Analysis of Antipsychotic Dosage in Patients With Tardive Dyskinesia: A Case-Control Study Using the Claims Database of the Corporate Health Insurance Association.

PURPOSE: This study aimed to assess the association between antipsychotic doses and the risk of tardive dyskinesia (TD) in clinical practice using a Japanese claims database from 2010 to 2020. METHODS: The study population included patients 15 years or older with a diagnosis record of schizophrenia, depression, or bipolar disorder who were prescribed antipsychotics. Using a case-control design, we categorized patients newly diagnosed with TD as cases, with corresponding 1:10 matching in the control group. The primary endpoint was the relative risk of TD in the >median dose and ≤median dose groups, as determined using conditional logistic regression analysis adjusted for age. RESULTS: The analysis population included 58,452 patients, and the median daily antipsychotic dose was 75 mg/d of chlorpromazine equivalent (CPZE). Of these, 80 were identified as TD cases, and doses >75 mg/d were associated with a significantly increased risk of TD at the last prescription and the maximum dose, respectively, before the date of the first diagnosis of TD. Post-hoc analysis further showed a significant association between doses ≥300 mg/d and the risk of TD compared to doses ≤75 mg/d and doses >75 to <300 mg/d. Comparing ≥300 mg/d versus >75 to <300 mg/d, the odd ratios at the last prescription and maximum dose before the first diagnosis of TD were 3.40 and 3.50, respectively. CONCLUSIONS: In the Japanese medical claims database of patients receiving relatively low doses of antipsychotics, doses >75 mg/d were associated with an increased risk of TD in a dose-dependent manner.

Renal outcomes with sodium-glucose cotransporter 2 inhibitors in Japanese people with grade 3 chronic kidney disease and type 2 diabetes: Analysis of medical administrative databases.

AIM: To evaluate whether sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy is associated with a reduction of renal events compared with other glucose-lowering drugs (oGLDs) among Japanese people with type 2 diabetes (T2D) and grade 3 (G3) chronic kidney disease (CKD) in a real-world clinical practice setting. MATERIALS AND METHODS: People with T2D who were newly prescribed an SGLT2i or an oGLD from April 2014 to November 2021 (without prior use of index drugs for ≥ 1 year prior to index date) and G3 CKD (estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) were selected from the Medical Data Vision database (MDV-DB) and the Real-World Data database (RWD-DB). SGLT2i and oGLD users were matched (1:1) using propensity score on patient background characteristics. The primary endpoint was a composite of the development of end-stage kidney disease or a sustained decline in eGFR of 50% or more. Hazard ratios (HRs) were estimated using the Cox proportional hazards model. RESULTS: Overall, 3190 (1595 per group) patients in the MDV-DB and 2572 (1286 per group) patients in the RWD-DB were included in the analyses. The composite outcome was significantly lower in the SGLT2i group than in the oGLD group in the MDV-DB (HR 0.49, 95% confidence interval [CI] 0.33 to 0.74, P < 0.001) and in the RWD-DB (HR 0.57, 95% CI 0.37 to 0.88, P = 0.011). CONCLUSIONS: Japanese people with T2D and G3 CKD initiating an SGLT2i had a lower risk of renal events than people initiating an oGLD.

Efficacy and safety of teneligliptin added to canagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: A multicentre, randomized, double-blind, placebo-controlled, parallel-group comparative study.

Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose co-transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP-4 inhibitor) added to canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed-dose combination of teneligliptin and canagliflozin. Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomized to receive add-on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between-group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (-0.94%; P < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM.

Long-term safety and efficacy of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes.

AIM: To evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy. METHODS: This open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight from baseline to week 52 (with last observation carried forward). RESULTS: Overall, 153 patients entered the treatment period and 142 completed the study. The overall incidence rates of AEs and drug-related AEs were 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean changes in HbA1c, FPG and body weight were -0.99% (95% confidence interval [CI] -1.12 to -0.85), -38.6 mg/dL (95% CI -43.4 to -33.9) and -3.92% (95% CI -4.53 to -3.31), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52. CONCLUSIONS: No new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese patients with T2DM who have inadequate glycaemic control on teneligliptin alone.

