids; Fatty Acids, Nonesterified - blood; Female; Follow-Up Studies; Glucose; Glucose transporter; Humans; Hyperglycemia - prevention & control; Hypoglycemia - chemically induced; Hypoglycemia - prevention & control; Insulin; Japan; Ketogenesis; Ketone Bodies - blood; Ketones; Male; Metabolites; Reproducibility of Results; Severity of Illness Index; Sex Characteristics; SGLT2 inhibitor; Sodium; Sodium-Glucose Transporter 2 Inhibitors - administration & dosage; Sodium-Glucose Transporter 2 Inhibitors - adverse effects; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; type 2 diabetes; Up-Regulation - drug effects; Japan; SGLT2 inhibitor; type 2 diabetes; canagliflozin
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/dom.13224

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.