The elevation of ketones is clinically concerned in the use of SGLT2 inhibitor (SGLT2i), however little is known about the association between that elevation and subsequent clinical process. We aimed to clarify the association of the initial beta-hydroxybutyrate (BHB) elevation via the SGLT2i, tofogliflozin with subsequent weight loss in type 2 diabetes participants. Analyzed were 774 type 2 diabetes participants who received tofogliflozin in two phase 3 studies. The participants were divided into four groups according to the quartiles for their change in BHB after 4 weeks of tofogliflozin therapy. The adjusted assessments of variables were analyzed using an analysis of covariance model with the quartiles, their baseline values, age, sex, and eGFR as covariates. BHB levels significantly increased (mean: +107.1 µmol/L) from baseline to week 4. Those changes in the first (Q1), second (Q2), third (Q3), and fourth (Q4) quartiles, respectively, were -33.7, +31.4, +98.0, and +331.1 µmol/L. Glycemic control at baseline was poorer, while CPI was lower within the higher quartiles. The difference of BHB changes among the quartiles was maintained during tofogliflozin therapy. At week 52, the increase of BHB levels from baseline was significant (+142.7 µmol/L) in Q4, but not changed in Q1. The weight loss at week 52 in Q4 (least square mean: -3.6 kg) was greater than in Q1 (-2.4 kg) although the improvement of hyperglycemia was identical. Furthermore, the reduction in waist circumference and increase in adiponectin were greater in Q4. And the increase in fasting free fatty acid was also greater in Q4, but not changed in Q1. The distinct response of BHB elevation was observed early after the SGLT2i, tofogliflozin therapy. The higher initial BHB elevation resulted in the greater reduction in body weight, especially fat mass via lipolysis. The progressive weight loss might be clinically associated with one of the signs of the higher ketone elevation.


Y. Sato: None. K. Nunoi: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd..

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