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Introduction This long-term post-marketing surveillance (SAPPHIRE) collected information on the safety and effectiveness of canagliflozin (approved dose 100 mg) prescribed to patients with type 2 diabetes mellitus (T2DM) in real-world practice in Japan. Methods Patients with T2DM who were prescribed canagliflozin between December 2014 and September 2016 were registered and observed for up to 3 years. Safety was evaluated in terms of adverse drug reactions (ADRs). Effectiveness was assessed in terms of glycaemic control. Data were also analysed across age subgroups (, Plain Language Summary Canagliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that lowers blood glucose levels by increasing urinary glucose excretion. It was approved for the management of blood glucose levels in patients with type 2 diabetes mellitus following clinical trials. However, clinical trials may not fully represent the safety or effectiveness of a drug in real-world clinical practice. Therefore, a 3-year post-marketing surveillance was performed in Japan to obtain safety and effectiveness data for a large group of 12,227 patients with type 2 diabetes mellitus and various demographic/clinical characteristics. Safety and effectiveness data were collected for up to 3 years while patients were treated with canagliflozin. Adverse drug reactions occurred in 10.73% of patients. The most common types of adverse drug reactions were those related to volume depletion (body fluid decreased), followed by genital infection, polyuria/pollakiuria (increased urination), and urinary tract infection. Adverse drug reactions tended to be more common in elderly patients and in patients with renal impairment. As expected, canagliflozin was associated with improvements in haemoglobin A1c, a marker of blood glucose control, in patients with type 2 diabetes, including in elderly patients and patients with moderate renal impairment. In this surveillance in real-world clinical practice, long-term treatment with canagliflozin raised no new safety concerns beyond the information already included in the Japanese package insert. Canagliflozin provides sustained glucose-lowering effects. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01984-4.

Introduction Teneligliptin, a dipeptidyl peptidase 4 inhibitor, was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. However, clinical trials of teneligliptin involved limited numbers of elderly patients. Therefore, we investigated the safety and efficacy of teneligliptin in elderly patients with T2DM. Methods This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. Data were analysed for patients in three age subgroups (, Plain Language Summary Teneligliptin is an oral drug taken once daily to manage blood glucose levels in people with type 2 diabetes. A number of studies of teneligliptin have investigated its safety and efficacy, but these studies included limited numbers of elderly people, aged 75 years or older. Following the approval of teneligliptin in Japan, post-marketing surveillance was started to monitor its safety and efficacy when prescribed by doctors to people in actual clinical practice. We analysed data from the surveillance to check if the safety and efficacy of teneligliptin differ in younger and older people separately. We found that there was no clear difference in the number of adverse drug reactions among three age subgroups

Introduction Healthy eating is a critical aspect of the prevention and management of type 2 diabetes (T2DM). Disrupted eating patterns can result in poor glucose control and increase the likelihood of diabetic complications. Teneligliptin inhibits dipeptidyl peptidase-4 activity for 24 h and suppresses postprandial hyperglycemia after all three daily meals. This interim analysis of data from the large-scale post-marketing surveillance of teneligliptin (RUBY) in Japan examined eating patterns and their relationship with metabolic parameters and diabetic complications. We also examined whether eating patterns affected safety and efficacy of teneligliptin. Methods We analyzed baseline data from survey forms collected in RUBY between May 2013 and June 2017, including patient characteristics, metabolic parameters, and eating patterns (eating three meals per day or not; timing of evening meal) before teneligliptin treatment was initiated. Safety and efficacy of 12 months’ teneligliptin (20–40 mg/day) treatment was assessed. Results Data from 10,532 patients were available for analysis. Most patients who did not eat three meals per day (n =757) or who ate their evening meal after 10 PM (n =206) were 64 years old or younger. At baseline, glycated hemoglobin (HbA1c), fasting blood glucose, triglycerides, total and low-density lipoprotein cholesterol, body mass index, alanine aminotransferase, and aspartate aminotransferase levels were higher in those patients who did not eat three meals per day (p

