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Purpose: Owing to the absence of the most recent evidence on the efficacy and safety of luseogliflozin, our study aimed to conduct a systematic review and meta-analysis of luseogliflozin in patients with type 2 diabetes mellitus., Methods: A comprehensive search of electronic databases like PubMed, Cochrane CENTRAL, and Google Scholar was performed from the inception to the 31 st of August 2023 to identify the randomized controlled trials (RCTs) that examined the glucose and body weight lowering efficacy and safety outcomes of luseogliflozin in comparison with control or other active treatments. The fixed or random-effect model was used based on the heterogeneity identified using the I 2 statistic and Cochran's Q test., Results: Out of 50 non-duplicate articles identified through database searching, 8 RCTs (11 studies) with 1922 patients were included in this study. The efficacy outcomes like HbA1c (MD: -0.59%; 95% CI: -0.90, -0.29; P < 0.001), FPG (MD: -16.01 mg/dL; 95% CI: -19.46, -12.57; P < 0.001), PPG (MD: -36.63 mg/dL; 95% CI: -43.71, -29.55; P < 0.001) and body weight (MD: -1.66 kg; 95% CI: -2.23, -1.12; P < 0.001) were significantly reduced with luseogliflozin compared to the control group. Regarding the safety outcomes, there was no statistically significant difference between the two groups for hypoglycemia (OR: 1.14; 95% CI: 0.70, 1.84; P = 0.60). However, pollakiuria (OR: 4.08; 95% CI: 1.71, 9.69; P < 0.001) and any ADRs (OR: 2.04; 95% CI: 1.33, 3.14; P < 0.001) were significantly higher in the luseogliflozin group compared to the control., Conclusion: The current study identified a significant improvement in efficacy outcomes of HbA1c, FPG, PPG, and body weight in the luseogliflozin group. Non-significant safety results may be due to a smaller population size and fewer studies. Hence, long-term multicentric RCTs are needed to identify the safety and efficacy in a diversified population., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: The aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes., Materials and Methods: We conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and <9.0% and BMI ≥20 kg/m 2 despite treatment with a drug naïve or other than DPP-4 inhibitors or SGLT2 inhibitors. A total of 103 subjects were randomly assigned to receive once daily oral luseogliflozin (L) or teneligliptin (T). The primary endpoint was the effect of L vs. T on the change in logarithmus naturalis (Ln) disposition index (DI) (DI 0-120min ; combining measures of insulin secretion and sensitivity) from baseline to week 25-26 (post intervention), which was calculated by conducting an oral glucose tolerance test., Results: Ln DI 0-120min were improved in both groups: -0.46 ± 0.68 to -0.20 ± 0.59 ( p =0.03) in L group and -0.26 ± 0.60 to -0.05 ± 0.62 ( p =0.01) in T group. The change in Ln serum proinsulin/C-peptide ratio, a marker of β-cell dysfunction, was reduced in L group (1.63 ± 0.63 to 1.56 ± 0.68, p =0.16), but rather increased in T group (1.70 ± 0.75 to 1.90 ± 0.51, p =0.01), with significant difference between the two groups (-0.27; p =0.004)., Conclusions: Improvement of disposition index in subjects with obese type 2 diabetes was comparable between luseogliflozin and teneligliptin. On the other hand, it is likely that alleviation of β-cell dysfunction is more effective with luseogliflozin compared to tenegliptin., Clinical Trial Registration: https://rctportal.niph.go.jp/en, identifier jRCTs061190008., Competing Interests: HK has received honoraria for lectures and received scholarship grants from Sanofi, Novo Nordisk, Lilly, Boehringer Ingelheim, MSD, Takeda, Ono Pharma, Daiichi Sankyo, Sumitomo Pharma, Mitsubishi Tanabe Pharma, Pfizer, Kissei Pharma, AstraZeneca, Astellas, Novartis, Kowa, Chugai and Taisho Pharma. KKa has been an advisor to, received honoraria for lectures from, and received scholarship grants from Novo Nordisk Pharma, Sanwa Kagaku Kenkyusho, Takeda, Taisho Pharmaceutical Co., Ltd, MSD, Kowa, Sumitomo Pharma, Novartis, Mitsubishi Tanabe Pharma, AstraZeneca, Nippon Boehringer Ingelheim Co., Ltd, Chugai, Daiichi Sankyo, and Sanofi. TK has received honoraria for lectures from Sumitomo Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shimoda, Katakura, Mashiko, Iwamoto, Nakanishi, Anno, Kawasaki, Obata, Fushimi, Sanada, Kohara, Isobe, Iwamoto, Hirukawa, Tatsumi, Kimura, Kimura, Mune, Kaku and Kaneto.)

Background: Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, potentially exerts pleiotropic effects on the liver. However, the sufficient evidence is still lacking. We aimed to investigate the effects of luseogliflozin on hepatic steatosis, fibrosis, and cardiometabolic risk factors in diabetic patients by a pooled meta-analysis., Methods: In this pooled meta-analysis, we enrolled diabetic patients who participated in phase III clinical trials of luseogliflozin (luseogliflozin group n = 302, placebo group n = 191). The primary outcomes were changes in fatty liver index (FLI) and Hepamet fibrosis score (HFS) after 24 weeks. The secondary outcomes were changes in cardiometabolic risk factors after 24 weeks. Statistical analysis was performed using propensity scoring analysis by the inverse probability of treatment weighting method., Results: Primary outcomes: Luseogliflozin significantly decreased FLI compared to placebo after 24 weeks (adjusted coefficient - 5.423, 95%CI - 8.760 to - 2.086, P = 0.0016). There was no significant difference in changes in HFS between the two groups. However, luseogliflozin significantly decreased HFS compared to placebo in diabetic patients with ALT > 30 U/L (adjusted coefficient - 0.039, 95%CI - 0.077 to - 0.001, P = 0.0438) and with FIB-4 index > 1.3 (adjusted coefficient - 0.0453, 95%CI - 0.075 to - 0.016, P = 0.0026). Secondary outcom8es: Luseogliflozin significantly decreased HbA1c level, HOMA-IR value, BMI, and uric acids level, and increased HDL cholesterol level compared to placebo., Conclusions: This pooled meta-analysis demonstrated that 24-week treatment with luseogliflozin improved hepatic steatosis and fibrosis indexes in diabetic patients, especially those with liver injury. Furthermore, luseogliflozin improved various cardiometabolic risk factors. Thus, luseogliflozin may be useful for improving MASLD in diabetic patients., (© 2024. The Author(s).)

Objectives: This study aimed to systematically review the effect of sugar substitute consumption on caries prevention in permanent teeth among children and adolescents., Data: Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing the clinical effect of sugar substitutes (both high- and low-intensity sweeteners) in preventing caries in permanent teeth among children and adolescents aged 6-19 were included., Sources: A systematic search was conducted in three databases (PubMed, Web of Science and Embase) without any restrictions on publication year., Study Selection: The initial search found 1,859 items, and finally, 15 studies (11 RCTs and 4 CCTs) with a total of 6325 participants (age: 6-18 years) were included. The Cochrane risk-of-bias assessment tools were used for quality assessment. Most (80%, 12/15) were graded as having a 'moderate' or 'high' risk of bias. All trials investigated sugar alcohol, which is a low-intensity sweetener. Xylitol was the most commonly investigated (73.3%, 11/15), followed by sorbitol (46.7%, 7/15), and erythritol (13.3%, 2/15). Results of the meta-analysis showed that both xylitol (standardized mean difference [SMD]: -0.50, 95% confidence interval [CI] -0.85 to -0.16, P = 0.005) and sorbitol (SMD: -0.10, 95% CI: -0.19 to -0.01, P = 0.03) had a significant effect in preventing dental caries compared to no treatment/placebo. No clinical trials on high-intensity sweeteners such as aspartame and saccharin were found., Conclusion: The consumption of xylitol or sorbitol is potentially effective in preventing caries in permanent teeth among children and adolescents. No clinical evidence is available regarding the role of high-intensity sweeteners in caries prevention., Clinical Significance: The use of xylitol or sorbitol as sugar substitutes has a beneficial effect in preventing dental caries among children and adolescents., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice., Method: C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated., Results: There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups., Conclusion: The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis., (© 2024 John Wiley & Sons Ltd.)

