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Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients

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Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients Cardiovascular Drugs and Therapy (2019) 33:435–442 https://doi.org/10.1007/s10557-019-06892-y ORIGINAL ARTICLE Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients Munemitsu Otagaki1 & Koichiro Matsumura1 & Hiromi Kin1 & Kenichi Fujii2 & Hiroki Shibutani2 & Hiroshi Matsumoto 1 & Hiroki Takahashi1 & Haengnam Park1 & Yoshihiro Yamamoto1 & Tetsuro Sugiura1 & Ichiro Shiojima2 Published online: 18 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardio- vascular events in diabetic patients. However, the underlying mechanism associated with a favorable outcome has not been clearly identified. The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). Methods We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiography before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out- patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 42 patients (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler-derived early diastolic velocity (E/e′). Results There were no significant differences in patient characteristics and echocardiographic parameters at baseline. The change in LVEF from baseline to follow-up was 5.0 ± 6.9% in the tofogliflozin group and − 0.6 ± 5.5% in the control group; difference significant, p = 0.006. The change in E/e′ was − 1.7 ± 3.4 in the tofogliflozin group and 0.7 ± 4.1 in the control group; difference significant, p =0.024. Conclusions In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM. Keywords Diabetes mellitus . Cardiac function . SGLT2 inhibitor . Tofogliflozin Introduction 4]. Underlying pathogenic mechanisms associated with DM- related LV dysfunction is considered to be myocardial fibro- Increased risk of cardiovascular disease including heart failure sis, necrosis, apoptosis due to hyperglycemia, oxidative stress, is observed in type 2 diabetes mellitus (T2DM) [1, 2]. and chronic inflammation [5, 6]. Unfortunately, conventional Diabetes mellitus (DM) induces left ventricular (LV) dysfunc- glucose-lowering therapies have shown insufficient results in tion which is independent of glycemic control, hypertension, improving LV dysfunction and preventing cardiovascular dis- and coronary artery disease, and DM-related LV dysfunction ease, because development of cardiovascular disease is related is associated with increased risk of cardiovascular disease [3, notonlytoglycemiccontrolbutalsotocombinedeffectsof T2DM [7–10]. Sodium glucose cotransporter 2 (SGLT2) inhibitors * Koichiro Matsumura emerged as a glucose-lowering drug via urinary glucose ex- [email protected] cretion. SGLT2 inhibitors have multifactorial effects on ath- erosclerotic risk factors such as reducing blood pressure and 1 Department of Cardiology, Kansai Medical University Medical body weight, and improving dyslipidemia [11–13]. In addi- Center, 10-15, Fumizono-cho, Moriguchi, Osaka 570-8507, Japan tion, T2DM patients taking SGLT2 inhibitors showed less 2 Division of Cardiology, Department of Medicine II, Kansai Medical incidence of cardiovascular disease and heart failure in University, Hirakata, Japan EMPA-REG and CANVAS trials [14, 15]. However, the 436 Cardiovasc Drugs Ther (2019) 33:435–442 underlying mechanism associated with a favorable effect of was approved by the ethics committees of Kansai Medical SGLT2 inhibitors on cardiac function is not well known. University Medical Center. Accordingly, we investigated the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function Statistical Analyses in patients with T2DM. Continuous variables are presented as medians with interquar- tile ranges or as means ± standard deviations. Categorical Methods variables are presented as numbers and percentages. Differences between the two groups were analyzed using the Patient Selection unpaired t test or Mann-Whitney U test for continuous vari- ables and the chi-square test for categorical variables. We studied 26 consecutive T2DM out-patients taking Differences between baseline and follow-up data were con- glucose-lowering drugs and initiated tofogliflozin (20 mg/ ducted using the paired t test. A p value < 0.05 was considered day) between February 2015 and December 2017. All patients significant. To minimize various biases between the two fulfilled the following