Sodium-glucose Cotransporter 2 Inhibitor Ipragliflozin Research Articles

Long-term observation of estimated fluid volume reduction after the initiation of ipragliflozin in patients with type 2 diabetes mellitus: a sub-analysis from a randomized controlled trial (PROTECT)

Backgrounds/AimRecent studies have shown that the addition of sodium-glucose co-transporter 2 (SGLT2) inhibitors gradually reduces the estimated fluid volume parameters in a broad range of patient populations, suggesting that this mediates the clinical benefits of SGLT2 inhibitors in preventing heart failure. Here, we sought to examine the long-term (24 months) effect of the SGLT2 inhibitor ipragliflozin on the estimated fluid volume parameters in patients with type 2 diabetes mellitus (T2DM).MethodsIn this prespecified sub-analysis of the PROTECT (Prevention of Atherosclerosis by SGLT2 Inhibitor: Multicenter, Randomized Controlled Study) trial, which was an investigator-initiated, multicenter, prospective, randomized, open-label, clinical trial primarily designed to evaluate the effect of ipragliflozin treatment administered for 24 months on carotid atherosclerosis in patients with T2DM, we evaluated serial changes in estimated plasma volume (ePV, %) calculated using the Straus formula and estimated extracellular volume (eEV, mL) calculated by the body surface area by 24 months following the initiation of 50-mg ipragliflozin once daily and compared them with those following standard care for T2DM (non-SGLT2 inhibitor use).ResultsThis sub-analysis included 464 patients (ipragliflozin, n = 232; control, n = 232), a full analysis set of the PROTECT trial. In an analysis using mixed-effects models for repeated measures, relative to the control group, ipragliflozin significantly reduced ePV by − 10.29% (95% confidence interval [CI] − 12.47% to − 8.11%; P < 0.001) at 12 months and − 10.76% (95% CI − 12.86% to − 8.67%; P < 0.001) at 24 months. Additionally, ipragliflozin significantly reduced eEV by − 190.44 mL (95% CI − 249.09 to − 131.79 mL; P < 0.001) at 12 months and − 176.90 mL (95% CI − 233.36 to − 120.44 mL; P < 0.001) at 24 months. The effects of ipragliflozin on these parameters over 24 months were mostly consistent across various patient clinical characteristics.ConclusionsThis prespecified sub-analysis from the PROTECT trial demonstrated that ipragliflozin treatment, compared with the standard care for T2DM, reduced two types of estimated fluid volume parameters in patients with T2DM, and the effect was maintained for 24 months. Our findings suggest that SGLT2 inhibitor treatment regulates clinical parameters incorporated into the calculating formulas analyzed and consequently fluid volume status for the long-term, and this may be at least partly associated with clinical benefits from chronic use of SGLT2 inhibitors.Trial registration Japan Registry of Clinical Trials, ID jRCT1071220089

The Role of SGLT2 Inhibitor Ipragliflozin on Cardiac Hypertrophy and microRNA Expression Profiles in a Non-diabetic Rat Model of Cardiomyopathy.

Evidence from clinical trials suggests that the cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors may arise through non-glycemic control-related mechanisms. Further, the cardiovascular advantages of SGLT2 inhibitors are likely present among non-diabetic patients with known cardiovascular diseases (CVDs). Here, we studied the impact of ipragliflozin, a selective SGLT2 inhibitor, on cardiac histopathology and microRNA (miRNA) expression profiles in a non-diabetic rat model of cardiomyopathy. Ipragliflozin was added to chow (0.01% (w/w)) and given to male DahlS.Z-Leprfa/Leprfa (DS/obese) rats for 6 weeks. Similarly aged male DahlS.Z-Lepr+/Lepr+ (DS/lean) rats were treated as controls. Measurements of systolic blood pressure (SBP) and heart rate (HR) were taken every other week. Following ipragliflozin treatment for 6 weeks, we conducted echocardiography, histopathological examination, and miRNA expression analysis (microarray). The impact of ipragliflozin on blood parameters was additionally examined. In DS/obese rats, ipragliflozin reduced SBP without affecting HR, reduced interventricular septal thickness in echocardiography and left ventricular (LV) organ weight, and improved hypertrophy of cardiomyocytes according to histopathological experiments. Further, ipragliflozin reduced plasma inflammatory cytokine levels in DS/obese rats. Additionally, ipragliflozin treatment altered the expression profile of miRNAs related to cardiac hypertrophy and heart failure in the LV compared to DS/obese control rats. Ipragliflozin prevented LV hypertrophy and altered related miRNA expression profiles in non-diabetic DS/obese rats. These findings suggest that miRNAs may play a partial role in regulating the structure of the heart and that SGLT2 inhibitors may exert cardio-protective effects by changing miRNA expression profiles in non-diabetic patients with CVDs.