Objectives: This study aimed to evaluate the safety and efficacy of remogliflozin compared to vildagliptin as an add-on drug to metformin in type 2 diabetes mellitus (T2DM) treatment. Metformin is considered a first-line drug in T2DM. However, as the disease progresses with heightened insulin resistance and declining β-cell function, the use of metformin alone is often inadequate to achieve optimum glucose levels., Methods: This prospective, randomised study was conducted at Maulana Azad Medical College and Associated Hospital in New Delhi, India, between February 2020 to January 2021. This study recruited 60 T2DM patients aged 35-70 years with glycated haemoglobin (HbA1c) >6.5% taking metformin at a daily dosage of 1,500-3,000 mg for ≥3 months. Patients were randomly assigned in a 1:1 ratio to receive either vildagliptin (50 mg) or remogliflozin (100 mg) twice daily for 90 days. The primary endpoint was a change in HbA1c levels from baseline to the end of 90 days whereas secondary endpoints were changes in lipid profile and weight., Results: The decrement in mean HbA1c levels was significantly higher in the remogliflozin group than in the vildagliptin group (-8.1% versus -2.4%; P <0.001). In addition, more significant weight loss was found in remogliflozin-treated patients (-5.2% versus -0.6%; P <0.01). Both treatments were well tolerated throughout the study., Conclusion: Compared to vildagliptin, remoglilflozin was significantly more effective in glycaemic control and weight loss in patients with T2DM and can therefore be considered as an add-on drug in T2DM not adequately controlled by metformin monotherapy., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflict of interest., (© Copyright 2024, Sultan Qaboos University Medical Journal, All Rights Reserved.)

Intramyocardial hydrogel injection is a promising therapy to prevent negative remodeling following myocardial infarction (MI). In this study, we report a mechanism for in-situ gel formation without external stimulation, resulting in an injectable and tissue-retainable hydrogel for MI treatment, and investigate its therapeutic outcomes. A liquid-like polymeric solution comprising poly(3-acrylamidophenylboronic acid-co-acrylamide) (BAAm), polyvinyl alcohol (PVA), and sorbitol (S) increases the viscous modulus by reducing the pre-added sorbitol concentration is developed. This solution achieves a sol-gel transition in-vitro in heart tissue by spontaneously diffusing the sorbitol. After intramyocardial injection, the BAAm/PVA/S with lower initial viscous modulus widely spreads in the myocardium and gelate compared to a viscoelastic alginate (ALG) hydrogel and is retained longer than the BAAm/S solution. Serial echocardiogram analyses prove that injecting the BAAm/PVA/S into the hearts of subacute MI rats significantly increases the fraction shortening and ejection shortening and attenuates the expansion of systolic LV diameter for up to 21 d after injection compared to the saline injection as a control, but the ALG injection does not. In addition, histological evaluation shows that only the BAAm/PVA/S decreases the infarct size and increases the wall thickness 21 d after injection. The BAAm/PVA/S intramyocardial injection is better at restraining systolic ventricular dilatation and cardiac failure in the rat MI model than in the control groups. Our findings highlight an effective injectable hydrogel therapy for MI by optimizing injectability-dependent distribution and retention of injected material. STATEMENT OF SIGNIFICANCE: In-situ gelling material is a promising strategy for intramyocardial hydrogel injection therapy for myocardial infarction (MI). Since the sol-gel transition of reported materials is driven by external stimulation such as temperature, pH, or ultraviolet, their application in vivo remains challenging. In this study, we first reported a synthetic in-situ gelling material (BAAm/PVA/S) whose gelation is stimulated by spontaneously reducing pre-added sorbitol after contacting the heart tissue. The BAAm/PVA/S solution spreads evenly, and is retained for at least 21 d in the heart tissue. Our study demonstrated that intramyocardial injection of the BAAm/PVA/S with more extensive distribution and longer retention had better effects on preventing LV dilation and improving cardiac function after MI than that of viscoelastic ALG and saline solution. We expect that these findings provide fundamental information for the optimum design of injectable biomaterials for treating MI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

We report a patient with an extremely rare, combined diagnosis of PMM2-CDG and hereditary fructose intolerance (HFI). By comparing with other patients, under-galactosylation was identified as a feature of HFI. Fructose/sorbitol/sucrose restriction was initiated right afterwards. The patient is at the mild end of the PMM2-CDG spectrum, raising the question of sorbitol's role in the pathogenesis of PMM2-CDG and whether fructose/sorbitol/sucrose restriction could benefit other PMM2-CDG patients. Additionally, epalrestat, an emerging potential PMM2-CDG therapy, may benefit HFI patients., Competing Interests: Declaration of Competing Interest This work was supported by U54 NS115198 (GB, ACE and MH)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background & Aims: Inflammatory bowel disease (IBD) is a widespread gastrointestinal inflammatory disorder with globally increasing incidence. Clostridioides difficile infection (CDI) often occurs in patients with intestinal dysbiosis, such as after antibiotic therapy. Patients with IBD have increased incidence of CDI and the clinical outcome of IBD is reportedly worsened by CDI. However, the underlying reasons remain poorly understood., Methods: We performed a retrospective single-center and a prospective multicenter analysis of CDI in patients with IBD, including genetic typing of C difficile isolates. Furthermore, we performed a CDI mouse model to analyze the role of the sorbitol metabolization locus that we found distinguished the main IBD- and non-IBD-associated sequence types (STs). Moreover, we analyzed sorbitol concentration in the feces of patients with IBD and healthy individuals., Results: We detected a significant association of specific lineages with IBD, particularly increased abundance of ST54. We found that in contrast to the otherwise clinically predominant ST81, ST54 harbors a sorbitol metabolization locus and was able to metabolize sorbitol in vitro and in vivo. Notably, in the mouse model, ST54 pathogenesis was dependent on intestinal inflammation-induced conditions and the presence of sorbitol. Furthermore, we detected significantly increased sorbitol concentrations in the feces of patients with active IBD vs patients in remission or healthy controls., Conclusions: Sorbitol and sorbitol utilization in the infecting C difficile strain play major roles for the pathogenesis and epidemiology of CDI in patients with IBD. CDI in patients with IBD may thus be avoided or improved by elimination of dietary sorbitol or suppression of host-derived sorbitol production., (Published by Elsevier Inc.)

Objectives: A systematic review of published data was conducted with the aim of assessing the effects of sugar-free polyol chewing gums on gingival inflammation., Materials and Methods: Electronic and hand searches were performed to find clinical studies concerning the effects of sugar-free chewing gums on gingival scores. Prospective randomized controlled clinical trials published between 1971 and 2021 were included in the review., Results: The initial search identified 46 erythritol, 102 xylitol, 23 sorbitol, and nine maltitol chewing gum articles. After applying inclusion and exclusion criteria, seven xylitol chewing gum studies, one sorbitol, and one maltitol chewing gum study with either high or fair quality were reviewed. In five out of the seven xylitol studies, xylitol gum decreased gingival scores. In two studies, xylitol decreased gingival scores compared to a polyol gum, and in three studies compared to no gum/gum base. As for sorbitol and maltitol, only sorbitol gum chewing showed a small decrease in gingival scores compared to the controls., Conclusions: Habitual xylitol gum chewing may reduce gingival inflammation. The low number of studies and their heterogeneity provide clear indications that the effects of sugar-free polyol chewing gums on gingival inflammation need further, well-controlled studies., Clinical Relevance: Sugar-free chewing gums, especially xylitol gum, may function as adjuncts to toothbrushing for reducing gingival inflammation, but the evidence so far is inconclusive., (© 2022. The Author(s).)

Background: In the present study, patients with symptomatic knee osteoarthritis (OA) were treated with single intra-articular injection of a high molecular weight, non-cross-linked hyaluronic acid (HA), highly concentrated (2%) and associated with sorbitol (4%). The aims of this study were to (1) evaluate clinical outcome after 6 months, (2) evaluate clinical outcomes after 12 months and (3) evaluate clinical outcomes according to OA grade. Hypothesis of the study was that a single intra-articular injection of this HA associated with sorbitol leads to a significant clinical improvement within 6 months in patients with early or moderate knee OA., Materials and Methods: A total of 77 patients were enrolled in this prospective multicentric study. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score was recorded at baseline and at months 1, 3, 6 and 12 following the intra-articular injection. Moreover, a stratified analysis of all WOMAC items following the OA grade was performed for both groups of patients, one with low (grade I-II according to Kellgren-Lawrence classification) and another with moderate OA grade (grade III according to Kellgren-Lawrence) and the differences between groups were evaluated., Results: Seventy-three patients completed the 12 months follow-up. Pain, stiffness, functional limitation and total scores were significantly reduced at 1, 3 and 6 months (p < 0.05), but not at 12 months. Stratified analysis of all subscores according to OA grade showed that pain, functional limitation and total score decreased at 1, 3, 6 and 12 months (p < 0.05) in both groups. Stiffness was the only item that decreased significantly at 1, 3 and 6 months but not at 12 months in both groups. All subscore values were significantly lower in the group of patients with low OA grade compared to the one with moderate OA grade. No adverse events were reported., Conclusion: At 6 months after a single intra-articular injection of a high molecular weight, non-cross-linked HA associated with sorbitol, WOMAC scores decreased significantly. Clinical benefits were observed both in patients with low and in those with moderate OA grade, with better results in the first group., (© 2021. Istituto Ortopedico Rizzoli.)

