Diabetic ketoacidosis characterized by lipolysis due to insulin deficiency is a side effect reported for SGLT2 inhibitors (SGLT2is). However, little is known about predictors of ketosis via SGLT2i. The antilipolytic effect of insulin in adipose tissue can be evaluated as adipose tissue insulin resistance (Adipo-IR). This study investigated predictors of ketosis via the SGLT2i, tofogliflozin (TOFO), in patients with type 2 diabetes (T2D) focusing on Adipo-IR. Analyzed were 304 T2D patients who received TOFO as initial monotherapy in two TOFO phase 2 and 3 studies. Adipo-IR was calculated by the product of fasting insulin (IRI) and fasting free fatty acids (FFA). Baseline characteristics were: males (67%), age (mean: 58 y), HbA1c (8%), BMI (26kg/m2), β-hydroxybutyrate (BHB) (75µmol/L), eGFR (84mL/min/1.73m2) and Adipo-IR (33pmol/L mmol/L). Participants were grouped by tertiles of baseline Adipo-IR levels (T1-T3). Differences across tertiles were analyzed by ANOVA, Kruskal Wallis and ANCOVA. Multivariate analysis explored the predictors of ketosis. In the order of T3-T1, younger age, higher baseline HOMA-IR levels and higher baseline HOMA-β levels were observed, while baseline HbA1c and BHB levels were identical across tertiles. At 24 weeks after TOFO administration, reduced HbA1c and body weight and increased urinary glucose excretion were identical among tertiles. Percent changes in FFA were T1, mean +50.9%* (* p<0.001 vs. baseline); T2, +25.8*; and T3, +6.6 (p<0.001 across tertiles); and those for BHB were T1, median +117.9%*; T2, +126.9*; and T3, +62.0* (p<0.05). Conversely, percent changes in IRI were T1, mean -11.3%*; T2, -24.2* and T3, -28.3* and in Adipo-IR were T1, +31.1%*; T2, -2.9 and T3, -24.1* (p<0.001 across tertiles). Multivariate analysis indicated an independent association of T3 with a weaker increase in BHB than T1 and T2.
In conclusion, high baseline Adipo-IR may attenuate ketosis via SGLT2i through improved Adipo-IR and the antilipolytic effect of insulin despite reduced IRI in T2D.
Y. Matsubayashi: None. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. T. Nojima: Employee; Self; Kowa Co., Ltd. H. Suganami: Employee; Self; Kowa Co., Ltd. K. Fujihara: None. 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.