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Clinical Comparison of Tofogliflozin and Empagliflozin Based on An Obesity Medicine 14 (2019) 100088 Contents lists available at ScienceDirect Obesity Medicine journal homepage: www.elsevier.com/locate/obmed Original research Clinical comparison of tofogliflozin and empagliflozin based on an analysis of 24-h accumulated urine in Japanese patients with type 2 diabetes mellitus T ∗ Kazuo Kobayashia, , Masao Toyodab, Nobuo Hatoric a Kobayashi Clinic of Internal Medicine, Sagamihara, Japan b Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan c Kobayashi Hospital, Odawara, Japan ARTICLE INFO ABSTRACT Keywords: Aim: In Japan, six sodium-glucose co-transporter 2 inhibitors have been approved for use, and some agents are Tofogliflozin associated with a significant decrease in cardiovascular events. In this study, the effects of tofogliflozin and Empagliflozin empagliflozin were compared. 24-H accumulated urine Methods: Patients with type 2 diabetes mellitus who were administered tofogliflozin (n = 10) and empagliflozin Sodium-glucose co-transporter 2 inhibitor (n = 12) were extracted. The clinical parameters and 24-h accumulated urine samples before and after 48 weeks Hematocrit were analyzed with generalized linear mixed model. Results: Both groups showed significant differences in the following parameters: body weight (p < 0.0001), mean blood pressure (p = 0.006), glycated hemoglobinA1c (p < 0.0001), alanine aminotransferase (p < 0.0001), high-density lipoprotein cholesterol (p < 0.0001), homeostatic model assessment 2 (%S) (p = 0.006), volume of 24-h accumulated urine (p < 0.0001), and 24-h urine glucose excretion (p < 0.0001). The hematocrit differed significantly over the study period (p < 0.0001); however, empaglifozin had a sig- nificantly stronger effect on the hematocrit than tofoglifozin (p = 0.007). In contrast, triglyceride, low-density lipoprotein cholesterol, estimated glomerular filtration rate, and 24-h creatinine clearance rates were not sig- nificantly different in both groups. Conclusions: The present results indicate that empagliflozin and tofogliflozin influence certain clinical para- meters similarly; however, empagliflozin significantly increased the hematocrit than tofogliflozin. Differences in the effects of tofogliflozin and empagliflozin might influence cardiovascular events. 1. Introduction against SGLT2/SGLT1 activity: 2900 for tofogliflozin (Suzuki et al., 2012) and 5000 for empagliflozin (Interview form of Jardian, 2017)), Sodium-glucose co-transporter (SGLT) 2 inhibitors enhance glucose respectively, were assessed. Tofogliflozin and empagliflozin have low elimination via urine. Therefore, they exhibit a glucose-lowering effect protein-binding ratios (82.3–82.6% for tofogliflozin (Interview form of and induce weight loss via calorie loss. SGLT2 inhibitors may be ef- Apleway, 2016) and 84.7% for empagliflozin (Interview form of fective in patients with type 2 diabetes mellitus (T2DM) with obesity. Jardian, 2017)) and high urinary excretion rates of their non-metabo- However, individual differences greatly influence urine volume, glu- lized forms (16.1% for tofogliflozin (Interview form of Apleway, 2016); cose excretion, and weight loss. Even if glucose-lowering effects of 21.3% and 22.9% for 10 and 25 mg empagliflozin (Interview form of SGLT2 inhibitors have not been observed, their clinical effects have Jardian, 2017), respectively). These characteristics of tofogliflozin and been reported previously by Cherney et al. (2018). Currently, six SGLT2 empagliflozin are believed to contribute to their strong inhibition of inhibitors have been approved clinically in Japan. The characteristics of SGLT2 in vivo. However, the T1/2 values of the two drugs are markedly 2 each SGLT2 inhibitor, such as half-life (T1/2), binding ratio for SGLT2, different (5.29 h for tofogliflozin and 9.88 h for empagliflozin pharmacokinetics (e.g., metabolism and excretion), and selectivity ratio (Interview form of Jardian, 2017)).Tofogliflozin may be a strong in- for SGLT1/SGLT2, have been reported previously. In the present study, hibitor of SGLT2 because of its high selectivity for the co-transporter tofogliflozin and empagliflozin, which are highly selective inhibitors of (Interview form of Apleway, 2016). Empagliflozin inhibits SGLT2 as SGLT2 and SGLT1 (ratio of half-maximal inhibitory concentration strongly as tofogliflozin; however, its half-life is longer than that of ∗ Corresponding author. Postal code 2520131, 5-1-1 la-flore3F Nishihasimoto, midoriku-ku, Sagamihara city, Kanagawa prefecture, Japan. E-mail address: [email protected] (K. Kobayashi). https://doi.org/10.1016/j.obmed.2019.100088 Received 2 November 2018; Received in revised form 15 March 2019; Accepted 3 April 2019 2451-8476/ © 2019 Published by Elsevier Ltd. K. Kobayashi, et al. Obesity Medicine 14 (2019) 100088 tofogliflozin (Interview form of Apleway, 2016; Interview form of Table 1 Jardian, 2017). The EMPA-REG OUTCOME trial revealed that cardio- Baseline characteristics of patients. fl vascular