Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: <scp>ILLUMINATE</scp>, a randomized, double‐blind, placebo‐controlled study

Kashiwagi, Atsunori; Kazuta, Kenichi; Goto, Kíyoshi; Yoshida, Satoshi; Ueyama, Eiji; Utsuno, Atsushi

doi:10.1111/dom.12331

Cited by 92 publications

(149 citation statements)

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“…Ipragliflozin was the first SGLT2 inhibitor to be approved in Japan for the treatment of T2DM on the basis of several randomized placebo-controlled studies, which demonstrated that it improved glycemic control when administered as monotherapy or in combination with other oral antidiabetic drugs [2][3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Real-world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): final results of a post-marketing surveillance study

Yokote

Terauchi

Nakamura

et al. 2016

Expert Opinion on Pharmacotherapy

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Objective: To investigate the real-world safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (T2DM). Research design and methods: Japanese patients (≥65 years old) who were first prescribed ipragliflozin within 3 months after its launch in April 2014 were registered in this post-marketing surveillance (PMS). Final data collection was in July 2015. Survey items included demographics, treatments, adverse drug reactions (ADRs), vital signs, and laboratory variables. Results: The PMS included 8505 patients (4181 males/4324 females). The mean age and diabetes duration were 72.3 years and 10.6 years, respectively. In 84.3% of patients, ipragliflozin was prescribed at 50 mg/day, which was continued unchanged. Overall, 16.91% of patients experienced 1880 ADRs, and 165 ADRs were classified as serious in 127 patients (1.49%). ADRs of special interest included skin complications, volume depletion, polyuria/pollakiuria, genital infection, urinary tract infection, renal disorders, hypoglycemia, cerebrovascular disease, cardiovascular disease, malignant tumor, fracture, and ketone body-related events. Conclusions: This 1-year PMS revealed probable ADRs in elderly Japanese patients with T2DM prescribed ipragliflozin in real-world settings, with no new safety concerns. The risk factors for ADRs varied but could be rationalized. The results should help physicians to identify possible treatment-emergent ADRs in ipragliflozin-treated patients.ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 99%

Real-world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): final results of a post-marketing surveillance study

Yokote

Terauchi

Nakamura

et al. 2016

Expert Opinion on Pharmacotherapy

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“…In a study in which patients were treated with ipragliflozin monotherapy, significant reductions in HOMA‐IR levels and significant increases in HOMA‐β levels from baseline were observed at the end of the 12‐week treatment 21. In another study in patients whose T2DM was inadequately controlled by metformin, addition of ipragliflozin resulted in significant decrease in HOMA‐IR levels compared with placebo after 24 weeks of treatment 14. Other studies of SGLT2 inhibitors also reported a significant decrease in insulin resistance and a significant increase in β‐cell function at the EOT 22, 23.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

Han

Chon

Chung

et al. 2018

Diabetes Obesity Metabolism

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AimTo evaluate the efficacy and safety of ipragliflozin vs placebo as add‐on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM).MethodsThis double‐blind, placebo‐controlled, multi‐centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT).ResultsIn total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add‐on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were −0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference −0.83% [95% CI −1.07 to −0.59]; P < .0001). More ipragliflozin‐treated patients than placebo‐treated patients achieved HbA1c target levels of <7.0% (44.4% vs 12.1%) and < 6.5% (12.5% vs 1.5%) at EOT (P < .05 for both). Fasting plasma glucose, fasting serum insulin, body weight and homeostatic model assessment of insulin resistance decreased significantly at EOT, in favour of ipragliflozin (adjusted mean difference −1.64 mmol/L, −1.50 μU/mL, −1.72 kg, and −0.99, respectively; P < .05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). No previously unreported safety concerns were noted.ConclusionsIpragliflozin as add‐on to metformin and sitagliptin significantly improved glycaemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.

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confidence: 99%

“…In a clinical study of overweight patients with T2DM, treatment with ipragliflozin induced modest weight loss accompanied by a reduction in fat mass, while also improving glycemic control. 14,15) Analysis of body composition revealed that the reduction of body fat was the largest contributor to the reduction in body weight. 15) Dapagliflozin also reduced total body weight in obese patients with T2DM, predominantly by reducing total-body fat mass, wherein the decrease in visceral fat mass was greater than that in subcutaneous fat mass.…”

Section: )mentioning

confidence: 99%

“…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.…”

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

Takasu

Hayashizaki

Hirosumi

et al. 2017

Biological & Pharmaceutical Bulletin

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Sodium glucose cotransporter 2 (SGLT2) inhibitors improve hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. In addition to their antihyperglycemic effect, SGLT2 inhibitors also reduce body weight and fat mass in obese and overweight patients with T2DM. However, whether or not SGLT2 inhibitors similarly affect body composition of non-obese patients with T2DM remains unclear. In this study, we investigated the effect of the SGLT2 inhibitor ipragliflozin on body composition in a Goto-Kakizaki (GK) rat model of non-obese T2DM. GK rats were treated with ipragliflozin once daily for 9 weeks, starting at 23 weeks of age. Body composition was then analyzed using dual-energy X-ray absorptiometry. Treatment with ipragliflozin increased urinary glucose excretion, reduced hemoglobin A1c (HbA1c) levels and suppressed body weight gain as the dose increased. Body composition analysis revealed that body fat mass was lower in the ipragliflozin-treated groups than in the control group, while lean body mass and bone mineral contents were comparable between groups. Thus, an SGLT2 inhibitor ipragliflozin was found to promote preferential loss of fat mass in a rat model of non-obese T2DM. Ipragliflozin might also promote preferential loss of fat in non-obese patients with T2DM.Key words ipragliflozin; sodium glucose cotransporter 2 (SGLT2) inhibitor; body composition; anti-diabetic drug; type 2 diabetes mellitus Type 2 diabetes mellitus (T2DM) is characterized by either or both disturbed insulin secretion from pancreatic β-cells or insufficient action of insulin (insulin resistance) in peripheral tissues.1,2) Treatment of T2DM typically starts with diet and exercise to reduce excess body weight, which is effective for glycemic control, 3) as extra fat is known to increase insulin resistance.4) If glycemic control cannot be effectively achieved through diet and exercise, treatment then progresses to the use of several types of oral antihyperglycemic drug. 5,6) However, most of these compounds either induce weight gain (insulin, sulfonylureas, glinides, and thiazolidinediones) or help maintain current weight (metformin, α-glucosidase inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors).5,6) Achieving weight loss along with fat loss using such medications has thus far proven difficult. 7)Sodium glucose cotransporter 2 (SGLT2) inhibitors have recently been developed as antidiabetic drugs. 8,9) SGLT2, a low-affinity and high-capacity glucose transporter, is expressed specifically on the luminal surface of cells in the S1 segment of the proximal tubule 10) and reabsorbs approximately 90% of glucose in the glomerular filtrates in normal glucose-tolerant individuals. 8)SGLT2 inhibitors prevent this reabsorption, thereby increasing urinary glucose excretion and subsequently decreasing blood glucose levels. Treatment with SGLT2 inhibitors improves glycemic parameters and is associated with reduction in body weight in patients with T2DM. 11,12) Further, reduction of waist circumference...

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Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double‐blind, placebo‐controlled study

Cited by 92 publications

References 11 publications

Real-world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): final results of a post-marketing surveillance study

Real-world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): final results of a post-marketing surveillance study

Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

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

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