Efficacy and safety of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: Results of a 24-week, randomized, double-blind, placebo-controlled trial.

AIMS: To investigate efficacy and safety of the sodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozin administered as add-on therapy to the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We conducted a multicentre, randomized, double-blind, placebo-controlled, phase 3 clinical trial in Japanese patients with T2DM who had inadequate glycaemic control with teneligliptin. Patients were randomized to receive teneligliptin 20 mg plus either canagliflozin 100 mg (T + C, n = 70) or placebo (T + P, n = 68) once daily. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. Other endpoints included changes in fasting plasma glucose, body weight, proinsulin/C-peptide ratio, homeostatic model assessment 2-%B and adverse events. Patients also underwent mixed-meal tolerance tests. RESULTS: The difference between the T + C and T + P groups for HbA1c change from baseline to week 24 was -0.88% (least-squares mean, P < .001). Fasting plasma glucose, body weight and the proinsulin/C-peptide ratio were significantly lower in the T + C group than in the T + P group. Homeostatic model assessment 2-%B improved with T + C compared with T + P. The T + C group exhibited a decrease in the 2-hour postprandial plasma glucose and plasma glucose area under the curve (AUC)0-2h in a mixed-meal tolerance test. No significant between-group differences were observed for C-peptide AUC0-2h or glucagon AUC0-2h after meals. Incidences of adverse events were 60.0% and 47.1% in the T + C and T + P groups, respectively. No hypoglycaemia was observed. CONCLUSIONS: Canagliflozin administered as add-on therapy to teneligliptin was effective and well tolerated in Japanese T2DM patients.

Association of denervation severity in the dermis with the development of mechanical allodynia and hyperalgesia in a murine model of postherpetic neuralgia.

BACKGROUND: Postherpetic neuralgia (PHN) is a common complication of herpes zoster and remains a challenging condition of neuropathic pain. Allodynia, a prominent feature of PHN, extends beyond the margins of the initial rash area. In the present study, we investigated the association between cutaneous denervation and the development of postherpetic allodynia and hyperalgesia by using a murine model of PHN. METHODS: Female C57BL/6j mice were used. Herpes simplex virus type-1 (HSV1) was inoculated on the unilateral shin, a region that is predominantly innervated by L3 dorsal root ganglion (DRG) neurons. After the zoster-like skin lesions healed, mice were classified by the presence of mechanical allodynia and hyperalgesia in the plantar aspect of the ipsilateral hindpaw. Scarred lumbar (innervated by L2-4 DRG neurons) and the ipsilateral plantar (innervated by L3-5 DRG neurons) skin sections were immunostained with an antibody against protein gene product (PGP)9.5. The number of PGP9.5-immunoreactive (IR) profiles in the epidermis and dermis were analyzed for quantification of cutaneous innervation. RESULTS: In the epidermis of the scarred lumbar skin, the intraindividual mean number of PGP9.5-IR profiles was significantly decreased in mice inoculated with HSV1. The intraindividual maximum and mean numbers of PGP9.5-IR profiles in the epidermis of the scarred skin were not significantly different between mice with and without postherpetic allodynia and hyperalgesia. In the dermis of the scarred lumbar skin, the intraindividual maximum and mean numbers of PGP9.5-IR profiles were significantly decreased in mice with postherpetic allodynia and hyperalgesia, but not in mice without these symptoms. The intraindividual minimum number of PGP9.5-IR profiles in the dermis and epidermis was significantly decreased by HSV1 inoculation. HSV1 inoculation significantly decreased the intraindividual mean number of PGP9.5-IR profiles in the epidermis, but not dermis, of the plantar skin on the inoculated side. CONCLUSIONS: The present results suggest that the severity of dermal denervation in the scarred skin is associated with the development of postherpetic allodynia and hyperalgesia that extend beyond the margins of the initial rash area. The decrease of epidermal nerve density in the scarred and stimulation skins may not be associated with postherpetic allodynia and hyperalgesia.