diseases were improved in patients administered empagli ozin Mean ± standard deviation (range) Statistics (Zinman et al., 2015); however, a large-scale clinical trial using to- fogliflozin has not yet been performed. In the present study, the clinical Tofo group (n = 10) Empa group effects of tofogliflozin and empagliflozin were compared via analysis of (n = 12) 24-h accumulated urine samples of patients with type 2 diabetes mel- Age (years) 52.6 ± 8.4 (39–66) 52.6 ± 8.0 (43–61) n.s. litus, and we aimed to clarify differences in the effects of these SGLT2 Sex (men/women) 4/6 9/3 n.s. inhibitors. Body weight (kg) 80.7 ± 12.3 84.3 ± 19.0 n.s. (66.2–105.2) (62.0–121.4) Body mass index 30.7 ± 4.3 30.7 ± 7.0 n.s. 2. Methods (25.5–39.3) (24.3–43.4) Duration of diabetes 11.1 ± 5.0 8.0 ± 2.9 n.s. 2.1. Study design and study patients mellitus (years) Complications This retrospective, observational study was conducted in a clinical Retinopathy 2 2 n.s. Nephropathy 5 (ACR 6 (ACR n.s. setting. The inclusion criteria were as follows: T2DM patients, 1) 2.7–565.9 μg/g) Cr) 2.7–609.1 μg/g Cr) treated with an SGLT2 inhibitor from March 2014 to March 2017 for 1, proteinuria more than 48 weeks; 2) 24-h accumulated urine samples obtained (1.82 g/day) regularly during administration of SGLT2 inhibitors; 3) data regarding Urine ACR (26.7; 5.1, 146.0) (20.4; 3.0, 120.9) n.s. Hypertension 8 12 n.s. 24-h accumulated urine sample being useful before and after 48 weeks Dyslipidemia 10 12 n.s. of administration of SGLT2 inhibitor. Following were the exclusion Fatty liver 10 10 n.s. criteria: 1) severe renal dysfunction, severe liver dysfunction, severe Glucose-lowering agents heart failure, or severe infection, 2) irregular use of SGLT2 inhibitor, SGLT2 inhibitor alone 1 2 n.s. and 3) individuals who opted to drop out of the study. Based on the BG 8 6 n.s. fl SU 6 6 n.s. aforementioned criteria, 10 patients receiving 20 mg tofogli ozin once DPP4 inhibitor 3 3 n.s. daily (Tofo group) and 12 patients receiving 10 mg empagliflozin once αGI 3 5 n.s. daily (Empa group) were included. This retrospective, observational GLP1RA 4 2 n.s. study was approved by the Human Ethics Committee of Kanagawa Pioglitazone 1 1 n.s. Medical Association (11 Jun 2018) and the opt-out approach was Glinide 1 0 n.s. Insulin 2 2 n.s. adopted to obtain informed consent from the patients. This paper fol- lows the standards for reporting observational studies outlined manu- Abbreviations: ACR, albumin to creatinine ratio; BG, biguanide; Cr, Creatinine; script was created according to the STROBE statement. DPP4, dipeptidyl peptidase-4; EMPA, empagliflozin; GLP1RA, glucagon-like peptide-1 receptor agonist; n.s., not significant; SGLT2, sodium-glucose co- 2.2. Sample analyses transporter 2; SU, sulphonylurea; TOFO, tofogliflozin; αGI, α-glucosidase in- hibitor. Within parenthesis means; median value, 25th percentile value, 75th On analyzing 24-h accumulated urine samples, the mean urine percentile value. creatinine levels were determined to exclude samples unsuitable for the study. Urine samples were used when the creatinine level was 3. Results within ± 30% of the mean value. Blood analysis, spot urine analysis, and analysis of 24-h accumulated urine samples were conducted by 3.1. Patient characteristics BML Co. (Tokyo, Japan). Homeostatic model assessment (HOMA) 2 (% S) and HOMA 2 (%B) were performed using HOMA Calculator software Patient demographic information is summarized in Table 1. Middle- developed at the Diabetes Trials Unit of the Oxford Centre for Diabetes, aged and obese T2DM patients with chronic T2DM were included, with fi ff Endocrinology and Metabolism (Oxford, UK). no signi cant di erence in age, sex ratio, body weight, or duration of T2DM between the Tofo and Empa groups. Half of the patients in both 2.3. Statistical analysis groups had diabetic nephropathy, almost all patients had hypertension, and all patients had dyslipidemia. IBM SPSS Statistics 24.0 software program (IBM Inc., Armonk, NY, USA) was used for statistical analyses. Comparisons between the two 3.2. Adverse effects and concomitant medication groups were analyzed using a Student's t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data. Among the adverse events occurring among patients, mild dry The chi-square test was performed to analyze categorical data. mouth (n = 2), mild frequent urination (n = 1), and Candida vaginitis Longitudinal data were analyzed using a generalized linear mixed (n = 1) were reported in the Tofo group but not in the Empa group. model, in which factors of group and time were set as the fixed effect Balanitis (n = 1) and urinary tract infection (n = 1) were reported in and time factor was also set as the repeated effect. If time was a sig- the Empa group. These infections were not severe and improved upon nificant factor, further analysis was performed using Dunnett's test; treatment with antibiotics after temporary discontinuation of SGLT2 furthermore, when group factors were significant, further analysis was inhibitors.
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