Introduction Teneligliptin is a novel oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Safety and efficacy of teneligliptin have been demonstrated in clinical studies; however, data supporting its use in patients with moderate or severe renal impairment are limited. This interim analysis of a post-marketing surveillance of teneligliptin, exploRing the long-term efficacy and safety included cardiovascUlar events in patients with type 2 diaBetes treated bY teneligliptin in the real-world (RUBY), aims to verify the long-term safety and efficacy of teneligliptin in Japanese patients with T2DM and impaired renal function. Methods For this analysis, we used the data from case report forms of the RUBY surveillance between May 2013 and June 2017. The patients were classified into G1–G5 stages of chronic kidney disease according to estimated glomerular filtration rate (eGFR) at initiation of teneligliptin treatment. Safety and efficacy were evaluated in these subgroups. Patients on dialysis were also assessed. Safety was assessed from adverse drug reactions (ADRs). Glycemic control was evaluated up to 2 years after teneligliptin initiation. Results A total of 11,677 patients were enrolled in the surveillance and 11,425 patient case-report forms were collected for the interim analysis. The incidence of ADRs in each subgroup was 2.98–6.98% of patients, with no differences in the ADR profile (including hypoglycemia and renal function ADRs) between subgroups. At 1 and 2 years after starting teneligliptin, the least-squares mean change in HbA1c adjusted to the baseline was − 0.68 to − 0.85% and − 0.71 to − 0.85% across the eGFR groups, respectively. Treatment with teneligliptin in patients on dialysis reduced or tended to reduce glycated albumin levels [− 2.29%, (p

This post-marketing surveillance examined the safety and efficacy of long-term teneligliptin therapy in Japanese patients.We report interim results (cut-off date: 28 June 2017) of a 3-year PMS undertaken in subjects with type 2 diabetes mellitus (T2DM). Survey items included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. A subgroup analysis was also performed across three age groups (65 years; 65 to75 years; ≥75 years). Main outcome measures were incidence of ADRs, laboratory variables, and change in glycated hemoglobin (HbA1c) from baseline over time.Of 11,677 patients registered, data from 10,532 patients (6,338 males/4,194 females) were analyzed for the safety analysis set; the median administration period was 731 days. Overall, ADRs and serious ADRs were reported in 364 (3.46%) and 91 patients (0.86%), respectively. The most common ADRs were all hypoglycemia (0.32%), constipation (0.27%), and hepatic function abnormal (0.24%). No change in mean body weight occurred, and a reduction in mean HbA1c was observed until 2 years. The safety and efficacy profiles did not differ markedly among the three age groups.These interim results show that teneligliptin was well tolerated and improved hyperglycemia in Japanese patients with T2DM in clinical practice.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been reported to improve obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) in addition to exercise training, whereas the combined effects remain to be elucidated fully. We investigated the effect of the combination of the SGLT2i canagliflozin (CAN) and exercise training in high-fat diet-induced obese mice. High-fat diet-fed mice were housed in normal cages (sedentary; Sed) or wheel cages (WCR) with or without CAN (0.03% of diet) for 4 wk. The effects on obesity, glucose metabolism, and hepatic steatosis were evaluated in four groups (Control/Sed, Control/WCR, CAN/Sed, and CAN/WCR). Numerically additive improvements were found in body weight, body fat mass, blood glucose, glucose intolerance, insulin resistance, and the fatty liver of the CAN/WCR group, whereas CAN increased food intake and reduced running distance. Exercise training alone, CAN alone, or both did not change the weight of skeletal muscle, but microarray analysis showed that each resulted in a characteristic change of gene expression in gastrocnemius muscle. In particular, in the CAN/WCR group, there was acceleration of the angiogenesis pathway and suppression of the adipogenesis pathway compared with the CAN/Sed group. In conclusion, the combination of an SGLT2i and exercise training improves obesity, insulin resistance, and NAFLD in an additive manner. Changes of gene expression in skeletal muscle may contribute, at least in part, to the improvement of obesity and insulin sensitivity.

Introduction Teneligliptin is a dipeptidyl peptidase 4 inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. We performed a long-term post-marketing surveillance (RUBY) to obtain real-world evidence regarding the safety and efficacy of teneligliptin in Japan. Methods This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs) and laboratory variables. Data were evaluated in all patients and in patients divided according to baseline renal function across categories of estimated glomerular filtration rate (G1–G5) and dialysis. Safety was assessed as the incidence of ADRs and efficacy was assessed in terms of glycaemic control, for up to 3 years. Results Of 11,677 patients registered, 10,696 and 10,249 were evaluable for safety and efficacy analyses, respectively. The median duration of exposure was 1096 days. ADRs occurred in 412 patients (3.85%) and were serious in 117 patients (1.09%). The most frequent ADR class was gastrointestinal disorders (0.68%), which included constipation. There were no new ADRs warranting attention beyond those already described in teneligliptin’s package insert. ADRs and serious ADRs in renal function subgroups occurred in 3.24–7.14% and 0.65–5.36% in G1–G5, and 4.49% and 1.92% in patients on dialysis, respectively. Reduction in HbA1c was sustained for 3 years after starting teneligliptin (− 0.70% ± 1.36%, p