Effect of sodium-glucose cotransporter 2 inhibitor medication on new prescriptions of antihypertensives, antigout/antihyperuricemics and antidyslipidemics in Japan: Analysis using the JMDC Claims Database.

AIMS/INTRODUCTION: This study aimed to investigate the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on new prescriptions of drugs, including antihypertensives, antigout/antihyperuricemics and antidyslipidemics, for the treatment of lifestyle-related diseases in Japanese patients with diabetes mellitus using the JMDC Claims Database. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus who were newly treated with SGLT2i or other oral antidiabetic drugs and had not been prescribed any antihypertensives, antigout/antihyperuricemics or antidyslipidemics for at least 1 year were extracted from the database. Using propensity score calibration matching (1:1), we assessed the proportion of patients who started the aforementioned concomitant medications within 2 years, and the risk ratio of SGLT2i to other antidiabetic medication groups was calculated. RESULTS: In 856,796 patients with diabetes mellitus, 734, 1,197 and 703 propensity score calibration-matched patients in each group were analyzed for the prescription of antihypertensives, antigout/antihyperuricemics and antidyslipidemics, respectively. The new prescriptions of antihypertensives and antigout/antihyperuricemics were lower in the SGLT2i group than those in the other oral antidiabetic drug group (risk ratio 0.66 and 0.37, respectively), whereas those of antidyslipidemics were more common in the SGLT2i group (risk ratio 1.43). CONCLUSIONS: New prescriptions of antihypertensives or antigout/antihyperuricemics were lower for patients taking SGLT2i than those taking other oral antidiabetic drugs, probably due to a reduction of blood pressure and uric acid levels by SGLT2i. The more frequent prescriptions of antidyslipidemics might partially reflect a moderate increase in low-density lipoprotein cholesterol levels as a result of sodium-glucose cotransporter 2 inhibition.

Association between glycemic control and cardiovascular events in older Japanese adults with diabetes mellitus: An analysis of the Japanese medical administrative database.

AIMS/INTRODUCTION: The relationship between glycated hemoglobin (HbA1c) and cardiovascular events in older adults was investigated using a Japanese administrative medical database. MATERIALS AND METHODS: Anonymized medical data on patients with diabetes mellitus aged ≥65 years for the period from January 2010 to December 2019 were extracted from the EBM Provider database. The primary end-point was a composite of cardiovascular events, whereas the other end-points included severe hypoglycemia and fracture. The association between cardiovascular events and HbA1c at the index date (i.e., approximately 10 months after initial diabetes mellitus diagnosis) was evaluated using the Cox proportional hazards model. RESULTS: Among the 3,186,751 patients in the database, 3,946 older adults with diabetes mellitus were eligible for inclusion and were subsequently grouped according to HbA1c quartiles at the index date. Cardiovascular events occurred in 142 patients. Patients with HbA1c in the highest quartile had significantly higher risk of hospitalization for cardiovascular disease than those with HbA1c in the lowest quartile (hazard ratio 1.948; 95% confidence interval 1.252-3.031, P = 0.003). However, the events risk was similar across subgroups with HbA1c <7.2%. The incidence of hypoglycemia and fracture was not significantly associated with the level of glycemic control. CONCLUSIONS: Among older adults with diabetes mellitus, those with poor glycemic control were at higher risk for cardiovascular events compared with those with better glycemic control. However, strict glycemic control had no effect on cardiovascular risk in patients with HbA1c <7.2%.

Trends in Corticosteroid Prescriptions for Ulcerative Colitis and Factors Associated with Long-Term Corticosteroid Use: Analysis Using Japanese Claims Data from 2006 to 2016.

