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Impact of the 8-Week Administration of Tofogliflozin for Glycemic Control and Body Composition in Japanese Patients with Type 2 Diabetes Mellitus

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Impact of the 8-Week Administration of Tofogliflozin for Glycemic Control and Body Composition in Japanese Patients with Type 2 Diabetes Mellitus □ ORIGINAL ARTICLE □ Impact of the 8-week Administration of Tofogliflozin for Glycemic Control and Body Composition in Japanese Patients with Type 2 Diabetes Mellitus Sachie Hirose 1, Shinsuke Nakajima 2, Yasuyuki Iwahashi 1, Akane Seo 1, Tetsuya Takahashi 1 and Yoshikazu Tamori 1,2 Abstract Objective The adverse effects of selective sodium-glucose co-transporter 2 (SGLT2) inhibitors generally ap- pear within about two or three months after treatment initiation in Japan. Therefore, we investigated the im- pact of tofogliflozin, a class of SGLT2 inhibitors, on glycemic control and body composition during this pe- riod in Japanese patients with type 2 diabetes mellitus. Methods This single-arm open-label study enrolled 20 patients. Patients received tofogliflozin 20 mg once daily for 8 weeks. At week 8, changes from baseline in body weight, serum metabolic markers, and body composition were evaluated. Results A total of 17 patients completed the 8-week administration of tofogliflodin. No serious adverse events were noted. Hemoglobin A1c (HbA1c) decreased significantly, from 7.8% to 7.3% with 8-week ad- ministration of tofogliflozin. Both the body weight and body mass index (BMI) also decreased. In addition, a decreased renal function of the boundary zone and hemoconcentration were detected. As for body composi- tion, the free fat mass, total body water, extracellular water and intracellular water were all decreased signifi- cantly. Interestingly, the amount of fat mass did not change. The degree of improvement in HbA1c was corre- lated with the baseline fat mass and BMI. Conclusion An eight-week administration of tofogliflozin improved glycemic control and reduced the body weight and free fat mass in type 2 diabetic patients without affecting the fat mass. In this period, the hema- tocrit level and renal function should be monitored to guard against hemoconcentration and renal impairment, respectively. Key words: tofogliflozin, SGLT2 inhibitor, body composition, hemoconcentration (Intern Med 55: 3239-3245, 2016) (DOI: 10.2169/internalmedicine.55.6367) through lifestyle improvement alone is difficult. Therefore, a Introduction number of novel anti-diabetic drugs have been developed. Recently, selective sodium-glucose co-transporter 2 (SGLT2) The incidence of type 2 diabetes has been dramatically inhibitors have been developed as a novel potential thera- increasing worldwide in association with the prevalence of peutic option for the treatment of type 2 diabetes. These obesity and an unhealthy lifestyle (1). This disease is char- drugs reduce the circulating glucose concentrations via a acterized by a decreased insulin action induced by insulin unique mechanism which inhibits the renal reabsorption of resistance and insulin deficiency. Diet and exercise are re- glucose and increases urinary glucose excretion (3, 4). garded as a basic and important strategy for treating type 2 Given that the mechanism of action of SGLT2 inhibitors is diabetes (2). However, controlling the blood glucose level independent of insulin secretion and action, the risk of hy- １Division of Diabetes and Endocrinology, Department of Internal Medicine, Chibune General Hospital, Japan and ２Division of Diabetes and En- docrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan Received for publication August 12, 2015; Accepted for publication March 31, 2016 Correspondence to Dr. Yoshikazu Tamori, [email protected] 3239 Intern Med 55: 3239-3245, 2016 DOI: 10.2169/internalmedicine.55.6367 Table 1. Characteristics of Study Participants. The inclusion criteria of this study were as follows: age >20 years old, body mass index (BMI) !18.5, hemoglobin n20 A1c (HbA1c) levels >6.2%, and estimated glomerular filtra- Age (years) 52.1 ± 9.8 tion rate (eGFR) >45 mL/min. In addition, C-peptide im- Sex (male/female) 9 / 11 munoreactivity index >1.5 was added to the inclusion crite- Diabetes duration (years) 6.4 ± 5.8 ria when the duration of diabetes exceeded 10 years. The Waist circumference (cm) 97.7 ± 10.2 exclusion criteria were as follows: using insulin; having se- Body weight (kg) 76.6 ± 15.8 vere hepatic, renal, or cardiac diseases; having severe infec- Body mass index (kg/m2) 28.9 ± 4.6 tion; having severe trauma; having cancer; and being preg- Casual plasma glucose (mg/dL) 166 ± 60.0 nant or breastfeeding. The study complied with the Declara- Hemoglobin A1c (%) 7.8 ± 1.5 tion of Helsinki, Good Clinical Practice, the International Conference on Harmonization of Technical Requirements for eGFR (mL/min/1.73m2) 80.7 ± 21.5 Registration of Pharmaceuticals for Human