Effects of Ipragliflozin on Postprandial Glucose Metabolism and Gut Peptides in Type 2 Diabetes: A Pilot Study

Diabetes Therapy, Jan 2018

Introduction Ipragliflozin is a novel antidiabetic drug that inhibits renal tubular sodium-glucose cotransporter-2 (SGLT2). The aim of this study was to evaluate the effects of ipragliflozin on glucose, insulin, glucagon, and gastrointestinal peptide responses to a meal tolerance test, as well as to investigate the glucose-lowering mechanisms of ipragliflozin. Methods Nine Japanese patients with obesity and type 2 diabetes mellitus were treated with ipragliflozin (50 mg/day) for 12 weeks. The postprandial profiles of glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), active glucose-dependent insulinotropic polypeptide (GIP), ghrelin, and des-acyl ghrelin were measured before and 12 weeks after ipragliflozin treatment. Results Body weight, body fat mass, systolic blood pressure, and HbA1c and serum uric acid levels were significantly decreased after the treatment. Postprandial glucose and insulin levels were also significantly decreased. Postprandial glucagon increased both before and after ipragliflozin treatment; however, the increment tended to be smaller after treatment. Active GLP-1, active GIP, ghrelin, and des-acyl ghrelin did not change after treatment. Conclusion Ipragliflozin improved glycemic control by reducing body weight, postprandial inappropriate glucagon secretion, and the postprandial insulin requirement. Although this was a short-term study with a small sample size, ipragliflozin may offer benefits for patients with obesity and type 2 diabetes mellitus. Trial Registration University Hospital Medical Information Network (UMIN No. 000017195).

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Effects of Ipragliflozin on Postprandial Glucose Metabolism and Gut Peptides in Type 2 Diabetes: A Pilot Study

Diabetes Ther Effects of Ipragliflozin on Postprandial Glucose Metabolism and Gut Peptides in Type 2 Diabetes: A Pilot Study Hiroaki Ueno 0 1 2 . Hiroko Nakazato . Emi Ebihara . Kenji Noma . 0 1 2 0 H. Ueno (&) H. Nakazato E. Ebihara K. Nagamine H. Sakoda M. Nakazato Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki , Miyazaki , Japan 1 T. Kawano Kawano Naika Clinic , Miyazaki , Japan 2 K. Noma Noma Naika Clinic , Miyazaki , Japan Introduction: Ipragliflozin is a novel antidiabetic drug that inhibits renal tubular sodiumglucose cotransporter-2 (SGLT2). The aim of this study was to evaluate the effects of ipragliflozin on glucose, insulin, glucagon, and gastrointestinal peptide responses to a meal tolerance test, as well as to investigate the glucose-lowering mechanisms of ipragliflozin. Methods: Nine Japanese patients with obesity and type 2 diabetes mellitus were treated with ipragliflozin (50 mg/day) for 12 weeks. The postprandial profiles of glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), active glucose-dependent insulinotropic polypeptide (GIP), ghrelin, and des-acyl ghrelin were measured before and 12 weeks after ipragliflozin treatment. Results: Body weight, body fat mass, systolic blood pressure, and HbA1c and serum uric acid levels were significantly decreased after the treatment. Postprandial glucose and insulin levels were also significantly decreased. Postprandial glucagon increased both before and after ipragliflozin treatment; however, the increment tended to be smaller after treatment. Active GLP-1, active GIP, ghrelin, and des-acyl ghrelin did not change after treatment. Conclusion: Ipragliflozin improved glycemic control by reducing body weight, postprandial inappropriate glucagon secretion, and the postprandial insulin requirement. Although this was a short-term study with a small sample size, ipragliflozin may offer benefits for patients with obesity and type 2 diabetes mellitus. Trial Registration: University Hospital Medical Information Network (UMIN No. 000017195). Ghrelin; GLP-1; Ipragliflozin; Type 2 diabetes mellitus - Glucagon; INTRODUCTION Individuals with obesity are at high risk of developing diabetes mellitus. In addition, after developing diabetes mellitus, their glycemic control easily worsens. These individuals are more likely to develop complications such as dyslipidemia, hypertension, and hepatic steatosis. Conversely, when obese diabetic patients lose 3?5% or more of their weight, they benefit from improvements in these complications [1]. Developed countries have an overabundance of inexpensive, high-calorie foods and advanced transportation systems; thus, individuals living in these countries may have difficulty reducing their energy consumption and adhering to lifestyle changes to their diets or exercise therapy. Sodium-glucose cotransporter-2 (SGLT2) inhibitors suppress the activity of SGLT2 expressed in renal tubules and increase urinary glucose excretion, thereby improving blood glucose levels [2]. In Japan, SGLT2 inhibitors became available in 2015; in most obese diabetic patients, these drugs help to decrease body weight and improve HbA1c levels [3]. A doubleblind comparative study of an SGLT2 inhibitor, empagliflozin, in diabetic patients (including Asian patients) who were at high risk of cardiovascular events showed that empagliflozin significantly reduced total mortality and the incidence of cardiovascular events [4?6]. The mechanisms underlying the weight loss and reduction of plasma glucose level using SGLT2 inhibitors are believed to occur through loss of glucose in the urine. However, it is possible that these medications may work through other mechanisms such as gastrointestinal peptides and glucagon. The effects of SGLT2 inhibitors on gastrointestinal peptides and glucagon in diabetic patients are not fully clarified. We hypothesized that ipragliflozin may affect the secretion of gastrointestinal peptides and glucagon to improve plasma glucose levels and to reduce body weight, at least in part. Therefore, we examined the glucose metabolism as well as gastrointestinal peptides before and after ipragliflozin treatment in this study. This study aimed to investigate the effects of an SGLT2 inhibitor, ipragliflozin, including its effects on glucose metabolism. Ipragliflozin was administered for 12 weeks to nine patients with obesity and type 2 diabetes mellitus. Meal tolerance tests (MTTs) were performed before and after ipragliflozin administration to study changes in glucose metabolism and gastrointestinal hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, ghrelin, and des-acyl ghrelin. METHODS Subjects We conducted an open-label study to investigate the effects of 50 mg/day of ipragliflozin in patients with type 2 diabetes mellitus. The patients ranged in age from 20 to (...truncated)


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Hiroaki Ueno, Hiroko Nakazato, Emi Ebihara, Kenji Noma, Takahisa Kawano, Kazuhiro Nagamine, Hideyuki Sakoda, Masamitsu Nakazato. Effects of Ipragliflozin on Postprandial Glucose Metabolism and Gut Peptides in Type 2 Diabetes: A Pilot Study, Diabetes Therapy, 2018, pp. 403-411, Volume 9, Issue 1, DOI: 10.1007/s13300-018-0366-8