Characteristics of Japanese patients with non-dialysis-dependent chronic kidney disease initiating treatment for anemia: a retrospective real-world database study

Objective: Anemia is a common complication of chronic kidney disease (CKD). The aim of this study was to evaluate the hemoglobin levels at the initiation of erythropoiesis stimulating agent (ESA) therapy in patients with non-dialysis-dependent CKD (NDD-CKD) and anemia using a large-scale administrative database in Japan. Methods: The longitudinal data of adult patients who initiated ESA therapy between April 2008 and December 2018 were extracted from a hospital-based administrative database. The primary outcome was the hemoglobin level at the initiation of ESA therapy, whereas the exploratory outcome was the hemoglobin level recorded 6 months after the onset of the ESA therapy. Results: A total of 4939 patients were included in the primary analysis. The mean hemoglobin level at the initiation of ESA therapy was 9.1 g/dL, which was lower than the level (11 g/dL) recommended for the initiation of treatment by the current Japanese treatment guidelines. Moreover, 42.1% and 15.0% of the patients had hemoglobin levels 11.0 g/dL, respectively. Conclusion: This real-world database study revealed that the hemoglobin levels at the initiation of ESA therapy in new users of ESA were lower than those recommended by the treatment guidelines in Japan.</p

Body weight, food intake, and body composition by dual-energy X-ray absorptiometry (DEXA) in KK-A^y mice.

<p>A: Body weight percent change, B: Cumulative food intake, C: Body composition (lean mass, open column; fat mass, closed column), and D: Body fat. Canagliflozin (Cana; 0.01% w/w food admixture), pioglitazone (Pio; 0.01% w/w food admixture), and their combination (Combo) were administered for 2 weeks. Body composition and body fat were measured at the end of the study using the DEXA scanner. Data are expressed as mean ± SEM (n = 7). ** <i>P</i> < 0.01 vs. control, † <i>P</i> < 0.05, †† <i>P</i> < 0.01 vs. Pio, § <i>P</i> < 0.05 vs. Cana. </p

Glycemic control and urinary glucose excretion (UGE) in KK-A^y mice.

<p>A: Plasma glucose, B: Plasma insulin, and C: UGE. Canagliflozin (Cana; 0.01% w/w food admixture), pioglitazone (Pio; 0.01% w/w food admixture), and their combination (Combo) were administered for 2 weeks. UGE was measured on days 14–15. Data are expressed as mean ± SEM (n = 7–8). * <i>P</i> < 0.05, ** <i>P</i> < 0.01 vs. control, † <i>P</i> < 0.05, †† <i>P</i> < 0.01 vs. Pio, § <i>P</i> < 0.05, §§ <i>P</i> < 0.01 vs. Cana. </p

Histological analysis of adipose tissue in KK-A^y mice.

<p>A: Representative images of mesenteric adipose tissue and B: Average size of adipocytes. Canagliflozin (Cana; 0.01% w/w food admixture), pioglitazone (Pio; 0.01% w/w food admixture), and their combination (Combo) were administered for 2 weeks. Mesenteric adipose tissue was stained with elastic van Gieson without nuclear staining at the end of the study. The size of 500 adipocytes was analyzed using Image-Pro Plus software. Data are expressed as mean ± SEM (n = 8). ** <i>P</i> < 0.01 vs. control, †† <i>P</i> < 0.01 vs. Pio, § <i>P</i> < 0.05 vs. Cana. Scale bar = 100 μm. </p

Body fat analysis by computed tomography (CT) in KK-A^y mice.

<p>A: Representative CT images (red, visceral fat; yellow, subcutaneous fat), B: Total fat, C: Visceral fat, and D: Subcutaneous fat. Canagliflozin (Cana; 0.01% w/w food admixture), pioglitazone (Pio; 0.01% w/w food admixture), and their combination (Combo) were administered for 2 weeks. Adipose tissue weight was measured at the end of the study using an experimental animal CT system. Data are expressed as mean ± SEM (n = 7–8). * <i>P</i> < 0.05, ** <i>P</i> < 0.01 vs. control, † <i>P</i> < 0.05 vs. Pio, § <i>P</i> < 0.05, §§ <i>P</i> < 0.01 vs. Cana. </p

The adipose tissue weight of ZDF and ZL rats.

<p>A: Mesenteric fat, B: Epididymal fat, and C: Perirenal fat. Canagliflozin (Cana; daily dose of 10 mg/kg), pioglitazone (Pio; daily dose of 10 mg/kg), and their combination (Combo) were administered by oral gavage for 6 weeks. Adipose tissue weight was measured at the end of the study. Data are expressed as mean ± SEM (n = 8). ## <i>P</i> < 0.01 vs. ZL rats, ** <i>P</i> < 0.01 vs. vehicle-treated ZDF rats, †† <i>P</i> < 0.01 vs. Pio-treated ZDF rats, §§ <i>P</i> < 0.01 vs. Cana-treated ZDF rats. </p

Novel Indole‑<i>N</i>‑glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes

Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia. To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-<i>N</i>-glucosides <b>6</b>. Optimization of <b>6</b> resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-<i>N</i>-glucoside <b>6a-4</b> (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-<i>N</i>-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2

Effects of canagliflozin on SGLT1-, SGLT2-, and facilitative glucose transporter-mediated glucose transport, and on SGLT3-induced currents.

<p>CHOK cells over-expressed with human, rat, or mouse SGLT1 or SGLT2 and rat L6 myoblast cells were used. AMG or 2-DG uptake was determined and IC₅₀ values were calculated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030555#s2" target="_blank">Methods</a> section. Data of human SGLT1 and SGLT2 were presented the summary of 5 studies. Other data presented the mean value of 2 experiments. Oocytes expressed with human SGLT3 were used to determine canagliflozin effect on DNJ-induced current.</p><p>2-DG, 2-deoxy-d-glucose; AMG, alpha-methylglucoside; CHOK, Chinese hamster ovary-K; IC₅₀, concentration required to inhibit 50% of activity; SGLT, sodium glucose co-transporter; DNJ, imino sugars 1-deoxynojirimycin.</p

Effects of canagliflozin on body weight, glycemia, UGE, and respiratory exchange ratio in DIO mice and ZF rats.^a

<p>DIO mice were treated with either vehicle or canagliflozin 30 mg/kg for 4 weeks. Body weight was monitored twice per week. BG, UGE, and energy expenditure were measured at the end of this study.</p><p>BG, blood glucose; DIO, diet-induced obesity; ND, not detected; RER, respiratory exchange ratio; UGE, urinary glucose excretion; VO₂, oxygen consumption; ZF, Zucker fatty.</p>a<p>ZF rats were treated with either vehicle or canagliflozin 3 mg/kg for 3 weeks. Body weight and food intake were monitored twice per week. BG, UGE, and energy expenditure were measured at the end of this study. In addition, the weight of epididymal fat pad and liver tissue were determined during necropsy. Data are presented as mean ± SEM (<i>n</i> = 8).</p>b<p><i>p</i><0.05 compared with vehicle-treated group.</p

Inhibitory effects of canagliflozin on human SGLT1 and human SGLT2.

<p>The inhibitory effect of canagliflozin on ¹⁴C-AMG uptake in CHOK-hSGLT1 and CHOK-hSGLT2 has been measured in 5 experiments. A typical inhibitory effect on CHOK-hSGLT1 (Panel A) and CHOK-hSGLT2 (Panel B) from a single experiment is presented here.</p