Background and Aim: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert multiple metabolic effects. Exercise training is a robust treatment of obesity and diabetes, but the effect of SGLT2 inhibitors on exercise training is unclear. We investigated the association between canagliflozin (CAN) and training effects on skeletal muscle and liver in obese diabetic mice. Method: Male mice loaded with a high-fat diet for 4 weeks were housed in a normal cage (sedentary; sed) or wheel cage (WCR). A total of 0.03%w/w CAN was administrated for 2 weeks. Glucose and lipid metabolism of skeletal muscle (gastrocnemius) was analyzed and compared among 4 groups (control/sed, control/WCR, CAN/sed, and CAN/WCR). Results: Body weight in control/WCR and CAN/sed mice was significantly lower compared with that in control/sed mice, and further weight loss was observed in CAN/WCR mice. There was no difference in running distance between control/WCR and CAN/WCR mice. Control/WCR mice showed lower blood glucose levels than did control/sed mice (200.0±4.2 vs. 231.9±8.7 mg/dL, p=0.01). CAN decreased glucose levels, but there was no difference between CAN/sed (118.9±6.29 mg/dL) and CAN/WCR mice (113.6±4.48 mg/dL). GLUT1 and GLUT4 mRNA levels in skeletal muscle in CAN/sed and CAN/WCR mice were significantly lower than those in control/sed mice. Levels of mRNA of CD36 (× 1.26 in CAN/sed and × 1.31 in CAN/WCR mice, both p Discussion: CAN promoted transition from glucose to lipid-dependent energy metabolism in skeletal muscle and this effect might have been enhanced by concomitant exercise. Conclusion: The combination of CAN and exercise may be effective for weight loss in obesity by an increase in lipid energy expenditure. Disclosure K. Tanaka: Research Support; Self; Mitsubishi Tanabe Pharma Corporation. H. Takahashi: Research Support; Self; Mitsubishi Tanabe Pharma Corporation. K. Sasaki: Employee; Self; Mitsubishi Tanabe Pharma Corporation. K. Inoue: None. Y. Matsuda: None. Y. Eguchi: None. K. Anzai: Research Support; Self; Mitsubishi Tanabe Pharma Corporation, Sysmex Corporation.

To evaluate the safety and efficacy of canagliflozin in elderly patients with type 2 diabetes mellitus (T2DM) in clinical settings.The authors conducted a 1-year post-marketing surveillance (PMS) of canagliflozin in almost all the elderly patients (≥65 years old) with T2DM who began taking canagliflozin during the first 3 months after its launch in Japan. The main outcomes included the incidences of adverse drug reactions (ADRs), serious ADRs, and the changes of laboratory tests as well as efficacy variables.An ADR was reported in 9.09% (125 of 1375 patients) in the safety analysis set. The main ADRs were dehydration, constipation, thirst, pollakiuria, dizziness, cystitis, eczema, pruritus, and rash. The incidence of serious ADRs was 1.02% (14 patients), which included urinary tract infection, dehydration, hypoglycemia, and cerebral infarction (two patients each). ADRs of special interest that had been reported in clinical trials of SGLT2 inhibitors, such as hypoglycemia, volume depletion-related events, genital/urinary tract infection, polyuria/pollakiuria, and ketone body increased were also observed in this PMS. The safety profiles were similar to the results of a previous clinical study of canagliflozin, and new safety concerns were not identified in this survey. The mean change in HbA1c was -0.77% after 12 months of treatment in the efficacy analysis set.In this PMS, the safety and efficacy profiles of canagliflozin in elderly patients with T2DM were obtained in the clinical settings in Japan and the drug was well tolerated and effective in improving glycemic control.

