SGLT2 inhibitors (SGLT2is) reduce body weight. They also reduce insulin levels, which trigger lipolysis leading to subsequent fat-mass loss. Lactate (LAC) was reported to inhibit lipolysis in adipocytes and to mediate insulin-dependent inhibition of lipolysis. However, little is known of the effect of SGLT2is on LAC and its relation to weight loss. We investigated the effect of the SGLT2i tofogliflozin on LAC and explored its relation to subsequent weight loss in patients with type 2 diabetes mellitus (T2DM). Analyzed were 584 T2DM patients receiving tofogliflozin as an add-on to other antidiabetic agents from a Phase 3 trial. Baseline characteristics were: men (66%), age (mean 59y), mean HbA1c (8%), BMI (26kg/m2), LAC (11mg/dL) and eGFR (84mL/min/1.73m2). Patients were divided into two groups based on baseline LAC (bottom quartile [Q1: LAC mean 6mg/dL] and 3 higher quartiles [Q2-4]: 13). Adjusted changes in variables between groups were compared to explore the relation between baseline LAC and weight loss using multivariate analysis. LAC significantly decreased at week 4 (mean, -1.4mg/dL* p<0.01 vs. baseline) and that reduction was maintained toward week 52 (-1.5*). Similar reductions in LAC were seen at week 52 in persons who had (-1.7mg/dL*) and had not received a biguanide (-1.4*). Baseline BMI, eGFR and fasting insulin were lower in Q1, while HbA1c was identical between groups. Mean changes in LAC in Q1 and Q2-4, respectively, were +1.6mg/dL*, and -2.4* at week 52 (p<0.01 between groups). Weight loss in Q1 and Q2-4, respectively, were -3.8%*, and -4.5* at week 24 (p<0.05) and -3.4*, and -4.4* at week 52 (p<0.01) while reductions in HbA1c and fasting insulin at week 52 were identical between groups. Multivariate analysis showed greater weight loss in Q2-4 at week 52 than in Q1. Results suggested that LAC was significantly influenced by togfogliflozin according to baseline LAC. Baseline LAC may be a predictor of weight loss associated with lipolysis via long-term SGLT2i treatment for T2DM. Disclosure T. Nojima: Employee; Self; Kowa Co., Ltd. Y. Matsubayashi: None. A. Yoshida: Employee; Self; Kowa Pharmaceutical 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.