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium-glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks. Licogliflozin 150 mg showed a significant 32% (80% confidence interval (CI): 21-43%; P = 0.002) placebo-adjusted reduction in serum alanine aminotransferase after 12 weeks of treatment, the primary endpoint of the study. However, the 30 mg dose of licogliflozin did not meet the primary endpoint (placebo-adjusted reduction 21% (80% CI: 7-32%; P = 0.061)). Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. No other major safety concerns were identified. Treatment with 150 mg licogliflozin led to reductions in serum alanine aminotransferase in patients with NASH. Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of licogliflozin as a therapeutic option for NASH. ClinicalTrials.gov identifier: NCT03205150., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Obesity, the prevalence of which is increasing due to the lack of exercise and increased consumption of Westernized diets, induces various complications, including ophthalmic diseases. For example, obesity is involved in the onset of cataracts., Methods: To clarify the effects and mechanisms of midodrine, an α1-adrenergic receptor agonist, in cataracts induced by obesity, we conducted various analytic experiments in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of obesity., Results: Midodrine prevented cataract occurrence and improved lens clearance in OLETF rats. In the lenses of OLETF rats treated with midodrine, we observed lower levels of aldose reductase, tumor necrosis factor-α, and sorbitol, but higher levels of hexokinase, 5'-adenosine monophosphate-activated protein kinase-alpha, adenosine 5´-triphosphate, peroxisome proliferator-activated receptordelta, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, superoxide dismutase, and catalase., Conclusion: The ameliorating effects of midodrine on cataracts in the OLETF obesity rat model are exerted via the following three mechanisms: direct inhibition of the biosynthesis of sorbitol, which causes cataracts; reduction of reactive oxygen species and inflammation; and (3) stimulation of normal aerobic glycolysis.

Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA 1c ) or serum uric acid, lower HbA 1c or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (C UA /C Cr ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the C UA /C Cr ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA 1c levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA 1c and high serum uric acid., (© 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved are not well understood. We previously discovered that hyperglycemia induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-mo-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reducing plasma glucose with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-mo-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage. NEW & NOTEWORTHY This study demonstrates that luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, improved CBF autoregulation in association with reduced vascular oxidative stress and AGEs production in the cerebrovasculature of 18-mo-old DM rats. SGLT2i also prevented BBB leakage, impaired functional hyperemia, neurodegeneration, and cognitive impairment seen in DM rats. Luseogliflozin did not have direct constrictive effects on VSMCs and MCAs isolated from normal rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.

Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol-producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low-absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

In a previous randomized trial, the non-inferiority of two hyaluronic acid injections (Synolis VA versus Synvisc-One) was assessed in patients with knee OA, with a response rate of 79% for Synolis VA. To assess whether a responder profile could be established for this treatment modality, we used the Synolis VA arm of a published 6-month prospective, multicenter, comparative, randomized, double-blinded trial. At baseline and during the study, pain and function were assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. Ninety-six subjects from the intention-to-treat trial were included in the analysis. The 6-month change of WOMAC Pain with Synolis VA was not associated with any baseline clinical data. However, the change in WOMAC Function was significantly associated with its baseline level, even after adjustment for potential confounding variables ( p = 0.028), i.e., a poorer physical function at baseline was associated with a better response. In conclusion, in addition to the high absolute response rate to Synolis VA, the probability of success is even increased if administered in patients with more limited physical function at baseline. Further research with other potential confounding clinical variables is warranted in order to better applicate the concept of personalized medicine.

The adsorption behavior of a lung cancer agent, Dianhydro-D-glucitol (DIS) on gold nanoparticles (AuNPs) was studied using surface-enhanced Raman scattering techniques. The stabilized geometry, inter- and intra-molecular hydrogen bond, and harmonic vibrational wavenumbers of DIS and DIS adsorbed on AuNPs (DISA) surface have been investigated with the help of the density functional theory (DFT) method. The stability of the molecules arising from stereoelectronic interactions, leading to its bioactivity, has been confirmed using natural bond orbital (NBO) analysis, which was further substantiated by the narrow HOMO LUMO energy gap obtained for DISA, from frontier molecular orbital analysis as well as electronic spectral analysis. The molecular electrostatic potential analysis along with local and global reactivity descriptors predicts the reactive site of the molecules. Molecular docking study was performed to obtain information about protein-ligand reactions for DIS and DISA, with different cancer proteins. This study enlightens the potential of SERS agents for targeted drug delivery and photothermal. The in vitro cytotoxic effects of DPH and DPHA molecules on lung cancer cell lines were analyzed using the MTT assay and the SERS method., (© 2021 John Wiley & Sons Ltd.)

Introduction: Several viscosupplement treatments are available for patients suffering from painful osteoarthritis (OA) of the knee, but few comparative clinical trials have been conducted. The primary objective of the trial was to demonstrate the non-inferiority of Synolis VA (80 mg hyaluronic acid and 160 mg sorbitol) (Group HA1) to Synvisc-One (48 mg hylan GF-20) (Group HA2) at Day 168 in terms of pain relief efficacy in patients with knee OA (Kellgren and Lawrence radiological stage II or III) in whom oral treatment with analgesics, NSAIDs or weak opioids provided insufficient clinical responses or were poorly tolerated., Methods: This was a prospective, multicentre, comparative, randomized, double-blinded trial comparing the two previously indicated viscosupplements, HA1 and HA2. The average VAS pain score (1-100) was 62.5 at baseline (Day 0). The patients were randomized into two parallel groups at Day 0 and followed until Day 168. They received one injection of either HA1 or HA2. The primary end point was the evolution of the Western Ontario and McMaster University (WOMAC) pain index at D168 in the groups. One of the secondary end points was the daily assessment of this index by the patient for 7 days following the injection and thereafter at Day 14. The other secondary end points were the WOMAC pain, stiffness, function and total scores assessed at Day 28, Day 84 and Day 168. At Day 168, efficacy and satisfaction were assessed by the evaluator and by the patient using a Likert scale (7 points). Moreover, the number of strict responders in each group was evaluated according to the The Osteoarthritis Research Society International (OARSI) Standing Committee for Clinical Trials Response Criteria Initiative and the Outcome Measures in Rheumatology (OMERACT) criteria (OMERACT-OARSI). The per protocol (PP) population was used for the primary analysis., Results: A total of 202 patients were randomized. The patients were predominantly female (66%). The median age of the whole population was 65 years, and the median body mass index was 27.4 kg/m 2 . No statistically significant differences between the two treatment groups were observed for any of the demographic criteria. At Day 168, 197 had had no protocol violations (94 in the HA1 group and 103 in the HA2 group). The WOMAC pain score decreased in the two groups: - 29.2 ± 24.1 (SD) in the HA1 group and - 31.6 ± 25.5 (SD) in the HA2 group, confirming the non-inferiority of Synolis VA (P = 0.57 for the difference between groups). Regarding the secondary end points, no significant difference was observed at Day 14, Day 28, Day 84 or Day 168 for all the outcomes except stiffness at Day 28 (P = in favour of treatment received in HA2). The rate of responders was comparable between the two groups: 79% for HA1 and 77% for HA2. Both products were well tolerated. Serious adverse events were reported by four patients in the HA1 group and 3 in the HA2 group., Conclusion: In this trial, we confirmed the non-inferiority of Synolis VA compared to Synvisc-One at Day 168 according to the WOMAC pain score. Safety was satisfying and comparable in the two groups., Trial Registration: 2017-A00034-49.

The clinical evidence is accumulating since 2015 that anti-diabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have the beneficial effect of cardiovascular and, recently, renal protection. Although it is not well analyzed how the transfer of this new evidence into daily practice has expedited, we hypothesize that the recent usage of the drugs is positively associated with several certified cardiologists in each region.The 2016 annual and 2016-2017 increased number of SGLT2 inhibitor tablets, based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan, were divided by the estimated number of patients with type 2 diabetes mellitus for each of the 47 prefectures. Then, regression analyses were performed to investigate the potential association of the number of certified cardiologists with the drug prescription.The 2016 prescription of ipragliflozin, dapagliflozin, luseogliflozin, canagliflozin, and empagliflozin was 2.7- to 4.4-fold different between prefectures. The 2016-2017 increased prescription volume also varied among prefectures by as large as 7.3-fold for ipragliflozin. Regression analysis revealed that the annual and increased prescription volume of all the SGLT2 inhibitors except luseogliflozin were higher in regions with more certified cardiologists (P < 0.05), even after adjusting for regional parameters.In conclusion, the regional number of certified cardiologists was positively associated with a 2016 annual of and 2016-2017 increase in SGLT2 inhibitor prescription amount, implying an early adopter role of clinical experts in healthcare delivery.

