This study was registered with the Japan Pharmaceutical Information Center (identifier: JapicCTI-142548). Open Access This short article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.. windows Fig.?1 a Twenty-four-hour glucose concentrations measured by continuous glucose monitoring (1?mg/dL?=?0.0556?mmol/L). Ideals are offered as the mean (were omitted for clarity). b Urinary glucose excretion rate. Ideals are as the mean?+?standard deviation. *value7.6 (3.5, 24.0)8.6 (3.4, 17.3)?1.4 (?4.7, 2.7)21.6 (9.4, 34.6)11.3 (4.1, 13.7)?10.6* (?16.4, ?3.9) Open in a separate window value7.8 (6.2, 26.5)5.6 (3.1, 9.0)?5.4* (?10.7, ?2.1)0.077 Open in a separate window Values are derived from 24-h continuous glucose monitoring. Normally distributed variables are offered as the least-squares mean (95% confidence interval) and the variations between luseogliflozin and placebo were analyzed using a mixed-effects model, which included treatment, sequence and period as fixed effects and individuals like a random effect. Non-normally distributed variables are offered as the median (interquartile range), and the variations between luseogliflozin and placebo were identified using Wilcoxon signed-rank test. To evaluate the difference between organizations in the difference between luseogliflozin and placebo, ANOVA were used to analyze the normally distributed variables, and KruskalCWallis test were used to analyze the non-normally distributed variables. Data are demonstrated for the pharmacodynamic analysis set Glucose : 1?mg/dL?=?0.0556?mmol/L area on the curve, area under the curve, standard deviation round the mean glucose concentration *?area under the curve, maximum concentration, urinary glucose excretion *? em P /em ? ?0.05 for luseogliflozin vs. placebo Although glucose variability was consistently lower with luseogliflozin than with placebo in the normal and normalCmild organizations, glucose variability was not consistently lower with luseogliflozin than with placebo in the mildCmoderate group, because of the smaller switch in postprandial glucose concentrations with this group. The mean 24-h glucose was lower with luseogliflozin than with placebo in all three groups. However, the placebo-subtracted 4-(tert-Butyl)-benzhydroxamic Acid switch in the mean 24-h glucose was smaller in the mildCmoderate group than in the normal and normalCmild organizations. The placebo-subtracted switch in mean 24-h glucose was consequently significantly different between organizations ( em P /em ?=?0.023, ANOVA). The AUC0C24?h for glycemic variability was smaller with luseogliflozin than with placebo in all three groups. However, the placebo-subtracted switch in the AUC0C24?h for glycemic variability was smaller in the mildCmoderate group than in the normal and normalCmild organizations. The placebo-subtracted switch in the AUC0C24?h for glycemic variability was significantly different between organizations ( em P /em ?=?0.023, ANOVA). The AUCs for glycemic variability after each meal (i.e., AUC0C5?h, AUC5C11?h, and AUC11C15?h) and during the sleeping period (AUC15C24?h) were also smaller with luseogliflozin than with placebo in all three groups. The placebo-subtracted AUCs for glycemic variability were significantly different between organizations at breakfast and lunch time ( em P /em ?=?0.006 and em P /em ?=?0.026, respectively, ANOVA). The peak glucose concentrations during the day and after each meal were significantly lower with luseogliflozin than with placebo in the normal and normalCmild organizations, but not in the mildCmoderate group. The placebo-subtracted difference in the peak glucose concentration was significantly different between organizations after breakfast ( em P /em ?=?0.047, ANOVA), but not in the other measurement occasions. The fasting glucose concentrations (i.e., glucose concentration measured before each meal Rabbit Polyclonal to RANBP17 and in the sleeping period) were consistently lower with luseogliflozin than with placebo in all three organizations. Furthermore, the placebo-subtracted changes in the fasting glucose concentrations were not significantly different between groups. The lowest glucose concentration from 0 to 24?h was lower with luseogliflozin than with placebo in all groups. The placebo-subtracted change in the lowest glucose concentration was not significantly different between groups. Luseogliflozin significantly increased the cumulative UGE compared with placebo in all of the periods in all three groups (all em P /em ? ?0.05). However, the placebo-subtracted changes in the cumulative UGE were smaller in the mildCmoderate group than in the normal and normalCmild groups, and these differences were statistically significant between groups for all measurement occasions except after dinner (throughout the day: em P /em ?=?0.007; after breakfast: em P /em ?=?0.037; after lunch: em P /em ?=?0.007; after dinner: em P /em ?=?0.198; sleeping period: em P /em ?