SGLT2 inhibitors (SGLT2is) reduce hyperglycemia and insulin levels via increased urinary glucose excretion (UGE). Reduced insulin triggers decreased tissue glucose disposal and increased lipid use followed by ketone production. The metabolic response to starvation, the production of beta-hydroxybutyrate (BHB), was reported to be influenced by sex and menopausal status in healthy persons. However, little is known of sex- and menopausal status-specific effects of SGLT2is on BHB. This study investigated the effect of the SGLT2i tofogliflozin on BHB according to sex and menopausal status in type 2 diabetes mellitus (T2DM). Analyzed were 190 T2DM patients taking tofogliflozin as initial monotherapy in a Phase 3 study. Baseline characteristics were: men (66%); premenopausal (7%) and postmenopausal women (27%), age (mean 58y), and mean HbA1c (7.8%), BMI (26kg/m2), BHB (69µmol/L) and eGFR (83mL/min/1.73m2). Sex- and menopausal status-specific differences were analyzed by multivariate analysis. Longer duration of diabetes and lower baseline HDL-C and adiponectin were noted in men while age and HbA1c, BMI, BHB and eGFR were identical between sexes. Increases in BHB at weeks 4 and 52 were: men, median +128%* and +64*, respectively (+ p<0.01 vs. baseline); women, +48* and +58*, respectively. Mean increases in the fasting free fatty acid-to-insulin ratio (FIR) at week 52 were +88%* for men and +53* for women. Reductions in HbA1c and fasting insulin and increases in UGE and free fatty acids at week 52 were similar between sexes. Multivariate analyses showed a greater increase in BHB at week 52 in men than in women, especially postmenopausal women. Further, FIR increased greater in men than in women. Finally, premenopausal women had a greater increase in BHB than postmenopausal women. Results suggest that the different degrees of BHB elevation between sexes via tofogliflozin may provide clinical insights into sex- and menopause-specific metabolic responses to increased lipid use via SGLT2is in T2DM.


A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. Y. Matsubayashi: None. T. Nojima: Employee; Self; Kowa Co., Ltd. H. Suganami: Employee; Self; Kowa Co., Ltd. K. Kaku: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.

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