Treatment with licogliflozin, a dual sodium-glucose co-transporter (SGLT)1/2-inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin-induced stools, a randomized, open-label, two-part (N = 24/part), three-period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3-day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well-tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin., (© 2020 Novartis Institute for Biomedical Research. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Background Effects of sodium-glucose cotransporter 2 inhibitors on reducing hospitalization for heart failure have been reported in randomized controlled trials, but their effects on patients with heart failure with preserved ejection fraction (HFpEF) are unknown. This study aimed to evaluate the drug efficacy of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus and HFpEF. Methods and Results We performed a multicenter, open-label, randomized, controlled trial for comparing luseogliflozin 2.5 mg once daily with voglibose 0.2 mg 3 times daily in patients with type 2 diabetes mellitus suffering from HFpEF (left ventricular ejection fraction >45% and BNP [B-type natriuretic peptide] concentrations ≥35 pg/mL) in a 1:1 randomization fashion. The primary outcome was the difference from baseline in BNP levels after 12 weeks of treatment between the 2 drugs. A total of 173 patients with diabetes mellitus and HFpEF were included. Of these, 83 patients were assigned to receive luseogliflozin and 82 to receive voglibose. There was no significant difference in the reduction in BNP concentrations after 12 weeks from baseline between the 2 groups. The ratio of the mean BNP value at week 12 to the baseline value was 0.79 in the luseogliflozin group and 0.87 in the voglibose group (percent change, -9.0% versus -1.9%; ratio of change with luseogliflozin versus voglibose, 0.93; 95% CI, 0.78-1.10; P =0.26). Conclusion In patients with type 2 diabetes mellitus and HFpEF, there is no significant difference in the degree of reduction in BNP concentrations after 12 weeks between luseogliflozin and voglibose. Registration URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000018395.

Objective: The aim of this study was to explore the dose response of licogliflozin, a dual inhibitor of sodium/glucose cotransporter 1 (SGLT1) and 2 (SGLT2), by evaluating change in body weight in adults with overweight or obesity., Methods: This dose-response analysis evaluated change in body weight following 24 weeks with four once-daily and twice-daily licogliflozin doses (2.5-150 mg) versus placebo (primary end point). A further 24-week analysis evaluated the efficacy and safety of two once-daily licogliflozin doses in maintaining initial weight reduction., Results: Licogliflozin once daily or twice daily produced a significant dose-response signal for weight loss versus placebo (P < 0.0001). However, mean adjusted percent changes in body weight after 24 weeks were modest, ranging from -0.45% to -3.83% (in the 50 mg twice daily group [95% CI: -5.26% to -2.48%]; n = 75). Responder analysis of ≥ 5% weight loss at week 24 revealed significant differences versus placebo, which were most pronounced with highest doses of 50 mg twice daily (45.3%) and 150 mg once daily (42.9%) (both P < 0.01). While weight loss was greater at higher doses, gastrointestinal adverse events were also more frequent. The 50-mg once-daily dose had perhaps the best balance between efficacy and tolerability., Conclusions: Licogliflozin produced significant reductions in body weight versus placebo. However, the magnitude of weight reduction was modest., (© 2020 Novartis. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).)

Introduction: Nocturnal hypertension is clinically important for patients with type 2 diabetes (T2D), considering its strong correlation with cardiovascular events. We aim to test the hypothesis that the sodium-glucose cotransporter 2 inhibitor, luseogliflozin, ameliorates nocturnal hypertension more effectively than a dipeptidyl peptidase (DPP)-4 inhibitor in patients with T2D., Methods and Analysis: This study is a multicentre, prospective, randomised, open-label, blinded endpoint parallel-group trial. Sixty participants with T2D and hypertension who have been treated with a DPP-4 inhibitor for more than 4 weeks and who have a glycated haemoglobin A1c (HbA1c) level of 6.0%-9.0% will be randomised based on age, body mass index (BMI) and HbA1c to continue taking their DPP-4 inhibitor or to switch to luseogliflozin 2.5 mg once daily for 8 weeks. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) will be performed twice at baseline and at the end of the study. All participants will continue their diet and exercise therapy, and the doses of concomitant medications will not be adjusted during the study. The primary endpoint is the effect of luseogliflozin on the mean change in systolic blood pressure (SBP) during the night, as measured by ABPM. The secondary endpoints are mean change in diastolic blood pressure (DBP) during the night, 24 hours of SBP and DBP, daytime SBP and DBP, pulse rate, BP M-value, trough SBP and DBP for 1 hour before the next dose, and other laboratory parameters. The sample size was calculated for a two-sided test at 90% power for the detection of a difference between treatments., Ethics and Dissemination: The Ethics Review Board of Hokkaido University Hospital has approved the protocol. The results will be disseminated in peer-reviewed journals and at scientific conferences., Trial Registration Numbers: The University Hospital Medical Information Network (UMIN000031451); Japan Registry of Clinical Trials (jRCTs011180019); Pre-results., Competing Interests: Competing interests: AN has received honoraria for lectures from Sanofi, Mitsubishi Tanabe Pharma, Daiichi Sankyo, Eli Lilly Japan, MSD, Novo Nordisk Pharma, Novartis Pharma, AstraZeneca, Takeda Pharmaceutical, Astellas, Kowa Pharmaceutical, Ono, Nippon Boehringer Ingelheim, and Taisho Toyama Pharmaceutical, and has obtained research support from Mitsubishi Tanabe Pharma, Daiichi Sankyo, MSD, Novo Nordisk Pharma, Novartis Pharma, AstraZeneca, Dainippon Sumitomo Pharma, Life Scan Japan, and Taisho Pharmaceutical Co., Ltd. YK has received honoraria for lectures from Astellas Pharma Inc., AstraZeneca, Mitsubishi Tanabe Pharma Co., Ltd., MSD, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. TA has received honoraria for lectures from Mitsubishi Tanabe Pharma, Chugai Pharmaceutical, Astellas Pharma, Takeda Pharmaceutical, Pfizer, and Eli Lilly, and has received research funding from Astellas Pharma, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Chugai Pharmaceutical, Daiichi Sankyo, and Otsuka Pharmaceutical. HM has received honoraria for lectures from Astellas Pharma, AstraZeneca, Dainippon Pharma, Eli Lilly, Kissei, Mitsubishi Tanabe Pharma, MSD, Novo Nordisk Pharma, Novartis Pharma, and Sanofi, and has received research funding from Astellas Pharma, Astra‐Zeneca, Eli Lilly, and Mitsubishi Tanabe Pharma., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A 60-year-old Japanese woman was referred to our hospital for further examination of persistent liver dysfunction. She had been suffering from type 2 diabetes mellitus since the age of 50 years. Her hemoglobin A1c (HbA1c) value was as high as 7.8% despite treatment with dipeptidyl peptidase-4 inhibitor, metformin, and sulfonylurea. After excluding viral hepatitis, alcohol or drug-induced liver injury, and autoimmune liver diseases, liver histology evidence of macrovesicular steatosis, hepatocyte ballooning, and pericellular fibrosis confirmed a diagnosis of non-alcoholic steatohepatitis (NASH). Luseogliflozin (2.5 mg/day), a sodium-glucose cotransporter 2 inhibitor (SGLT2I), was co-administered to strengthen glycemic control. Liver enzymes and HbA1c gradually improved without any adverse events. A second liver biopsy at 15 months after luseogliflozin commencement revealed improvements in steatosis, fibrosis, and overall histological activity score. This case demonstrates that long-term luseogliflozin may be a good therapeutic option for diabetic NAFLD/NASH patients. The merits of persistent SGLT2I administration for NAFLD/NASH patients warrant validation in future studies.

