Reduced plasma volume (PV) to decrease ventricular filling pressure and increased beta-hydroxybutyrate (BHB) as a substitute for the energy source by SGLT2 inhibitors (SGLT2is) might contribute to preserving the heart in type 2 diabetes mellitus (T2DM). However, the impact of SGLT2is on PV and BHB is little known according to cardiac workload. We investigated the effect of long-term treatment with the SGLT2i, tofogliflozin, on PV and BHB according to baseline brain natriuretic peptide (BNP) levels in T2DM. Analyzed were 774 T2DM patients who received tofogliflozin for 52 weeks as mono- and add-on-therapy in two phase-3 studies. Percent change in estimated PV (%ΔePV) was calculated by the Strauss formula: {100*(pre Hb/post Hb)*[(100 - post Ht)/(100 - pre Ht)] - 100}. We divided patients into two groups (Quartiles 1-3[Q1-3] and Quartile 4[Q4]) according to baseline BNP. Differences in characteristics were analyzed using unpaired t-test, wilcoxon rank sum test or Fisher’s exact test. Differences in changes between groups were analyzed using an analysis of covariance model. Multivariate analysis evaluated the association of baseline BNP with changed variables. Baseline characteristics were: male (71 vs. 52% *, * p<0.05, Q1-3 vs. Q4), age (mean: 57 vs. 64 y *), HbA1c (8.1 vs. 8.0%), BMI (26 vs. 25 kg/m2 *), BNP (median: 9 vs. 27 pg/mL *) and BHB (45 vs. 54 µmol/L). Reduction in Ln-transformed BNP (ln-BNP) was greater in Q4 (least square mean: -0.5 ln[pg/mL]) than in Q1-3 (-0.1) as was %ΔePV (Q4 [-6 %] vs. Q1-3 [-4]). Increase in Ln-transformed BHB (ln-BHB) was larger n Q4 (+0.7 ln[µmol/L]) than in Q1-3 (+0.5). Changes in HbA1c, body weight and blood pressure were similar. Q4 was independently correlated with the greater reduction in %ΔePV and increase in ln-BHB. Results suggested that reduced PV and increased BHB might be greater in T2DM patients with higher baseline BNP levels after long-term tofogliflozin therapy.


A. Yoshida: Employee; Self; Kowa Company, Ltd. Y. Matsubayashi: None. T. Nojima: Employee; Self; Kowa Company, Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd. M. Oe: Employee; Self; Kowa Company, Ltd. K. Fujihara: None. S. Tanaka: None. K. Kaku: Advisory Panel; Self; Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc. Consultant; Self; Sanwa Kagaku Kenkyusho. Research Support; Self; Taisho Pharmaceutical Co., Ltd. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

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