SGLT2 inhibitor ipragliflozin exerts antihyperglycemic effects via the blood glucose-dependent increase in urinary glucose excretion in type 2 diabetic mice

This study investigated the antihyperglycemic effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin via the blood glucose-dependent increase in urinary glucose excretion in KK/Ay type 2 diabetic mice. In oral glucose tolerance tests (glucose load: 1, 2, or 4 g/kg) in 24-h-fasted mice, blood glucose levels increased in a glucose-loading dose-dependent manner. Oral administration of ipragliflozin (1 mg/kg) significantly inhibited the increase in blood glucose concomitant with urinary glucose excretion. To investigate the effects of ipragliflozin under low blood glucose conditions, blood glucose level and urinary glucose excretion were examined under fasting conditions in diabetic mice that had prefasted for 0, 6, 12, 18, or 24 h. Ipragliflozin significantly lowered blood glucose levels in mice that had prefasted for 0, 6, or 12 h, but not 18 h or more. Blood glucose level was well correlated with ipragliflozin-induced antihyperglycemic and urinary glucose excretion effects, suggesting that these effects occur in a blood glucose-dependent manner. Thus, in a hyperglycemic state, ipragliflozin exerts a potent antihyperglycemic effect and marked increases in urinary glucose excretion; however, in a non-hyperglycemic or hypoglycemic state, the hypoglycemic effect is weak. Ipragliflozin may therefore be a useful antidiabetic agent for normalizing daily blood glucose fluctuations in type 2 diabetes.

Study of glucagon response and its association with glycemic control and variability after administration of ipragliflozin as an adjunctive to insulin treatment in patients with type 1 diabetes (Suglat-AID)

Abstract Background: Despite advances in insulin preparation, insulin delivery systems and glucose monitoring, it is extremely difficult to maintain glucose levels within the non-diabetic range in patients with type 1 diabetes (T1D). Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently raised the prospect of improving glucometabolic outcomes in an insulin-independent manner. SGLT2 inhibitors adjunctive to insulin treatment have been shown in T1D clinical trials to improve glycemic variability without increasing hypoglycemia. Conversely, some meta-analyses raised valid concerns regarding increased risk of euglycemic ketoacidosis after treatment of SGLT2 inhibitors in T1D. Increased hepatic ketogenesis caused by elevated glucagon secretion in patients receiving SGLT2 inhibitors has been discussed as a potential mechanism for euglycemic ketoacidosis in insulinopenic T1D, but the mechanism has not been fully elucidated. In this study, we investigate 1) whether glucagon secretions are altered by treatment with the SGLT2 inhibitor ipragliflozin as an adjunctive to insulin therapy in T1D patients, and 2) whether the glucagon responses are associated with amelioration/deterioration in glycemic control and serum ketone levels. Methods/design: This is a single-arm, multicenter, open-label, prospective exploratory trial designated Suglat-AID. Eligible participants are absolute-insulin-deficient T1D patients with glycated hemoglobin levels over 7.5%, who are receiving intensive insulin therapy using intermittently scanned continuous glucose monitoring. Thirty patients will be recruited and will take orally administered ipragliflozin as an add-on to insulin therapy. The primary endpoint is the change in glucagon levels during a mixed meal tolerance test between before and 12 weeks after initiation of ipragliflozin. Secondary endpoints include the changes in insulin and glucose levels during mixed meal tolerance test, the change in the patients’ glycemic control, change in the intermittently scanned continuous glucose monitoring-based profile and others. Discussion: To the best of our knowledge, this will be the first study assessing changes in glucagon response to an SGLT2 inhibitor in patients with T1D in a clinical setting. This study may help to clarify the pathophysiological role of glucagon in glycemia and ketogenesis in patients with T1D receiving SGLT2 inhibitors. Trial registration: This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (https://umin.ac.jp) on 24 March, 2020 under registration no. UMIN000039635.