The glucose-induced secretion of incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), is dependent on luminal glucose levels and transport of glucose via the sodium-glucose transporter 1 (SGLT1) in the small intestine. Because GLP-1 and GIP function in decreasing and increasing the body weight, respectively, we aimed to analyze the effect of transient inhibition of SGLT1 by canagliflozin on incretin secretion in an obese rat model. Male Sprague-Dawley rats were maintained on a high-fat high-sucrose diet for 6–7 weeks, and plasma GLP-1 and GIP levels were measured during an oral glucose tolerance test (OGTT). In addition, GLP-1 secretion was examined in a murine GLP-1 producing enteroendocrine cell line, GLUTag. Concomitant administration of 10 mg/kg canagliflozin with glucose loading suppressed glucose excursion, increased total GLP-1 levels, and reduced total GIP levels in systemic circulation, as revealed in the OGTT. Total and active GLP-1 levels were increased in portal blood, whereas total and active GIP levels tended to be decreased 15 min after the administration of canagliflozin with glucose. Canagliflozin (at 0.1–30 μM) did not directly affect release of GLP-1 in vitro. These results suggest that the oral administration of canagliflozin suppresses GIP secretion via the inhibition of SGLT1 in the upper part of the intestine and enhances GLP-1 secretion by increasing the glucose delivery to the lower part of the small intestine in an obese rodent model.

We aimed to investigate the efficacy of canagliflozin (based on its effect on liver function and blood glucose levels) and its safety in high alanine aminotransferase (ALT) patients (ALT >30 U/L). This post hoc analysis of canagliflozin in type 2 diabetes mellitus (T2DM) patients was divided into Study 1 (pooled analysis of 12- and 24-week placebo-controlled, monotherapy studies) and Study 2 (52-week monotherapy/combination therapy study). The canagliflozin 100 mg group data were compared with placebo or baseline ALT subgroup (baseline ALT >30 or ≤30 U/L) data. The primary endpoint was change in ALT level from baseline. Secondary endpoints were changes in efficacy-related parameters. Adverse events (AEs) were evaluated. The mean ALT change at 12 weeks was −10.3 ± 11.7 and −3.2 ± 17.6 U/L in the canagliflozin vs. placebo group in the high ALT subgroup (P = 0.0206); no significant difference was shown in the low ALT subgroup (Study 1). In both ALT subgroups, glycosylated hemoglobin (HbA1c) and body weight were significantly reduced in the canagliflozin vs. placebo group (all P

Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.

In the present study, we examined the concentration dependence of odor discrimination in turtle olfactory bulbar responses using the cross-adaptation technique. In the odorant pairs with diverse molecular structures, the degree of discrimination was unchanged or only slightly decreased with an increase in odorant concentrations, suggesting that odorants are well discriminated even at high concentrations. In the odorant pairs with closely related molecular structures, the degree of discrimination was decreased with an increase in odorant concentrations. An increase in the temperature of turtle olfactory epithelium also decreased the ability to discriminate these odorants. There was a good correlation between changes in the odor discriminating ability induced by an increase in odor concentrations and those induced by a temperature increase. The liposomes were made of lipids extracted from the turtle olfactory epithelia and changes of their membrane fluidity induced by adsorption of odorants were monitored with DPH. There was a good correlation between a decrease in odor discriminating ability and the membrane fluidity changes induced by odorants. We suggest that decreases in odor discriminating ability induced either by an increase in odor concentration or by a temperature increase are ultimately caused by changes in the membrane fluidity.

The mechanisms involved in pheromone-induced responses in the vomeronasal neurons, especially in mammals, are still unclear. In the present study, we examined the effects of rat urine samples containing various types of pheromones regulating gonadal functions on the accumulation of cAMP and inositol 1,4,5-trisphosphate (IP3) in a vomeronasal membrane preparation from the female Wistar rat. Stimulation of the preparation with forskolin induced cAMP accumulation, but stimulation with urine samples excreted from the male Wistar rat, the female Wistar rat, and the male Donryu rat did not change cAMP levels. These results were consistent with the electrophysiological results showing that dialysis of a high concentration of cAMP into the vomeronasal neuron does not induce currents. Stimulation with the three urine samples induced the accumulation of IP3 in the membrane preparation. These results are consistent with previous electrophysiological results [K. Inamura, M. Kashiwayanagi, K. Kurihara, Inositol-1,4,5-trisphosphate induces responses in receptor neurons in rat vomeronasal sensory slices, Chem. Senses 22 (1997) 93–103; K. Inamura, M. Kashiwayanagi, K. Kurihara, Blockage of urinary responses by inhibitors for IP3-mediated pathway in rat vomeronasal sensory neurons, Neurosci. Lett. 233 (1997) 129–132]. After the treatment with Pertussis toxin (PTX), the male Wistar urine did not induce IP3 accumulation significantly. Application of the male Wistar urine decreased ADP-ribosylation of Gi with PTX, while that of the male Donryu urine decreased ADP-ribosylation of Go. Thus, the present results support a mechanism by which the responses of the rat vomeronasal neurons to urinary pheromones are mediated by IP3, Gi and/or Go.