Background: Home parenteral nutrition (HPN) is a life-preserving therapy for patients with chronic intestinal failure (CIF) indicated for patients who cannot achieve their nutritional requirements by enteral intake. Intravenously administered lipid emulsions (ILEs) are an essential component of HPN, providing energy and essential fatty acids, but can become a risk factor for intestinal-failure-associated liver disease (IFALD). In HPN patients, major effort is taken in the prevention of IFALD. Novel ILEs containing a proportion of omega-3 polyunsaturated fatty acids (n-3 PUFA) could be of benefit, but the data on the use of n-3 PUFA in HPN patients are still limited., Methods/design: The HOME study is a prospective, randomized, controlled, double-blind, multicenter, international clinical trial conducted in European hospitals that treat HPN patients. A total of 160 patients (80 per group) will be randomly assigned to receive the n-3 PUFA-enriched medium/long-chain triglyceride (MCT/LCT) ILE (Lipidem/Lipoplus® 200 mg/ml, B. Braun Melsungen AG) or the MCT/LCT ILE (Lipofundin® MCT/LCT/Medialipide® 20%, B. Braun Melsungen AG) for a projected period of 8 weeks. The primary endpoint is the combined change of liver function parameters (total bilirubin, aspartate transaminase and alanine transaminase) from baseline to final visit. Secondary objectives are the further evaluation of the safety and tolerability as well as the efficacy of the ILEs., Discussion: Currently, there are only very few randomized controlled trials (RCTs) investigating the use of ILEs in HPN, and there are very few data at all on the use of n-3 PUFAs. The working hypothesis is that n-3 PUFA-enriched ILE is safe and well-tolerated especially with regard to liver function in patients requiring HPN. The expected outcome is to provide reliable data to support this thesis thanks to a considerable number of CIF patients, consequently to broaden the present evidence on the use of ILEs in HPN., Trial Registration: ClinicalTrials.gov, ID: NCT03282955. Registered on 14 September 2017.

Background : The efficacy and safety of SGLT-2 and DPP-4 inhibitor monotherapies in T2DM is well established; however, data on the effect of combination therapies and sequence of administration are lacking. We investigated the efficacy and safety of the sequence of SGLT-2 and DPP-4 inhibitor administration in Japanese T2DM patients. Research design and methods : In this single-institution, open-label, randomized controlled study, T2DM patients inadequately controlled (HbA1c ≥6.5%) with conventional therapy were randomized to receive luseogliflozin-sitagliptin (LS; luseogliflozin 2.5 mg for 0-12 weeks, then luseogliflozin plus sitagliptin 50 mg for 12-24 weeks) or sitagliptin-luseogliflozin (SL; sitagliptin 50 mg for 0-12 weeks, then sitagliptin plus luseogliflozin 2.5 mg for 12-24 weeks). The main outcome was the difference in mean change in HbA1c at 24 weeks relative to baseline between both groups. Results : Of the 41 enrolled and randomized patients, 34 completed the study. Mean ± SD HbA1c at baseline was 10.35 ± 1.04% and 10.02 ± 1.40% in the LS and SL groups, respectively, and mean ± SD change in HbA1c at 24 weeks from baseline was -3.81 ± 1.21% vs -2.46 ± 1.42% (P < 0.01), respectively. No drug-related adverse events were reported. Conclusion : Over the 24-week period, LS was more effective in reducing HbA1c levels than SL in Japanese T2DM patients.

Objective: Intravenous lipid infusions improve both short- and long-term outcomes of premature neonates. However, prolonged infusion of lipids has been implicated in the development of parenteral nutrition-associated cholestasis (PNAC). We speculated that the multicomponent SMOFlipid would be hepatoprotective against PNAC., Study Design: This is a retrospective review comparing the incidence and severity of direct hyperbilirubinemia in preterm infants <1,500 g who were hospitalized for a minimum of 2 weeks during a 20-month period in which all preterm infants on total parenteral nutrition (TPN) received fat as Lipofundin with the following 20-month period in which all preterm infants on TPN received SMOFlipid., Results: Infants in the SMOFlipid period had a lower incidence of PNAC (6 vs. 13%; p  = 0.022), lower peak direct bilirubin levels (3.2 vs. 7.1 mg/dL; p  = 0.018), and a shorter length of stay (51 vs. 60 days; p  = 0.019). The relative risk of developing direct hyperbilirubinemia during the Lipofundin period was 2.22 (1.1-4.3) as compared with period 1; p  = 0.018; NNT-14., Conclusion: SMOFlipid was hepatoprotective in our population of preterm neonates <1,500 g receiving long-term TPN as compared with those receiving Lipofundin, despite similar levels of exposure to both intravenous lipid load and duration in the two groups., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Previous studies have demonstrated intrarenal hypoxia in patients with diabetes. Hypoxia-inducible factor (HIF)-1 plays an important role in hypoxia-induced tubulointerstitial fibrosis. Recent clinical trials have confirmed the renoprotective action of SGLT2 inhibitors in diabetic nephropathy. We explored the effects of an SGLT2 inhibitor, luseogliflozin on HIF-1α expression in human renal proximal tubular epithelial cells (HRPTECs). Luseogliflozin significantly inhibited hypoxia-induced HIF-1α protein expression in HRPTECs. In addition, luseogliflozin inhibited hypoxia-induced the expression of the HIF-1α target genes PAI-1, VEGF, GLUT1, HK2 and PKM. Although luseogliflozin increased phosphorylated-AMP-activated protein kinase α (p-AMPKα) levels, the AMPK activator AICAR did not changed hypoxia-induced HIF-1α expression. Luseogliflozin suppressed the oxygen consumption rate in HRPTECs, and subsequently decreased hypoxia-sensitive dye, pimonidazole staining under hypoxia, suggesting that luseogliflozin promoted the degradation of HIF-1α protein by redistribution of intracellular oxygen. To confirm the inhibitory effect of luseogliflozin on hypoxia-induced HIF-1α protein in vivo, we treated male diabetic db/db mice with luseogliflozin for 8 to 16 weeks. Luseogliflozin attenuated cortical tubular HIF-1α expression, tubular injury and interstitial fibronectin in db/db mice. Together, luseogliflozin inhibits hypoxia-induced HIF-1α accumulation by suppressing mitochondrial oxygen consumption. The SGLT2 inhibitors may protect diabetic kidneys by therapeutically targeting HIF-1α protein.

Introduction: Type 2 diabetes mellitus (T2DM) is a strong risk factor for coronary artery disease and heart failure, particularly heart failure with preserved ejection fraction (HFpEF). The aim of the ongoing MUSCAT-HF (It stands for Prospective Comparison of Luseogliflozin and Alpha-glucosidase on the Management of Diabetic Patients with Chronic Heart Failure and Preserved Ejection Fraction) trial is to evaluate the efficacy of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, versus voglibose, an alpha-glucosidase inhibitor, using brain natriuretic peptide (BNP) as the index of therapeutic effect in T2DM patients with HFpEF., Methods and Analysis: A total of 190 patients with T2DM and HFpEF (ejection fraction >45%) who are drug-naïve or taking any anti-diabetic agents will be randomised (1:1) to receive luseogliflozin 2.5 mg one time per day or voglibose 0.2 mg three times per day. The patients will be stratified by age (<65 years, ≥65 years), baseline haemoglobin A1c (<8.0%, ≥8.0%), baseline BNP (<100 pg/mL, ≥100 pg/mL), baseline renal function (estimated glomerular filtration rate ≥60 mL/min/1.73 m 2 , <60 mL/min/1.73 m 2 ), use of thiazolidine or not and presence or absence of atrial fibrillation and flutter at screening. After randomisation, participants will receive the study drug for 12 weeks in addition to their background therapy. The primary endpoint is the proportional change in baseline BNP after 12 weeks of treatment. The key secondary endpoints are the change from baseline in the ratio of early mitral inflow velocity to mitral annular early diastolic velocity, body weight and glycaemic control after 12 weeks of treatment., Ethics and Dissemination: The study has been approved by the ethics committee and the patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals., Trial Registration Number: UMIN000018395., Competing Interests: Competing interests: KE, SS, MM, SN and AT have no competing interests to declare. TM and KN has received honorarium from Novartis Pharmaceuticals (Basel, Switzerland). HI has received research funding and honorarium from Novartis Pharmaceuticals (Basel, Switzerland)., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A new series of C-phenyl d-glucitol derivatives was designed and synthesized, and their SGLT1 inhibitory potency and absorbability were evaluated. We also investigated whether kidney drug retention could be avoided by creating molecules with different excretion pathways. To achieve a class of molecules with low absorption and that were excreted in bile, optimized synthesis was performed to bring the ClogP value and the topological polar surface area to within the appropriate ranges. Compounds 34d and 34j were poorly absorbed, but the absorbed compounds were mainly excreted in bile. Thus, smaller amounts of persistent residue in the kidneys were observed. Since 34d exerted a glucose-lowering effect at a dose of 0.3 mg/kg (p.o.) in SD rats, this compound (SGL5213) could be a clinical candidate for the treatment of type 2 diabetes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims/introduction: It is unclear how changes in body composition induced by sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment correlate with metabolic profile changes. We aimed to clarify how metabolic profile changes correlate with body component changes, and if SGLT2 inhibitor treatment causes sarcopenia and bone mineral content (BMC) loss., Materials and Methods: Moderately obese Japanese type 2 diabetes patients, treated with luseogliflozin for a year, were observed prospectively and evaluated for body composition changes. We analyzed the changes in the individual body components during treatment, and their correlation with other clinical variables., Results: The efficacy analysis set comprised 37 of 43 enrolled patients. The total fat mass significantly decreased early in the treatment at and after week 4, with a mean decrease of -1.97 kg (95% confidence interval -2.66 to -1.28) at week 24. The visceral fat area at week 24 showed an average downward trend, although this was not significant. The changes in visceral fat area in individual patients showed a significant negative correlation with the extent of the baseline visceral fat area (r = -0.399, P = 0.023). The skeletal muscle mass index showed a significant but small change at and after week 36. The BMC profile showed a transient significant decrease only at week 12. No significant change in BMC was noted at other time-points., Conclusions: Luseogliflozin treatment brought about favorable changes in body composition and metabolism of moderately obese Japanese type 2 diabetes patients, accompanied by body fat reduction, and minimal muscle and BMC reduction., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

