An elevated resting heart rate (RHR) is a risk factor for vascular complications in patients with and without type 2 diabetes mellitus (T2DM). Recently, the beneficial effects of SGLT2 inhibitors (SGLT2i) on cardiovascular and renal events were reported in large-scale clinical trials. However, their mechanisms are not fully clarified. This study aimed to investigate the effect of SGLT2i on RHR and the clinical factors that affect changes in RHR in patients with T2DM. Analyzed were 419 T2DM patients on diet and exercise therapy who received an SGLT2i, tofogliflozin (TOFO), or a placebo as initial monotherapy in two TOFO phase 2 and 3 studies. Adipose tissue insulin resistance (Adipo-IR) was calculated by the product of fasting free fatty acid and fasting insulin. Differences in heart rate-related variables between TOFO and the placebo were analyzed with an ANCOVA model. Multivariate analysis was performed to clarify independent factors that were associated with changes in RHR. Baseline characteristics were: male (67%), age (mean: 58 years), HbA1c (8.1%), BMI (26 kg/m2), RHR (66 bpm), eGFR (84 mL/min/1.73m2) and Adipo-IR (32.5 pmol/L•mmol/L). Concerning the effects on RHR, TOFO reduced RHR levels (least squares mean: -1.7 and -1.1 bpm, p<0.01 vs. baseline, p<0.vs. placebo) at weeks 12 and 24, respectively. Changes in quartiles of RHR from baseline to 24 weeks were 7.7, 0.7, -3.7, and -11.2, respectively. The change in RHR at week 24 did not correlate with changes in HbA1c, body weight and systolic blood pressure; however, it was correlated with baseline RHR levels (r = -0.37) and the change in Adipo-IR (r = 0.39) significantly. Multivariate analysis indicated that higher RHRs and Adipo-IR levels at baseline were independently associated with a greater reduction in RHR. Our results showed that the beneficial effects of the SGLT2i on cardiovascular and renal events may be associated with suppression of the sympathetic nervous system by improvement in Adipo-IR and amelioration of hyperinsulinemia.
Y. Matsubayashi: None. T. Nojima: Employee; Self; Kowa Company,LTD. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd.. T. Yamada: None. K. Fujihara: None. S. Tanaka: 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. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..