=?0.050, ANOVA). The serum insulin and plasma glucagon levels on day 7 in each treatment period 4-(tert-Butyl)-benzhydroxamic Acid are shown in.b Twenty-four-hour plasma glucagon levels after 7?days of once-daily administration of 2.5?mg luseogliflozin or placebo. glucose monitoring (1?mg/dL?=?0.0556?mmol/L). Values are 4-(tert-Butyl)-benzhydroxamic Acid presented as the mean (were omitted for clarity). b Urinary glucose excretion rate. Values are as the mean?+?standard deviation. *value7.6 (3.5, 24.0)8.6 (3.4, 17.3)?1.4 (?4.7, 2.7)21.6 (9.4, 34.6)11.3 (4.1, 13.7)?10.6* (?16.4, ?3.9) Open in a separate window value7.8 (6.2, 26.5)5.6 (3.1, 9.0)?5.4* (?10.7, ?2.1)0.077 Open in a separate window Values are derived from 24-h continuous glucose monitoring. Normally distributed variables are presented as the least-squares mean (95% confidence interval) and the differences between luseogliflozin and placebo were analyzed using a mixed-effects model, which included treatment, sequence and period as fixed effects and patients as a random effect. Non-normally distributed variables are presented as the median (interquartile range), and the differences between luseogliflozin and placebo were decided using Wilcoxon signed-rank test. To evaluate the difference between groups in the difference between luseogliflozin and placebo, ANOVA were used to analyze the normally distributed variables, and KruskalCWallis test were used to analyze the non-normally distributed variables. Data are shown for the pharmacodynamic analysis set Glucose : 1?mg/dL?=?0.0556?mmol/L area over the curve, area under the curve, standard deviation around the mean glucose concentration *?area under the curve, maximum concentration, urinary glucose excretion *? em P /em ? ?0.05 for luseogliflozin vs. placebo Although glucose variability was consistently lower with luseogliflozin than with placebo in the normal and normalCmild groups, glucose variability was not consistently lower with luseogliflozin than with placebo in the mildCmoderate group, because of the smaller change in postprandial glucose concentrations in this group. The mean 24-h glucose was lower with luseogliflozin than with placebo in all three groups. However, the placebo-subtracted change in the mean 24-h glucose was smaller in the mildCmoderate group than in the normal and normalCmild groups. The placebo-subtracted change in mean 24-h glucose was therefore significantly different between groups ( em P /em ?=?0.023, ANOVA). The AUC0C24?h for glycemic variability was smaller with luseogliflozin than with placebo in all three groups. However, the placebo-subtracted change in the AUC0C24?h for glycemic variability was smaller in the mildCmoderate group than in the normal and normalCmild groups. The placebo-subtracted change in the AUC0C24?h for glycemic variability was significantly different between groups ( em P /em ?=?0.023, ANOVA). The AUCs for glycemic variability after each meal (i.e., AUC0C5?h, AUC5C11?h, and AUC11C15?h) and during the sleeping period (AUC15C24?h) were also smaller with luseogliflozin than with placebo in all three groups. The placebo-subtracted AUCs for glycemic variability were significantly different between groups at breakfast and lunch ( em P /em ?=?0.006 and em P /em ?=?0.026, respectively, ANOVA). The 4-(tert-Butyl)-benzhydroxamic Acid peak glucose concentrations throughout the day and after each meal were significantly lower with luseogliflozin than with placebo in the normal and normalCmild groups, but not in the mildCmoderate group. The placebo-subtracted difference in the peak glucose concentration was significantly different between groups after breakfast ( em P /em ?=?0.047, ANOVA), but not at the other measurement occasions. The fasting glucose concentrations (i.e., glucose concentration measured before each meal and in the sleeping period) were consistently lower with luseogliflozin than with placebo in all three groups. Furthermore, the placebo-subtracted changes in the fasting glucose concentrations were not significantly different between groups. The lowest glucose concentration from 0 to 24?h was lower 4-(tert-Butyl)-benzhydroxamic Acid with luseogliflozin than with placebo in all groups. The placebo-subtracted change in the lowest glucose concentration was not significantly different between groups. Luseogliflozin significantly increased the cumulative UGE compared with placebo in all of the periods in all three groups (all em P /em ? ?0.05). However, the placebo-subtracted changes in the cumulative UGE were smaller in the mildCmoderate group than in the normal and normalCmild groups, and these differences were statistically significant between groups for all measurement occasions except after dinner (throughout the day: em P /em ?=?0.007; after breakfast: em P /em ?=?0.037; after lunch: em P /em ?=?0.007; after dinner: em P /em ?=?0.198; sleeping period: em P /em ?=?0.050, ANOVA). The serum insulin and plasma glucagon levels on day 7 in each.