BACKGROUND AND AIMS: Recent treatment guidelines for ulcerative colitis [UC] do not recommend long-term corticosteroid [CS] use. The present study aimed to capture the changes in CS use from 2006 to 2016 and to identify factors associated with long-term CS use after 2014, when the first two anti-tumour necrosis factor antibodies [infliximab and adalimumab] became available. METHODS: A retrospective study using the JMDC Claims Database included UC patients who initiated UC medications in any year from January 2006 to December 2016, or after January 2014, who were under continuous observation from 6 months before to 12 months after initiation. Patients with Crohn's disease before initiation and those prescribed <8 days of CSs were excluded. RESULTS: Among 7907 UC patients who initiated UC medications within the study period, 1555 were prescribed CSs. The proportion of patients using CSs in each year decreased from 2011 as use of thiopurines and biologics increased. The proportion of patients with a starting dose ≥30 mg/day of CSs and patients continuing CSs for <90 days increased from 2011, reaching 49.1% and 41.0%, respectively, in 2016. However, even in 2016, 34.3% continued to use CSs for ≥180 days. Among 1230 patients with CS use after January 2014, low initial CS dose [<10 mg/day] was most strongly associated with long-term CS use [≥180 days]. CONCLUSIONS: CS use became more appropriate as use of thiopurine and biologics increased, although there were still many cases of inappropriate use. Long-term CS use was most strongly associated with low initial doses of CSs.

The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin: Implications for Clinical Practice.

Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan and Korea and is being researched in several countries. Teneligliptin is a potent, selective, and long-lasting DPP-4 inhibitor with a t½ of approximately 24 h and unique pharmacokinetic properties: it is metabolized by cytochrome P450 (CYP) 3A4 and flavin-containing monooxygenase 3 (FMO3), or excreted from the kidney in an unchanged form. Because of its multiple elimination pathways, dose adjustment is not needed in patients with hepatic or renal impairment, and it is considered to have a low potential for drug-drug interactions. Clinical studies and postmarketing surveillance show that teneligliptin, administered as monotherapy and/or in combination with antihyperglycemic agents, is effective and well tolerated in T2DM patients, including in elderly patients and those with renal impairment. Furthermore, teneligliptin has antioxidative properties, which induce the antioxidant cascade, as well as ·OH scavenging properties. In addition, it has shown endothelial protective effects in several non-clinical and clinical studies. From its unique profile and clinical data, teneligliptin represents a potential therapeutic option in a wide variety of patients, including elderly diabetic patients and those with renal impairment. The fixed-dose combination (FDC) tablet of teneligliptin and canagliflozin has been approved in Japan; this is the first FDC tablet of a DPP-4 inhibitor and sodium glucose co-transporter 2 inhibitor in Japan, and the third globally. The FDC tablet may also provide additional prescribing and adherence benefits.

Associations between eating habits and glycemic control and obesity in Japanese workers with type 2 diabetes mellitus.

PURPOSE: To investigate the impact of poor eating habits on glycemic and metabolic control, we analyzed the associations between eating behaviors and HbA1c and body mass index (BMI) in Japanese workers with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: The Japan Medical Data Center database of workers' medical health insurance claims was used to identify individuals with T2DM who were receiving antidiabetic medication between April 2012 and March 2015 (the primary analysis population). The database included routine medical check-up results and responses to questions on lifestyle and eating habits. Using these, we retrospectively analyzed the associations between the individuals' eating habits and their HbA1c levels and BMIs. RESULTS: In total, 31,722 individuals were included in the primary analysis. The mean values of HbA1c and BMI were 7.27% and 26.29 kg/m2, respectively; these tended to be higher among the younger population. Approximately 36% of the individuals regularly ate supper within 2 hours of bedtime, 14.5% regularly consumed late-night snacks, and 13.4% regularly skipped breakfast. Each of these eating habits correlated significantly with higher HbA1c and BMI. In addition, the population with two or all three of these poor dietary habits showed the highest association with HbA1c ≥7.0% and BMI ≥25 kg/m2. Approximately 38% of workers ate fast. Fast eating was significantly associated with BMI ≥25 kg/m2 but not with HbA1c ≥7.0%. CONCLUSION: Poor eating habits were significantly associated with poor glycemic and body weight control in Japanese workers with T2DM. Improved eating habits may help with glycemic and body weight management.