Ipragliflozin Ameliorates Diabetic Nephropathy Associated with Perirenal Adipose Expansion in Mice.

Sodium glucose cotransporter-2 (SGLT2) inhibitors inhibit the development of diabetic nephropathy (DN). We determined whether changes in perirenal fat (PRAT) by a SGLT2 inhibitor ipragliflozin (Ipra) contribute to the suppression of DN development. High-fat diet (HFD)-fed mice were used as a DN model and were treated with or without Ipra for 6 weeks. Ipra treatment reduced urinary albumin excretion (UAE) and glomerular hypertrophy in HFD-fed mice. In the PRAT of Ipra-treated mice, adipocyte size was increased, and inflammation, fibrosis, and adipocyte death were suppressed. In conditioned medium made from PRAT (PRAT-CM) of Ipra-treated mice, the concentration of leptin was significantly lower than PRAT-CM of mice without Ipra treatment. Serum leptin concentration in renal vein positively correlated with UAE. PRAT-CM from HFD-fed mice showed greater cell proliferation signaling in mouse glomerular endothelial cells (GECs) than PRAT-CM from standard diet-fed mice via p38MAPK and leptin-dependent pathways, whose effects were significantly attenuated in PRAT-CM from Ipra-treated mice. These findings suggest that Ipra-induced PRAT expansion may play an important role in the improvement of DN in HFD-fed mice. In vitro experiments suggest that reduced PRAT-derived leptin by Ipra could inhibit GECs proliferation, possibly contributing to the suppression of DN development.

Sodium-glucose cotransporter 2 inhibition attenuates protein overload in renal proximal tubule via suppression of megalin O-GlcNacylation in progressive diabetic nephropathy

AimsThe crosstalk between sodium-glucose cotransporter 2 (SGLT2) inhibition and a membrane-associated endocytic receptor megalin function involved in renal proximal tubular protein overload in progressive diabetic nephropathy (DN) is uncertain. Here, we determined whether SGLT2 inhibition affects megalin endocytic function through suppressing its O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) and protects the diabetic kidney from protein overload. Materials and methodWe treated 8-week-old male non-obese and hypoinsulinemic KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DN with an SGLT2 inhibitor ipragliflozin or insulin for 6 weeks, and investigated the endocytic function (proximal tubular protein reabsorption), renal expression and O-GlcNAcylation of megalin along with their effects on renal phenotypes including histology and biochemical markers. ResultsThe treatment with ipragliflozin, but not insulin, suppressed megalin O-GlcNAcylation and accelerated its internalization, resulting in reduction in proximal tubular reabsorption of the highly filtered plasma proteins such as albumin and neutrophil gelatinase-associated lipocalin. These alterations following the ipragliflozin treatment contributed to amelioration of proximal tubular protein overload, mitochondrial morphological abnormality, and renal oxidative stress and tubulointerstitial fibrosis. ConclusionsThe present study provides a novel crosstalk mechanism between SGLT2 inhibition and megalin underlying the potential renal benefits of SGLT2 inhibition in DN.

SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation.

Cancer is currently one of the major causes of death in patients with type 2 diabetes mellitus. We previously reported the beneficial effects of the glucagon-like peptide-1 receptor agonist exendin-4 against prostate and breast cancer. In the present study, we examined the anti-cancer effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin using a breast cancer model. In human breast cancer MCF-7 cells, SGLT2 expression was detected using both RT-PCR and immunohistochemistry. Ipragliflozin at 1-50 μM significantly and dose-dependently suppressed the growth of MCF-7 cells. BrdU assay also revealed that ipragliflozin attenuated the proliferation of MCF-7 cells in a dose-dependent manner. Because the effect of ipragliflozin against breast cancer cells was completely canceled by knocking down SGLT2, ipragliflozin could act via inhibiting SGLT2. We next measured membrane potential and whole-cell current using the patch clamp technique. When we treated MCF-7 cells with ipragliflozin or glucose-free medium, membrane hyperpolarization was observed. In addition, glucose-free medium and knockdown of SGLT2 by siRNA suppressed the glucose-induced whole-cell current of MCF-7 cells, suggesting that ipragliflozin inhibits sodium and glucose cotransport through SGLT2. Furthermore, JC-1 green fluorescence was significantly increased by ipragliflozin, suggesting the change of mitochondrial membrane potential. These findings suggest that the SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation via membrane hyperpolarization and mitochondrial membrane instability.

