Ipragliflozin as an Initial Therapy in Drug Naïve Subjects with Type 2 Diabetes

Kutoh, Eiji; Wada, Asuka; Murayama, T.; Hirate, M.

doi:10.1055/s-0035-1569454

Cited by 4 publications

(20 citation statements)

References 28 publications

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“…Similar glycemic and non-glycemic efficacies were reported with other SGLT-2 inhibitors [6–8]. With the simple mechanism of discarding glucose into the urine, SGLT-2 inhibitors including canagliflozin were shown to ameliorate beta-cell function and insulin resistance [1–3, 6–9]. However, consistent with their mechanisms of action, they are associated with a higher incidence of certain adverse events including genital mycotic infections, urinary tract infections, osmotic diuretic-related adverse events, and volume depletion-related adverse events [10].…”

Section: Introductionmentioning

confidence: 79%

Canagliflozin as an Initial Therapy in Drug-Naïve Subjects with Type 2 Diabetes Mellitus: A Potential Involvement of Atherogenic Lipids in its Glycemic Efficacy

Kutoh

Wada²,

Murayama

et al. 2017

Drugs R D

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Background and ObjectivesThe aim of this study is to investigate canagliflozin as an initial therapy in type 2 diabetes mellitus and to explore the effects on metabolic parameters in relation to effects on glycemic control.Subjects and MethodsTreatment-naïve subjects with type 2 diabetes mellitus received canagliflozin 50–100 mg/day monotherapy. At 3 months, levels of glycemic and non-glycemic parameters were compared with those at baseline (n = 39). As a comparator, our previous data of baseline glycosylated hemoglobin (HbA1c)-matched treatment-naïve subjects with ipragliflozin 25–50 mg monotherapy (n = 27) were employed.ResultsSignificant reductions in HbA1c (from 9.96 to 8.33%), fasting blood glucose (−23.9%), homeostasis model assessment-R (HOMA-R, −33.5%), body mass index (−1.8%), and uric acid (UA, −5.2%) levels and significant increases in homeostasis model assessment-B (HOMA-B, 30.1%) levels were observed. Approximately one third of the subjects experienced certain adverse events. Similar results were obtained with ipragliflozin. Baseline levels of HbA1c, triglycerides, non-high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were chosen as significant contributing factors for the changes in HbA1c levels with canagliflzoin, while only baseline HbA1c levels were selected as such a factor with ipragliflozin. Significant positive correlations between the changes in HbA1c and changes in non-HDL-C (R = 0.3954) or between changes in HbA1c and changes in LDL-C (R = 0.4317) were observed with canagliflozin. With ipragliflozin, no such correlations were noted. No correlations between the changes in HbA1c and changes in body mass index were seen with both drugs.ConclusionsThese results suggest that (1) canagliflozin appears to offer clinically beneficial outcomes as an initial therapy in subjects with type 2 diabetes mellitus, although with certain adverse events. (2) Atherogenic cholesterols including non-HDL-C and LDL-C could be involved in the glycemic efficacy of canagliflozin. This was not the case with ipragliflozin. (3) Unexpectedly, weight reductions with canagliflozin are not associated with its glycemic efficacy.

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Section: Introductionmentioning

confidence: 79%

Canagliflozin as an Initial Therapy in Drug-Naïve Subjects with Type 2 Diabetes Mellitus: A Potential Involvement of Atherogenic Lipids in its Glycemic Efficacy

Kutoh

Wada²,

Murayama

et al. 2017

Drugs R D

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“…Similar glycemic and non-glycemic efficacies were reported with other SGLT-2 inhibitors [8, 9]. Via the simple mechanism of discarding glucose into the urine (correcting glucotoxicity) [10], ipragliflozin was shown to ameliorate impaired beta-cell function and insulin resistance [11]. Furthermore, preliminary reports indicated that ipragliflozin could regulate free fatty acid (FFA) levels, which might consequently influence lipotoxicity and thereby affect beta-cell function [12].…”

Section: Introductionmentioning

confidence: 88%

“…SGLT2 inhibitors are currently used as add-on therapy to metformin or other drugs as part of dual or triple therapy. However, they could also be used as an alternative first-line option in patients with contraindications to or intolerance of metformin (see Kutoh et al [11] and the references therein).…”