This open-label, parallel-group, multicenter study aimed to assess the effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of luseogliflozin. A single 5-mg dose of luseogliflozin was administered to Japanese patients with type 2 diabetes mellitus in the following groups: G1, normal renal function; G2, mild renal impairment; G3a, mild to moderate impairment; G3b, moderate to severe impairment; G4, severe impairment, based on estimated glomerular filtration rate (eGFR; ≥90, 60-89, 45-59, 30-44, 15-29 mL/min/1.73 m 2 , respectively). While luseogliflozin pharmacokinetics were similar for patients across all renal function groups, the increase in plasma concentration was slightly slower and maximum concentration was slightly reduced in the lower eGFR groups compared with the other groups. However, luseogliflozin pharmacodynamics were affected by the severity of renal impairment. Urinary glucose excretion (UGE) increased in all groups relative to baseline levels, but the degree of UGE increase was smaller in the lower eGFR groups. Moreover, plasma glucose AUC changes from baseline tended to be smaller in the lower eGFR groups. No clear trends were observed between eGFR and incidence, type, or severity of adverse events. Thus, luseogliflozin administration should be carefully considered, as patients with renal impairment may show an insufficient response to treatment., (© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice. Luseogliflozin significantly suppressed development of renal fibrosis, prevented peritubular capillary congestion/hemorrhage, attenuated CD31-positive cell loss, suppressed hypoxia, and increased vascular endothelial growth factor (VEGF)-A expression in the kidney after ischemia/reperfusion injury. Luseogliflozin failed to induce the above-mentioned protection in animals co-treated with sunitinib, a VEGF receptor inhibitor. Additionally, luseogliflozin reduced glucose uptake and increased VEGF-A expression in the kidneys of glucose transporter 2 (GLUT2)-downregulated mice following ischemia/reperfusion and in GLUT2-knock-down cells compared with those in normal controls. Withdrawal of glucose from cultured medium, to halt glucose uptake, remarkably increased VEGF-A expression and reversed the luseogliflozin-induced increase in VEGF-A expression in the proximal tubular cells. Thus, luseogliflozin prevented endothelial rarefaction and subsequent renal fibrosis after renal ischemia/reperfusion injury through a VEGF-dependent pathway induced by the dysfunction of proximal tubular glucose uptake in tubules with injury-induced GLUT2 downregulation., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

We evaluated the changes in heart rate on the treatment with SGLT2 inhibitor, luseogliflozin, in Japanese patients with type 2 diabetes mellitus (T2DM). It is suggested that luseogliflozin can effectively decrease in heart rate in patients with higher baseline.

Aims/introduction: The aim of the present study was to evaluate the safety and efficacy of luseogliflozin added to liraglutide monotherapy in Japanese individuals with type 2 diabetes., Materials and Methods: This 52-week, multicenter, open-label, single-arm clinical study enrolled Japanese patients who had inadequate glycemic control with diet/exercise and liraglutide monotherapy. Major efficacy end-points included the changes from baseline in glycated hemoglobin, fasting plasma glucose and bodyweight. Body composition was also assessed in individuals who had access to bioelectrical impedance analysis. Safety assessments included adverse events, clinical laboratory tests, vital signs and 12-lead electrocardiograms., Results: Of 76 patients who received luseogliflozin, 62 completed the study. The changes from baseline in glycated hemoglobin, fasting plasma glucose, and bodyweight (mean ± SE) were -0.68 ± 0.10%, -32.1 ± 3.6 mg/dL and -2.71 ± 0.24 kg at week 52, respectively (all, P < 0.001 vs baseline). Luseogliflozin was associated with greater reductions in fat mass than lean mass at all measuring points (n = 22): fat vs lean mass changes (mean ± SE) at week 52 were -2.49 ± 0.45 kg (P < 0.001 vs baseline) and -0.44 ± 0.26 kg (P = 0.107 vs baseline), respectively. Insulin secretion and Matsuda Index were also improved at weeks 12 and 52 compared with baseline. Adverse events and adverse drug reactions occurred in 65.8 and 27.6% of patients, respectively. The overall safety profile, including frequency of hypoglycemia, was found to be consistent with those of previous studies and there were no new safety concerns., Conclusions: Luseogliflozin added to liraglutide was well tolerated, and improved glycemic control with bodyweight and fat mass reductions in Japanese type 2 diabetes patients., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

This study aimed to assess the effect of luseogliflozin on liver fat deposition and compare luseogliflozin to metformin in type 2 diabetes (T2D) patients with non-alcoholic fatty liver disease (NAFLD). Thirty-two T2D patients with NAFLD diagnosed by computed tomography or abdominal sonography were recruited. Participants were randomly assigned to receive either luseogliflozin (2.5 mg, newly administered) or metformin (1500 mg, newly or additionally administrated). Data on the liver-to-spleen attenuation ratio (L/S), visceral fat area, body mass index, glycated hemoglobin (HbA1c), alanine aminotransferase (ALT), fasting plasma glucose, C-peptide immunoreactivity (CPR), and CPR index were collected at baseline and after 6 months. The change in L/S was significantly greater in the luseogliflozin group than in the metformin group. Similarly, the changes in the visceral fat area, HbA1c, and body mass index were significantly greater in the luseogliflozin group than in the metformin group. The changes in ALT, fasting glucose, CPR, and CPR index were not significant in both groups. In conclusion, luseogliflozin significantly reduced liver fat deposition as compared to metformin, which may indicate clinical relevant benefits for NAFLD., (© 2017 John Wiley & Sons Ltd.)

Recent clinical studies have revealed the treatment of diabetic patients with sodium glucose co-transporter2 (SGLT2) inhibitors to reduce the incidence of cardiovascular events. Using nicotinamide and streptozotocin (NA/STZ) -treated ApoE KO mice, we investigated the effects of short-term (seven days) treatment with the SGLT2 inhibitor luseogliflozin on mRNA levels related to atherosclerosis in the aorta, as well as examining the long-term (six months) effects on atherosclerosis development. Eight-week-old ApoE KO mice were treated with NA/STZ to induce diabetes mellitus, and then divided into two groups, either untreated, or treated with luseogliflozin. Seven days after the initiation of luseogliflozin administration, atherosclerosis-related mRNA levels in the aorta were compared among four groups; i.e., wild type C57/BL6J, native ApoE KO, and NA/STZ-treated ApoE KO mice, with or without luseogliflozin. Short-term luseogliflozin treatment normalized the expression of inflammation-related genes such as F4/80, TNFα, IL-1β, IL-6, ICAM-1, PECAM-1, MMP2 and MMP9 in the NA/STZ-treated ApoE KO mice, which showed marked elevations as compared with untreated ApoE KO mice. In contrast, lipid metabolism-related genes were generally unaffected by luseogliflozin treatment. Furthermore, after six-month treatment with luseogliflozin, in contrast to the severe and widely distributed atherosclerotic changes in the aortas of NA/STZ-treated ApoE KO mice, luseogliflozin treatment markedly attenuated the progression of atherosclerosis, without affecting serum lipid parameters such as high density lipoprotein, low density lipoprotein and triglyceride levels. Given that luseogliflozin normalized the aortic mRNA levels of inflammation-related, but not lipid-related, genes soon after the initiation of treatment, it is not unreasonable to speculate that the anti-atherosclerotic effect of this SGLT2 inhibitor emerges rapidly, possibly via the prevention of inflammation rather than of hyperlipidemia., Competing Interests: The authors declare no conflict of interest.