Acute and Direct Effects of Sodium-Glucose Cotransporter 2 Inhibition on Glomerular Filtration Rate in Spontaneously Diabetic Torii Fatty Rats.

Recent clinical studies indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors exhibit a renoprotective effect. While studies at the single nephron level suggest that direct effects of SGLT2 inhibitors on renal hemodynamics may be a possible mechanism underlying their renoprotective effect, few studies have focused on such direct effects at the whole-kidney level. In the present study, we investigated the acute and direct effect of SGLT2 inhibition on creatinine clearance, an index of whole-kidney glomerular filtration rate (GFR), in a rat model of type 2 diabetes. Twelve to fifteen-week-old male Spontaneously Diabetic Torii (SDT) fatty rats and Sprague-Dawley rats were used as diabetic animals and non-diabetic controls, respectively. Under general anesthesia, baseline urine samples were collected from the left and right ureters for 1 h. The selective SGLT2 inhibitor ipragliflozin or vehicle was subsequently administered intravenously and post-drug urine was collected for 1 h. Baseline and post-drug blood samples were collected immediately before baseline urine collection and immediately after post-drug urine collection, respectively. Plasma glucose, urine volume, urinary glucose and albumin excretion were measured, and creatinine clearance was calculated. Blood pressure and heart rate were monitored continuously throughout the experiment. A single intravenous injection of ipragliflozin increased both urine output and glucose excretion, but reduced creatinine clearance without affecting systemic blood pressure. These results suggest that SGLT2 inhibition directly reduced whole-kidney GFR, most likely due to a reduction in intraglomerular pressure, by altering local renal hemodynamics, which may contribute to the renoprotective effects demonstrated in clinical studies.

Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice

BackgroundPerivascular adipose tissue (PVAT) plays a critical role in the pathogenesis of cardiovascular disease. It is unclear whether inhibition of sodium glucose cotransporter 2 (SGLT2) in subjects with type 2 diabetes (T2DM) could affect PVAT characters, and whether the SGLT2 inhibitors-induced changes of adipose tissue, especially the alternation of adipose tissue-derived secretory factors, affect vascular pathophysiology.MethodsWestern-type diet (WD) fed wild-type mice were treated with or without an SGLT2 inhibitor ipragliflozin (Ipra) for 10 weeks. WEHI 274.1 and primary vascular smooth muscle cells were incubated with conditioned media (CM) of epididymal adipose tissue (Epi) or abdominal PVAT of Ipra- or vehicle-treated mice fed a WD. Epi of Ipra- or vehicle-treated mice fed a WD was implanted onto cuff-placed femoral arteries of apoE-deficient mice.ResultsIpra increased adipocyte size associated with decreased expression of pro-inflammatory and fibrosis-related genes in abdominal PVAT of WD-fed mice. Ipra also suppressed WD-induced macrophages accumulation, fibrosis, and adipocyte death in abdominal PVAT. In CM of abdominal PVAT from Ipra-treated mice, concentration of leptin was significantly lower than that from vehicle-treated mice. In vitro, migration of WEHI 274.1 and primary vascular smooth muscle cells were more enhanced by CM of Epi or abdominal PVAT from vehicle-treated mice than that from Ipra-treated mice. Perivascular implantation of Epi from Ipra-treated mice to apolipoprotein E-deficient mice attenuated cuff-induced neointimal hyperplasia and vascular remodeling compared to that from vehicle-treated mice.ConclusionsThe Ipra-induced changes of abdominal PVAT will lead to a better understanding of unveiled mechanisms by which SGLT2 inhibitors prevent cardiovascular complications in T2DM, and the development of new therapeutic strategies targeting PVAT.

Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat.

The chronic intrinsic diuretic and natriuretic tone of sodium-glucose cotransporter 2 (SGLT2) inhibitors is incompletely understood because their effect on body fluid volume (BFV) has not been fully evaluated and because they often increase food and fluid intake at the same time. Here we first compared the effect of the SGLT2 inhibitor ipragliflozin (Ipra, 0.01% in diet for 8 wk) and vehicle (Veh) in Spontaneously Diabetic Torii rat, a nonobese type 2 diabetic model, and nondiabetic Sprague-Dawley rats. In nondiabetic rats, Ipra increased urinary excretion of Na+ (UNaV) and fluid (UV) associated with increased food and fluid intake. Diabetes increased these four parameters, but Ipra had no further effect, probably because of its antihyperglycemic effect, such that glucosuria and, as a consequence, food and fluid intake were unchanged. Fluid balance and BFV, determined by bioimpedance spectroscopy, were similar among the four groups. To study the impact of food and fluid intake, nondiabetic rats were treated for 7 days with Veh, Ipra, or Ipra+pair feeding+pair drinking (Pair-Ipra). Pair-Ipra maintained a small increase in UV and UNaV versus Veh despite similar food and fluid intake. Pair-Ipra induced a negative fluid balance and decreased BFV, whereas Ipra or Veh had no significant effect compared with basal values. In conclusion, SGLT2 inhibition induces a sustained diuretic and natriuretic tone. Homeostatic mechanisms are activated to stabilize BFV, including compensatory increases in fluid and food intake.

As-required administration of sodium glucose co-transporter-2 inhibitors: three case studies

Sodium glucose co-transporter-2 (SGLT2) inhibitors are used to reduce glycated hemoglobin (HbA1c) levels. Although they have the potential to reduce body weight in patients with type 2 diabetes mellitus (T2DM), some patients may gain weight. We found that the effects of the SGLT2 inhibitor ipragliflozin were maintained for 48 h when used in combination with nifedipine, so we considered that a daily SGLT2 inhibitor might be unnecessary. Therefore, we investigated whether as-required single doses of an SGLT2 inhibitor would be clinically relevant in three patients having difficulty maintaining blood glucose control when they were unable to exercise or during social situations. All three patients demonstrated improved HbA1c levels with as-required single doses of an SGLT2 inhibitor. These patients experienced no adverse effects or weight gain relative to taking an SGLT2 inhibitor daily. Thus, as-required single-dose SGLT2 inhibitors could be one of the many options to improve blood glucose control in T2DM.

Antidiabetic effects of SGLT2 inhibitor ipragliflozin in type 2 diabetic mice fed diets containing different carbohydrate contents

AimsDaily intake of carbohydrates differs among individual patients with type 2 diabetes. Here, we investigated whether or not dietary carbohydrate content affects the efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in type 2 diabetic mice. Main methodsDiabetic mice were fed a regular (50% kcal), high (75% kcal)-, or low (25% kcal)-carbohydrate diet. Ipragliflozin was orally administered once a day for 4 weeks. Key findingsIn all groups, mice exhibited characteristics of type 2 diabetes, including hyperglycemia, hyperinsulinemia, and obesity. Hyperglycemia was more severe in the high-carbohydrate diet group and milder in the low-carbohydrate diet group than in the regular diet group. In all diabetic mice, ipragliflozin significantly increased urinary glucose excretion and improved hyperglycemia, hyperinsulinemia, glucose tolerance, insulin resistance, obesity, and nephropathy. Although these antidiabetic effects of ipragliflozin were more marked in the high-carbohydrate diet group (which showed more severe hyperglycemia) than in the other two groups, no significant differences in effective dose or degree of response were observed among the three groups. SignificanceThe antidiabetic effects of ipragliflozin were not greatly affected by dietary carbohydrate content, suggesting that ipragliflozin may have similar efficacy for patients with type 2 diabetes regardless of carbohydrate intake.