Effect of Canagliflozin on Urinary Albumin Excretion in Japanese Patients with Type 2 Diabetes Mellitus and Microalbuminuria: A Pilot Study.

BACKGROUND: Albuminuria characterizes the progression of kidney injury. The effect of canagliflozin on the excretion of microalbumin was assessed for investigating its renoprotective potential in Japanese patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: Twenty Japanese patients with T2DM and microalbuminuria were enrolled and administered with 100 mg of canagliflozin once a day for 12 weeks. These subjects were admitted to the clinic at the start and end of the treatment period for 24-h urine collection. The primary endpoint was the percentage change in geometric mean 24-h urinary albumin excretion from baseline to week 12. RESULTS: The urinary albumin level decreased by 42.0% (95% confidence interval: 21.9-57.0; P = 0.0011) after 12 weeks of canagliflozin treatment. A number of blood and urinary parameters also significantly decreased, including hemoglobin A1c, fasting plasma glucose, estimated glomerular filtration rate, and creatinine clearance, while hematocrit was elevated. Among the biomarkers associated with kidney injury and inflammation, the urinary level of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine was also decreased. There were no meaningful correlations noted between changes in urinary albumin excretion and other parameters/biomarkers. No severe adverse events were reported over the 12-week treatment period. CONCLUSIONS: The results of this study indicate that canagliflozin decreases microalbuminuria in Japanese patients with T2DM. Albuminuria could be reduced as a result of changes in various physiological pathways; therefore, it is imperative that future, large-scale, studies attempt to determine the detailed mechanisms involved. Canagliflozin may offer a novel therapeutic option for Japanese patients with T2DM and incipient nephropathy.

Efficacy and safety of teneligliptin add-on to insulin monotherapy in Japanese patients with type 2 diabetes mellitus: a 16-week, randomized, double-blind, placebo-controlled trial with an open-label period.

OBJECTIVE: To assess the efficacy and safety of teneligliptin as add-on to insulin monotherapy in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: In a 16-week, double-blind period, 148 Japanese T2DM patients with inadequate glycemic control with insulin and diet/exercise therapies were randomized to placebo or teneligliptin 20 mg. In a subsequent 36-week, open-label period, all patients received teneligliptin once daily. The primary outcome measure was change in HbA1c at the end of the double-blind period. RESULTS: The difference between placebo and teneligliptin in change in HbA1c in the double-blind period (least squares mean ± SE) was -0.80% ± 0.11%; teneligliptin was superior (ANCOVA, P < 0.001). The HbA1c-lowering effect of teneligliptin was maintained throughout the open-label period. The incidence of adverse events was 53.5% with placebo and 44.2% with teneligliptin in the double-blind period, 66.7% in the placebo/teneligliptin group in the open-label period, and 77.9% in the teneligliptin/teneligliptin group over both double-blind/open-label periods. The incidence of hypoglycemic symptoms was 11.1% in the placebo/teneligliptin group in the open-label period and 27.3% in the teneligliptin/teneligliptin group over both double-blind/open-label periods. CONCLUSION: Teneligliptin was effective and well tolerated in Japanese T2DM patients with inadequate glycemic control. CLINICAL TRIAL REGISTRATION: NCT02081599.

Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats.

BACKGROUND: We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements. METHODS: Different doses of 6-OHDA (0, 7, 14, and 28 µg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing. RESULTS: Accumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations. CONCLUSIONS: Ki values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD).