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)