Section: Introductionmentioning

confidence: 99%

“…One of the most favorable non-glycemic efficacies of SGLT-2 inhibitors, including ipragliflozin, is their ability to reduce body weight [4, 11]. However, little is known about whether a reduction in body weight affects glycemic and non-glycemic parameters.…”

Section: Introductionmentioning

confidence: 99%

“…However, little is known about whether a reduction in body weight affects glycemic and non-glycemic parameters. Preliminary results suggested that reductions in body weight were not associated with changes in glycemic parameters [11, 15]. This study was initiated to investigate the link between changes in body weight and changes in glycemic and non-glycemic parameters.…”

Section: Introductionmentioning

confidence: 99%

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Distinct Glucose-Lowering Mechanisms of Ipragliflozin Depending on Body Weight Changes

Kutoh¹,

Murayama²,

Wada³

et al. 2016

Drugs R D

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BackgroundSodium-glucose co-transporter 2 inhibitors have been shown to reduce body weight. However, little is known about whether a reduction in body weight affects glycemic and non-glycemic parameters.ObjectivesThe aim of this study was to investigate the link between the changes in body weight and those in metabolic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM) receiving ipragliflozin monotherapy.MethodsSubjects received ipragliflozin monotherapy 25–50 mg/day for 3 months (n = 33). They were then divided into two groups: group L (‘lost’; n = 17) comprised patients who lost weight (change [Δ] in body mass index [BMI] ≤ −0.75, p < 0.00001), and group N (‘neutral’; n = 16) comprised patients who did not lose weight (ΔBMI > −0.75, not significant [NS]).ResultsIn these two groups, similar reductions were observed in glycated hemoglobin (HbA1c) levels (group L: 9.76–8.02%, p < 0.00001; group N: 10.07–8.36%, p < 0.0005). Homeostasis model assessment (HOMA)-B levels increased in both groups, with inter-group differences (p < 0.05; +38.91 vs. +96.83% in group L and N, respectively). However, some parameters showed distinct regulatory patterns. For instance, in group L, reductions were observed in HOMA-R (−20.18%, p < 0.04) and uric acid (UA; −8.91%, p < 0.02) levels. Correlations were seen between the change in HOMA-R and those in fasting blood glucose (FBG) levels (R = 0.557, p < 0.02). Non-significant increases in free fatty acid (FFA) levels and decreases in non-high-density lipoprotein cholesterol (non-HDL-C) or low-density lipoprotein cholesterol (LDL-C) levels were also noted. In group N, reductions in FFA levels (−17.07%, p < 0.05) were observed, and negative correlations were seen between ΔHOMA-B and ΔFBG (R = −0.4781, p < 0.05) and between Δ FFA and Δ HOMA-B levels (R = −0.4305, p < 0.05). Non-significant increases in non-HDL-C and LDL-C levels were also noted. Inter-group differences existed between group L and group N in the changes in non-HDL-C and LDL-C levels (both p < 0.05).ConclusionsThese results indicate that ipragliflozin may possess distinct dual glucose-lowering mechanisms depending on body weight changes. Degrees of insulin resistance decrease in subjects who lose weight. Conversely, ipragliflozin reduces lipotoxicity (FFA levels), thereby activating beta-cell function, in subjects who do not lose weight. Similar glycemic efficacies were observed in both cases. In patients who lost weight, ipragliflozin was associated with improvements in the levels of metabolic parameters related to cardiovascular risk factors, including UA and atherogenic lipid levels (non-HDL-C and LDL-C) compared with those who did not lose weight.

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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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Ipragliflozin as an Initial Therapy in Drug Naïve Subjects with Type 2 Diabetes

Cited by 4 publications

References 28 publications

Canagliflozin as an Initial Therapy in Drug-Naïve Subjects with Type 2 Diabetes Mellitus: A Potential Involvement of Atherogenic Lipids in its Glycemic Efficacy

Canagliflozin as an Initial Therapy in Drug-Naïve Subjects with Type 2 Diabetes Mellitus: A Potential Involvement of Atherogenic Lipids in its Glycemic Efficacy

Distinct Glucose-Lowering Mechanisms of Ipragliflozin Depending on Body Weight Changes

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

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