Use guidelines, Anti-diabetic treatment and Japanese law. This study was approved by the ethics Sulfonylurea (%) 25 % committee at Chibune General Hospital. All patients pro- Glinide (%) 0 % vided their informed consent prior to being enrolled. DPP-4 inhibitor (%) 65 % Measurements GLP-1 receptor agonist (%) 10 % Į-glucosidase inhibitor (%) 15 % At weeks 0 and 8, body weight and serum metabolic Biguanide (%) 75 % markers were measured. The body composition was evalu- ated by a bioelectrical impedance analysis (BIA) using an Thiazolidinedione (%) 20 % In-Body S20Ⓡ body composition analyzer (Biospace, Seoul, Insulin (%) 0 % Korea). In this analysis, the body weight, total body water, eGFR: estimated glomerular filtration rate, DPP-4: dipeptidyl peptidase-4, and extracellular body water were actually measured by seg- GLP-1: glucagon-like peptide-1. Values are mean ± SD. mental bioelectric impedance using eight tactile elec- trodes (8-10). The free fat mass and fat mass were calcu- poglycemia is low (3-5). lated from total body water. The free fat mass consists of to- Existing reports have indicated that the long-term admin- tal body water and protein and mineral content. The fat istration of SGLT2 inhibitors improves hyperglycemia and mass is obtained by subtracting the free fat mass from the reduces body weight, fat mass, and subcutaneous and vis- body weight. ceral adipose tissue (6). SGLT2 inhibitors have been avail- All measurements were performed regardless of meals. able for clinical use in Japan since 2014. In many cases, However, the changes in body composition estimated after various side effects of SGLT2 inhibitors, such as urogenital food or drink consumption were relatively small and fell infection, volume depletion, and skin disorders, appear within the values of imprecision for the impedance tech- within about 2-3 months after beginning to use these inhibi- nique, and so are unlikely to be of clinical significance (11). tors in Japan (7), indicating the importance of close observa- We evaluated any adverse effects during visits every 2 tion of any physiological and metabolic changes during this weeks and performed blood examinations every 4 weeks. period. We herein addressed the impact of tofogliflozin, a Statistical analysis class of SGLT2 inhibitors, by examining the serum markers and body composition measurements in Japanese type 2 dia- Since all continuous variables were confirmed to be nor- betic patients for 8 weeks from the beginning of its admin- mally distributed in this study, Student’s t-test was used to istration. compare between time points. The values are expressed as the mean ± standard deviation (SD), and p <0.05 was con- Materials and Methods sidered to be statistically significant. Correlations among variables were tested using Pearson’s correlation coefficient. All calculations were performed using the JMP software Study design and participants program version 8 (SAS Institute, Cary, USA). This study was carried out at Chibune General Hospital between August 2014 and March 2015 as a single-arm Results open-label study in Japanese patients with type 2 diabetes mellitus. All participants continued their pre-study treatment The baseline characteristics and medications for the par- without any change. In addition to any pre-study treatment, ticipants are shown in Table 1. The mean age and diabetes the participants received a single 20 mg dose of tofogliflozin duration were 52.1 years old and 6.4 years, respectively. The daily for 8 weeks. All patients received general diet and ex- mean body weight, BMI, HbA1c and casual plasma glucose ercise advice. The treatment was not changed in any partici- levels at baseline were 76.6 kg, 28.9 kg/m2, 7.8% and 166 pants throughout the current study. mg/dL, respectively. As anti-diabetic agents, sulfonylureas, 3240 Intern Med 55: 3239-3245, 2016 DOI: 10.2169/internalmedicine.55.6367 Table 2. Laboratory Findings before and after Administration of Tofogliflodine for 8 Weeks. n=17 Week 0 Week 8 mean SD mean SD p value Blood cells count WBC (×104/ȝL) 0.68 0.18 0.69 0.20 0.90 RBC (×104/ȝL) 458 37 482 34 <0.001 Hct (%) 40.3 3.4 42.6 3.1 <0.001 Plt (×104/ȝL) 25.4 6.3 26.0 6.0 0.45 Biochemisty Total protein (g/dL) 7.0 0.4 7.3 0.5 0.02 Albumin (mg/dL) 4.2 0.4 4.4 0.3 0.01 Triglyceride (mg/dL) 190 101 192 109 0.94 HDL cholesterol(mg/dL) 52.7 12.3 56.4 12.1 0.03 LDL cholesterol (mg/dL) 111 18 120 26 0.04 AST (IU/L) 22.7 6.7 22.5 9.8 0.93 ALT (IU/L) 32.5 19.0 29.4 16.0 0.11 LDH (IU/L) 175 25 174 40 0.90 ALP (IU/L) 226 83 232 85 0.61 Ȗ-GTP (IU/L) 33.8 15.3 29.8 12.8 0.04 Urea nitrogen (mg/dL) 12.2 3.5 14.5 4.0 0.002 Creatinine (mg/dL) 0.75 0.25 0.79 0.28 0.02 eGFR (mL/min/1.73m2) 78.9 20.0 75.1 19.2 0.06 Uric acid (mg/dL) 5.5 1.70 5.2 1.81 0.16 Plasma osmolarity (mOsm/L) 283.5 4.3 284.5 6.0 0.55 Glucose metabolism HbA1c (%) 7.8 1.6 7.3 1.3 0.04 GA (%) 17.2 3.5 16.3 2.9 0.12 Casual plasma glucose (mg/dL) 161 60
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