inclusion criteria; age ≥ 20 years, no groups, propensity score matching method was conducted. previous SGLT2 inhibitor administration, and performed Propensity score was calculated by multivariate logistic re- echocardiography before initiation of tofogliflozin (baseline) gression analysis using seven variables: age, sex, serum cre- and ≥ 6 months after administration of tofogliflozin (follow- atinine level, HbA1c at baseline, hypertension, body mass up). During this period, 162 out-patients with T2DM taking index, and number of glucose-lowering drugs. All seven var- other glucose-lowering drugs and fullfilling the inclusion iables are reported as influencing factors for systolic and dia- criteria were used as a control group. During the study periods, stolic cardiac function and to avoid possible differences in the patients having cardiovascular events including myocardial severity of diabetic status between the two groups, the number infarction or heart failure hospitalization were not included of glucose-lowering drugs was included in the propensity in this study. Propensity score analysis was performed to matching analysis [19]. JMP 13.0.0 software (SAS Institute match the patient characteristics. As a result, 42 patients Inc., Cary, NC, USA) was used for all statistical analyses. (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Results Evaluated Variables Median follow-up periods were 8.0 (6.5–10.9) months in the Clinical characteristics including demographic characteristics, tofogliflozin group and 9.1 (6.1–10.3) months in the control comorbidity, prescribed medicine, laboratory parameters, and group (p = 0.414). Patient characteristics are shown in Table 1. echocardiographic findings were obtained at baseline and at There were no significant differences in comorbidities and follow-up. Baseline medications were obtained from the med- oral medications between the two groups. Baseline and ical record. Echocardiography was performed with commer- follow-up laboratory and echocardiographic parameters are cially available ultrasound system using Vivid 7 or Vivid E9 shown in Tables 2 and 3. There was no significant difference GE Medical System. Standard transthoracic and Doppler in blood pressure between the two groups during the study echocardiographic parameters were examined according to period. Blood pressure-lowering drugs including angiotensin- the current guideline of the American Society of converting enzyme inhibitor, angiotensin II receptor blocker, Echocardiography/European Association of Cardiovascular and beta blocker were prescribed continuously with no change Imaging [16]. Systolic cardiac function was evaluated by mea- in the dose, whereas glucose-lowering drugs were adjusted in suring left ventricular ejection fraction (LVEF) using each patient except tofogliflozin. There were no significant Modified Simpson method. Early diastolic (E) and atrial wave differences in baseline laboratory and echocardiographic pa- (A) flow velocities of the mitral valve and E wave deceleration rameters between the two groups but the hemoglobin level at time were measured by pulsed wave Doppler echocardiogra- follow-up was significantly higher in the tofogliflozin group phy from the apical four-chamber view. Spectral pulsed wave than the control group (tofogliflozin 15.5 (14.2–16.6) g/dL vs. Doppler-derived early diastolic velocity (e′) was calculated by control 13.8 (12.2–14.6) g/dL, p = 0.002). The majority of the averaging the septal and lateral mitral annulus. E/e′ was used patients in this study had preserved LVEF which is common in as a diastolic cardiac function [17, 18]. All classic views were out-patient DM clinic. At follow-up, there were no significant analyzed by a physician who was board certified in echocar- differences in echocardiographic parameters between the two diography. Follow-up information was obtained from the groups, except E/e′ at follow-up (tofogliflozin 10.6 (8.1–14.8) medical record. Informed consent was obtained through an vs. control 13.2 (11.7–17.7), p = 0.021). LVEF improved sig- opt-out procedure from all participants. The study protocol nificantly in tofogliflozin group (baseline 55 ± 14% to follow- Cardiovasc Drugs Ther (2019) 33:435–442 437 Table 1 Baseline patient characteristics Tofogliflozin (n = 21) Control (n =21) p value Age (years) 70 (54–72) 72 (61–74) 0.307 Male 15 (71) 14 (67) 0.739
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