Antidiabetic and antiobesity effects of SGLT2 inhibitor ipragliflozin in type 2 diabetic mice fed sugar solution

Obesity due to excessive calorie intake is a known aggravating factor contributing to the development and progression of type 2 diabetes. Recently, excessive intake of sugar-sweetened beverages has presented challenges in stemming the tide of obesity. Here, we investigated the possible effects of sugar solution intake on the antidiabetic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in type 2 diabetic mice that were fed ordinary drinking water, water + glucose solution, or water + sucrose solution. Under all feeding conditions, all mice exhibited type 2 diabetic symptoms, including hyperglycemia, hyperinsulinemia, and obesity; ipragliflozin subsequently improved these symptoms through increases in urinary glucose excretion. Effective dose of and response to ipragliflozin for diabetes improvement did not significantly differ by feeding condition. Further, under all feeding conditions, ipragliflozin administration resulted in significantly increased intake of both water and sugar solutions in association with increased urine volume resulting from increased urinary glucose excretion. In sugar solution-fed diabetic mice, ipragliflozin administration tended to slightly increase the proportion of sugar solution intake in total drinking volume, although not significantly so. In addition, ipragliflozin significantly decreased calorie balance, as calculated using calorie intake from food and sugar solution and calorie excretion via urinary glucose excretion. Our observation that the antidiabetic and antiobesity effects of the SGLT2 inhibitor ipragliflozin were not greatly affected by sugar solution intake in type 2 diabetic mice suggests that, in a clinical setting, ipragliflozin will remain an effective treatment for type 2 diabetic patients with excessive intake of carbohydrates.

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

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.

Effects of Ipragliflozin on Diabetic Nephropathy and Blood Pressure in Patients With Type 2 Diabetes: An Open-Label Study.

BackgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors are novel agents used to treat type 2 diabetic patients. We investigated the efficacy of the SGLT2 inhibitor ipragliflozin on diabetic nephropathy in Japanese patients with type 2 diabetes.MethodsA 50 mg dose of ipragliflozin was administered for 24 weeks to 50 patients with type 2 diabetes who were concomitantly managed with diet and exercise therapy alone or antidiabetic medications other than SGLT2 inhibitors.ResultsAt the end of the 24-week ipragliflozin treatment, significant decreases in mean glycated hemoglobin (HbA1c) (1.0±1.2%) and body weight (2.7 ± 2.5 kg) were observed; in addition, median urinary albumin-to-creatinine ratio (UACR) significantly decreased from 15.5 (8.0 - 85.7) to 12.9 (7.4 - 36.3) mg/gCr. Sub-analysis by renal function at baseline revealed that median UACR in patients with estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2 decreased significantly from 12.3 (7.5 - 89.6) to 10.6 (5.8 - 27.3) mg/gCr. Furthermore, mean eGFR decreased significantly from 102.4 ± 8.6 to 93.6 ± 10.5 mL/min/1.73 m2 in these patients. In contrast, UACR and eGFR did not change significantly in patients with eGFR < 90. In addition, analysis of the relationship between the amount of change in UACR and blood pressure at 24 weeks revealed a significant positive correlation between UACR and SBP values, independently of the presence of diabetic nephropathy.ConclusionsOur results indicate that ipragliflozin may facilitate HbA1c control and body weight reduction. Furthermore, our results also raise the possibility that ipragliflozin significantly reduces urinary albumin levels and improves glomerular hyperfiltration in a subset of patients with type 2 diabetes.

Effect of 24-week treatment with ipragliflozin on proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes

ABSTRACTBackground: Chronic hyperglycemia has an adverse influence on beta-cell function, which is known as ‘glucotoxicity’. Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower the blood glucose concentration by enhancing urinary glucose excretion. This study was performed to clarify the influence of the SGLT2 inhibitor ipragliflozin on beta-cell function assessed from the plasma intact proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes.Research design and methods: This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio.Results: After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10–3 to 14.3 ± 9.0 × 10–3 and from 23.2 ± 14.9 × 10–3 to 13.7 ± 5.4 × 10–3, respectively (both p < 0.01 vs. baseline).Conclusions: These findings indicate that ipragliflozin might have a beneficial effect on beta-cells.

Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction.

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.