Randomized, placebo‐controlled, double‐blind glycemic control trial of novel sodium‐dependent glucose cotransporter 2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus

Abstract

Aims/IntroductionIn the present dose–response study, we evaluated the efficacy and safety of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium‐dependent glucose cotransporter 2, in Japanese patients with type 2 diabetes mellitus.Materials and MethodsA total of 361 patients from 39 Japanese centers were randomized to receive either once‐daily oral ipragliflozin (12.5, 25, 50 or 100 mg) or a placebo for 12 weeks.ResultsAll ipragliflozin‐treated groups had clinically significant, dose‐dependent decreases in glycated hemoglobin (HbA1c) and fasting plasma glucose levels compared with placebo‐treated groups. The adjusted mean difference in HbA1c change from baseline to the end of treatment between the placebo and 12.5, 25, 50, and 100 mg ipragliflozin groups were −0.61%, −0.97%, −1.29%, and −1.31%, respectively (P < 0.001). Reductions in HbA1c levels were similar between obese and non‐obese patients, and were larger in patients with baseline HbA1c ≥8.4% than in those with HbA1c <8.4%. Furthermore, bodyweight significantly (P < 0.001) and dose‐dependently decreased among ipragliflozin‐treated groups compared with the placebo group. The incidence of adverse events was similar across all groups. However, mild increases in hematocrit and blood urea nitrogen were found in ipragliflozin treated groups.ConclusionsOnce‐daily administration of ipragliflozin was dose‐dependently effective in glycemic control without major adverse effects. Ipragliflozin was equally effective between obese and non‐obese patients, and led to weight loss in both groups. Ipragliflozin was safe and well‐tolerated in Japanese patients with type 2 diabetes mellitus. This trial was registered with ClinicalTrials.gov (no. NCT00621868).

The Sodium Glucose Cotransporter 2 Inhibitor Ipragliflozin Promotes Preferential Loss of Fat Mass in Non-obese Diabetic Goto–Kakizaki Rats

“…11,12) Further, reduction of waist circumference or fat mass has been reported in overweight or obese patients with T2DM. [13][14][15] In animal studies, SGLT2 inhibitors enhanced glucosuria, increased usage of fatty acids instead of glucose as an energy source, and reduced body fat mass in high-fat diet-induced obese (DIO) rats. [16][17][18] However, whether or not SGLT2 inhibitors similarly affect body weight and body composition in non-obese T2DM patients or animal models of T2DM remains unclear.…”

“…19) The GK rats exhibit decreased β-cell numbers and function which is accompanied by mild hyperglycemia, impaired glucose-induced insulin secretion, and peripheral insulin resistance. [20][21][22][23][24] Here, using dual-energy X-ray absorptiometry (DEXA), we investigated the effect of the selective SGLT2 inhibitor ipragliflozin 13,[25][26][27][28][29] on body composition in GK rats.…”

“…11,12) Further, reduction of waist circumference or fat mass has been reported in overweight or obese patients with T2DM. [13][14][15] In animal studies, SGLT2 inhibitors enhanced glucosuria, increased usage of fatty acids instead of glucose as an energy source, and reduced body fat mass in high-fat diet-induced obese (DIO) rats.16-18) However, whether or not SGLT2 inhibitors similarly affect body weight and body composition in non-obese T2DM patients or animal models of T2DM remains unclear.Goto-Kakizaki (GK) rats, a model of spontaneous nonobese T2DM, were produced from a colony of non-diabetic Wistar rats by selective breeding with glucose intolerance as a selection index.19) The GK rats exhibit decreased β-cell numbers and function which is accompanied by mild hyperglycemia, impaired glucose-induced insulin secretion, and peripheral insulin resistance. [20][21][22][23][24] Here, using dual-energy X-ray absorptiometry (DEXA), we investigated the effect of the selective SGLT2 inhibitor ipragliflozin 13,[25][26][27][28][29] on body composition in GK rats.…”

“…[13][14][15] In animal studies, SGLT2 inhibitors enhanced glucosuria, increased usage of fatty acids instead of glucose as an energy source, and reduced body fat mass in high-fat diet-induced obese (DIO) rats.…”

Long-Term Effects of Ipragliflozin on Adipose Tissue in Japanese Patients with Obese Type 2 Diabetes

“…No drugs for treating obesity were available until recently in Japan. The SGLT2 inhibitor, ipragliflozin (Astellas Pharma, Tokyo, Japan and Kotobuki Pharmaceutical, Nagano, Japan), a drug approved for T2D treatment in Japan, was reported to induce weight loss [4,5]. SGLT2 inhibitors improve glycemia in T2D patients by enhancing urinary glucose excretion via blocking its reabsorption in the renal proximal tubules and reduce body weight due to urinary calorie loss [6,7].…”