Background: The effects of sodium-glucose co-transporter type 2 inhibitors on home blood pressure were examined in type 2 diabetes with nephropathy., Methods: The patients with diabetic nephropathy were screened from medical records in our hospitals. Among them, 52 patients who measured home blood pressure and started to take sodium-glucose co-transporter type 2 inhibitors were selected. Clinical parameters including estimated glomerular filtration rate, albuminuria and home blood pressure for 6 months were analysed., Results: Sodium-glucose co-transporter type 2 inhibitors (luseogliflozin 5 mg/day or canagliflozin 100 mg/day) reduced body weight, HbA1c, albuminuria, estimated glomerular filtration rate and office blood pressure. Although sodium-glucose co-transporter type 2 inhibitors did not alter morning blood pressure, it reduced evening systolic blood pressure. Regression analyses revealed that decreases in evening blood pressure predicted decrements in albuminuria., Conclusion: The present data suggest that sodium-glucose co-transporter type 2 inhibitors suppress sodium overload during daytime to reduce evening blood pressure and albuminuria.

The red maple (Acer rubrum) is a rich source of phenolic compounds which possess galloyl groups attached to different positions of a 1,5-anhydro-D-glucitol core. While these glucitol-core containing gallotannins (GCGs) have reported anti-oxidant and anti-glycative effects, they have not yet been evaluated for their cosmetic applications. Herein, the anti-tyrosinase and anti-melanogenic effects of a proprietary phenolic-enriched red maple leaves extract [Maplifa ™ ; contains ca. 45% ginnalin A (GA) along with other GCGs] were investigated using enzyme and cellular assays. The GCGs showed anti-tyrosinase activity with IC 50 values ranging from 101.4 to 1047.3 μM and their mechanism of tyrosinase inhibition (using GA as a representative GCG) was evaluated by chelating and computational/modeling studies. GA reduced melanin content in murine melanoma B16F10 cells by 79.1 and 56.7% (at non-toxic concentrations of 25 and 50 μM, respectively), and its mechanisms of anti-melanogenic effects were evaluated by using methods including fluorescent probe (DCF-DA), real-time PCR, and western blot experiments. These data indicated that GA was able to: (1) reduce the levels of reactive oxygen species, (2) down-regulate the expression of MITF, TYR, TRP-1, and TRP-2 gene levels in a time-dependent manner, and (3) significantly reduce protein expression of the TRP-2 gene. Therefore, the anti-melanogenic effects of red maple GCGs warrant further investigation of this proprietary natural product extract for potential cosmetic applications.

This study investigated the safety and efficacy of the sodium-glucose co-transporter-2 (SGLT2) inhibitor luseogliflozin with differing carbohydrate intakes in Japanese individuals with type 2 diabetes (T2D). Participants were randomly assigned to 3 carbohydrate-adjusted meals for 14 days (days 1-14; a high carbohydrate [HC; 55% total energy carbohydrate] and high glycaemic index [HGI] meal; an HC [55% total energy carbohydrate] and low glycaemic index [LGI] meal; or a low carbohydrate [LC; 40% total energy carbohydrate] and HGI meal). All participants received luseogliflozin for the last 7 days (days 8-14), continuous glucose monitoring (CGM) before and after luseogliflozin treatment (days 5-8 and days 12-15) and blood tests on days 1, 8 and 15. Luseogliflozin significantly decreased the area under the curve and mean of CGM values in all 3 groups similarly. Fasting plasma glucose, insulin and glucagon were similar at all time points. Ketone bodies on day 15 were significantly higher in the LC-HGI group compared with the HC-HGI and HC-LGI groups. In conclusion, luseogliflozin has similar efficacy and safety in Japanese people with T2D when meals contain 40% to 55% total energy carbohydrate, but a strict LC diet on this class of drug should be avoided to prevent SGLT2 inhibitor-associated diabetic ketoacidosis., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Previous studies have suggested that sorbitol, a known polyol sweetener, possesses glycemic control potentials. However, the effect of sorbitol on intestinal glucose absorption and muscle glucose uptake still remains elusive. The present study investigated the effects of sorbitol on intestinal glucose absorption and muscle glucose uptake as possible anti-hyperglycemic or glycemic control potentials using ex vivo and in vivo experimental models. Sorbitol (2.5% to 20%) inhibited glucose absorption in isolated rat jejuna (IC 50 = 14.6% ± 4.6%) and increased glucose uptake in isolated rat psoas muscle with (GU 50 = 3.5% ± 1.6%) or without insulin (GU 50 = 7.0% ± 0.5%) in a concentration-dependent manner. Furthermore, sorbitol significantly delayed gastric emptying, accelerated digesta transit, inhibited intestinal glucose absorption, and reduced blood glucose increase in both normoglycemic and type 2 diabetic rats after 1 h of coingestion with glucose. Data of this study suggest that sorbitol exhibited anti-hyperglycemic potentials, possibly via increasing muscle glucose uptake ex vivo and reducing intestinal glucose absorption in normal and type 2 diabetic rats. Hence, sorbitol may be further investigated as a possible anti-hyperglycemic sweetener.

Background: Accumulation of epicardial fat (EF) is associated with increased cardio-metabolic risks and coronary events, independently of traditional cardiovascular risk factors. Therefore, the reduction of EF volume (EFV) may be associated with reduced cardio-metabolic risks and future cardiovascular events. Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce body fat including visceral fat and cardiovascular events in patients with type 2 diabetes. However, it has still been unknown whether SGLT2 inhibitors can reduce EFV., Methods: Type 2 diabetic patients with HbA1c 6.5-9.0% and body mass index (BMI, kg/m 2 ) ≥25.0 were enrolled in this single arm pilot study. Participants were administered luseogliflozin 2.5 mg daily and the dosage was tolerated to be increased up to 5.0 mg daily. EFV [median (interquartile range), cm 3 ] was measured by magnetic resonance imaging. Primary endpoint was the decrease in EFV at 12 weeks. Visceral fat area (VFA, cm 2 ) and liver attenuation index (LAI) measured by the abdominal computed tomography, and skeletal muscle index (SMI) and body fat (%) measured by the whole body dual-energy X-ray absorptiometry were also determined at baseline and at 12 weeks., Results: Nineteen patients (mean age: 55 ± 12 years; 26% female) completed this study. Luseogliflozin treatment significantly reduced EFV at 12 weeks [117 (96-136) to 111 (88-134), p = 0.048]. The body weight, BMI, systolic and diastolic blood pressure, HbA1c, fasting plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, SMI, and body fat were significantly reduced by luseogliflozin at 12 weeks. The reduction of EFV was significantly correlated with the reduction of C-reactive protein (r = 0.493, p = 0.019). Neither VFA nor LAI were significantly reduced by the luseogliflozin treatment. No severe adverse events were observed., Conclusions: Our data suggest that luseogliflozin could reduce the EFV in parallel with the improvement of systemic micro-inflammation and the reduction of body weight in Japanese patients with type 2 diabetes. The reduction of muscle mass after the administration of SGLT2 inhibitors may require a particular attention. Trial registration umin.ac.jp, UMIN000019072.

Objective and Methods An SGLT2 inhibitor (ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin, or canagliflozin) was administered to 132 outpatients with type 2 diabetes mellitus with or without other antidiabetic drugs for 6 months to evaluate its efficacy, the incidence of adverse events, and its influence on the renal function. Results The patient's mean glycated hemoglobin level significantly improved from 7.52±1.16% to 6.95±0.98% (p<0.001). The body weight of the patients was significantly reduced from 78.0±15.3 kg to 75.6±15.1 kg (p<0.001). The estimated visceral fat area was also significantly reduced from 108.4±44.6 cm 2 to 94.5±45.3 cm 2 (p<0.001). The waist circumference, blood pressure, serum alanine aminotransferase, γ-glutamyl transpeptidase, and uric acid levels also showed a significant decrease. The urinary albumin/creatinine ratio (U-ACR) was significantly reduced in the patients whose U-ACR levels were 30-300 mg/gCr at the baseline. The mean eGFR significantly decreased in the patients with a pre-treatment eGFR value of ≥90 mL/min/1.73 m 2 but remained unchanged in the patients with a pre-treatment value of <90 mL/min/1.73 m 2 . A total of 13 adverse events were noted, including systemic eruption (n=1), cystitis (n=2), pudendal pruritus (n=2), nausea (n=1), malaise (n=1), a strong hunger sensation and increased food ingestion (n=1), and non-serious hypoglycemia (n=5). Conclusion SGLT2 inhibitors seemed to be useful in the treatment of obese type 2 diabetes mellitus patients. Furthermore, these data suggest that SGLT2 inhibitors may protect the renal function.

Luseogliflozin, a selective inhibitor of sodium glucose co-transporter 2 (SGLT2), was previously shown to improve the blood glucose and hemoglobin A1c (HbA1c) levels of patients with type 2 diabetes in a clinical setting. Although patients with type 2 diabetes often have hepatic impairment, few reports have been published concerning the influence of luseogliflozin on HbA1c and hepatic function in patients with type 2 diabetes accompanied by hepatic impairment. The present study was undertaken to evaluate the influence of luseogliflozin on HbA1c and hepatic function in patients with type 2 diabetes divided into 2 groups according to hepatic function parameters (a normal group and an elevated group). In this study, luseogliflozin significantly improved both HbA1c and body weight to similar extents in both the normal group and the elevated group, accompanied by marked reductions in the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (γ-GTP) levels. These results suggested that luseogliflozin can be safely used in patients with type 2 diabetes who also exhibit hepatic impairment. The results additionally suggest the possibility that luseogliflozin might be capable of alleviating hepatic impairment in patients with type 2 diabetes., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To evaluate the efficacy of xylitol-sweetened milk as a caries-preventive strategy., Methods: In this nine-month prospective proof-of-principle trial, Peruvian schoolchildren were randomized to one of five different milk groups: (1) eight g of xylitol per 200 mL milk once per day; (2) four g of xylitol per 100 mL milk twice per day; (3) eight g of sorbitol per 200 mL milk once per day; (4) four g of sorbitol per 100 mL milk twice per day; or (5) eight g of sucrose per 200 mL milk once per day. The primary outcome was plaque mutans streptococci (MS) at nine months. A secondary outcome was caries incidence. We hypothesized that children in the xylitol groups would have a greater MS decline and lower caries incidence., Results: One hundred fifty-three children were randomized in the intent-to-treat analyses. Children receiving xylitol had a greater decline in MS than children receiving sucrose (P=0.02) but were not different from children receiving sorbitol (P=0.07). Dental caries incidence for xylitol once per day or twice per day was 5.3±3.4 and 4.3±4.0 surfaces, respectively, compared to sorbitol once per day, sorbitol twice per day, or sucrose (4.1±2.8, 3.7±4.2, and 3.2±3.4 surfaces, respectively). There were no differences in caries incidence between xylitol and sucrose (rate ratio [RR] = 1.51; 95 percent confidence interval [CI] = 0.88, 2.59; P=0.13) or between xylitol and sorbitol (RR = 1.28; 95 percent CI = 0.90, 1.83; P=0.16)., Conclusion: Xylitol-sweetened milk significantly reduced mutans streptococci levels compared to sucrose-sweetened milk, but differences in caries incidence were not detected.

Lactic acidosis that is not secondary to tissue hypoperfusion or hypoxemia (type B lactic acidosis) is a rare but potentially fatal condition that has been associated with drugs like metformin, linezolid, and nucleoside reverse-transcriptase inhibitors in patients with HIV. We report the first case of type B lactic acidosis caused by overdose of the serotonin-norepinephrine reuptake inhibitor, venlafaxine. A 55-year-old man with no significant medical history was brought to the emergency department after intentional ingestion of around 80 capsules of venlafaxine (a total dose of over 6000 mg) in an attempt to commit suicide. Complete blood count and comprehensive metabolic panel were unremarkable except for a bicarbonate level of 13 mEq/L and an anion gap of 22 mEq/L. An arterial blood gas revealed a pH of 7.39, partial pressure of CO2 of 19 mm Hg, calculated bicarbonate of 11.5 mEq/L, and a lactate level of 8.6 mmol/L. The patient was started on aggressive intravenous hydration with normal saline along with oral activated charcoal with sorbitol. Repeat laboratory work after 4 hours showed an improvement in anion gap (15 mEq/L) and serum lactate (5.6 mmol/L). The patient remained stable throughout the hospital stay and lactic acidosis resolved in 24 hours. In the absence of hypotension, hypoxemia, kidney or liver dysfunction, myopathy, malignancy, or use of other medications, venlafaxine was the most likely cause of lactic acidosis in our case. Rapid improvement of acidosis was probably related to clearance of the drug.

Introduction: In our previous study investigating effects of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, on 24-h glycemic variability by continuous glucose monitoring (CGM), luseogliflozin elicited parallel downward shifts in fasting and postprandial glucose levels. However, further review of individual patients' data revealed that postprandial hyperglycemia was not reduced in some patients, while preprandial glucose was ameliorated in most patients. Therefore, we divided patients into two groups according to their postprandial glucose responses and conducted a post hoc subanalyses to elucidate which factors contributed to the differential effects of luseogliflozin., Methods: Thirty-four Japanese type 2 diabetic patients in our previous randomized, double-blind, placebo-controlled, crossover study with 7-day luseogliflozin administration were divided into postprandial glucose responders (PGR, n = 23, ameliorated peak glucose) and postprandial glucose non-responders (PGNR; n = 11, non-ameliorated peak glucose). Baseline characteristics, variations in CGM-measured 24-h glucose levels, and other pharmacodynamic variabilities were compared., Results: Baseline characteristics did not differ significantly between groups. Placebo-subtracted peak glucose was significantly lowered in PGR and significantly increased in PGNR (-43.8 and 17.9 mg/dL; both p < 0.05). Luseogliflozin significantly lowered "lowest glucose" (defined as the lowest level measured throughout a 24-h period) similarly in PGR and PGNR (-19.2 and -24.0 mg/dL; both p < 0.05), significantly reduced the mean amplitude of glucose excursions in PGR (-15.50 mg/dL; p < 0.05), and increased the area under the curve for plasma glucagon over 24 h in PGNR (median difference vs. placebo: 240 pg/mL h; p < 0.05). Luseogliflozin increased urinary glucose excretion (UGE) and decreased serum insulin by similar magnitudes in both groups., Conclusions: Luseogliflozin diminished glucose fluctuations in most patients by lowering peak glucose to a greater extent than lowest glucose. Luseogliflozin may also lower lowest glucose in patients whose peak glucose was not ameliorated despite increasing UGE. The glucagon increase in PGNR might explain its hypoglycemic effect on postprandial glucose., Funding: Taisho Pharmaceutical Co., Ltd, Tokyo, Japan., Trial Registration: JapicCTI-142548.

Aim: A well-documented, clinically proven per rectum treatment for childhood constipation is needed. This phase two clinical trial evaluated the efficacy of suppositories containing free fatty acids (FFA) compared with Klyx docusate sodium and sorbitol enemas., Methods: A randomised, controlled, single-blind study was undertaken on 77 children aged between one and 17 who presented to an emergency department in Iceland and were diagnosed with constipation. In stage one, 23 patients were randomised to receive lower dose FFA suppositories or Klyx (n = 33). In stage two, 21 different patients were randomised to receive higher dose suppositories and compared with the same Klyx control subjects., Results: The suppositories were effective at bowel emptying in 39% of the group who received the lower FFA doses and 81% of the group receiving higher doses, compared with 88% in the Klyx control group. Symptom relief was obtained in 30% of the group receiving the lower doses and 71% of the group receiving the higher doses, compared with 73% in the control group., Conclusion: The higher dose FFA suppositories were as effective as the Klyx enemas with regard to bowel emptying and symptom relief and might provide an important and less invasive alternative for childhood constipation., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objective: Experiments were carried out to investigate whether diuretics (hydrochlorothiazide + furosemide) impact on the effects of a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor on glucose metabolism and blood pressure (BP) in metabolic syndrome SHR/NDmcr-cp(+/+) rats (SHRcp)., Methods: Male 13-week-old SHRcp were treated with: vehicle; the SGLT2-inhibitor luseogliflozin (10 mg/kg per day); diuretics (hydrochlorothiazide; 10 mg/kg/day + furosemide; 5 mg/kg per day); or luseogliflozin + diuretics (n = 5-8 for each group) daily by oral gavage for 5 weeks. BP and glucose metabolism were evaluated by a telemetry system and oral glucose tolerance test, respectively., Results: Vehicle-treated SHRcp developed nondipper type hypertension (dark vs. light-period mean arterial pressure: 148.6 ± 0.7 and 148.0 ± 0.7 mmHg, respectively, P = 0.2) and insulin resistance. Compared with vehicle-treated animals, luseogliflozin-treated rats showed an approximately 4000-fold increase in urinary excretion of glucose and improved glucose metabolism. Luseogliflozin also significantly decreased BP and turned the circadian rhythm of BP from a nondipper to dipper pattern (dark vs. light-period mean arterial pressure: 138.0 ± 1.6 and 132.0 ± 1.3 mmHg, respectively, P < 0.01), which were associated with a significant increase in urinary excretion of sodium. Addition of diuretics did not influence luseogliflozin-induced improvement of glucose metabolism and circadian rhythm of BP in SHRcp., Conclusion: These data suggest that a SGLT2 inhibitor elicits its beneficial effects on glucose metabolism and hypertension in study participants with metabolic syndrome undergoing treatment with diuretics.