Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan.

PURPOSE: To estimate the incidence of lactic acidosis (LA) and role of metformin in Japanese patients with type 2 diabetes mellitus (T2DM) treated with anti-diabetes drugs. METHODS: This retrospective propensity score matched cohort study was conducted using the Japanese Medical Data Vision claims database. T2DM patients aged 18 or above who received diabetes drugs during January 2010 through August 2014 were identified. Cases of LA were identified based on reimbursement codes and confirmed by lactic acid test and subsequent treatment by hemodialysis or intravenous sodium bicarbonate. Poisson regression and Cox proportional hazard models were used to estimate the incidence and assess if metformin use was associated with increased risk of LA. RESULTS: Thirty cases of LA were identified among 283 491 treated T2DM patients with 504 169 patient-years of follow-up. Crude incidence of LA was 5.95 per 100 000 patient-years. T2DM patients with chronic kidney disease (CKD) were seven-fold more likely to develop LA than those without CKD (adjusted hazard ratio (aHR), 7.33, 95%CI, 3.17-16.96). Use of metformin was not associated with risk of LA in the study population (aHR, 0.92, 95%CI, 0.33-2.55), and in the propensity score matched cohort (aHR, 0.90, 95%CI, 0.26-3.11). Similar findings were observed among diabetes patients with chronic liver disease (CLD) and CKD. The age-sex adjusted incidence rates in metformin users and non-users were 5.80 and 5.78 per 100 000 person-years, respectively (Incidence rate ratio, 1.00, p = 0.99). CONCLUSIONS: This study found that use of metformin was not associated with increased risk of LA in diabetic patients including those with CKD or CLD. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.

Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study.

BACKGROUND: Drug-induced interstitial lung disease (ILD) is one of the most serious adverse reactions associated with the molecularly targeted drugs. Panitumumab has been approved for advanced or recurrent colorectal cancer. Although there were no adverse reaction reports of ILD in panitumumab monotherapy, 4 cases in combination chemotherapy were reported prior to its approval in Japan in 2010. Several studies also reported that the incidence of drug-induced ILD was higher in Japan than in other countries. The clinical features of ILD and the associated risk factors therefore need investigation. METHODS: We analyzed the data from 3085 unresectable, advanced or recurrent colorectal cancer patients enrolled in a postmarketing all-case surveillance study of panitumumab in Japan. ILD case reports were assessed based on the clinical and radiologic findings by a committee of external experts. Multivariate analysis using Cox's hazard model identified the risk factors. RESULTS: ILD incidence (1.3 %) and mortality rates (51.3 %) were similar to those of patients receiving another anti-epidermal growth factor receptor (EGFR) monoclonal antibody in Japan. No specific onset timing was determined. Although panitumumab-specific ILD findings were not observed in computed tomography images or clinical practice, panitumumab can induce ILD with diffuse alveolar damage, as do the other anti-EGFR targeting drugs. A history/complication of ILD, male sex, poor general condition, and 65 years or older were identified as ILD risk factors, and no history of previous drug treatment was an apparent risk factor. CONCLUSION: Panitumumab-induced ILD can occur at any time after initiation, and close and regular monitoring is needed.

Prevalence and incidence of cyclic vomiting syndrome in Japan: A study using Japanese claims data.

Cyclic vomiting syndrome (CVS) is a gastrointestinal disorder that is characterized by recurrent episodes of vomiting. Previous studies have provided reliable data on the prevalence of CVS among children in Japan; however, neither prevalence data nor incidence of CVS is available for adults. Hence, we obtained detailed prevalence and incidence data for CVS and estimated the total number of CVS cases in Japan. This retrospective cross-sectional study was conducted using the JMDC (JMDC, Inc.; formerly known as Japan Medical Data Center Co., Ltd.,) database, which is a de-identified Japanese claims database. Individuals enrolled between January 2017 and December 2017 were included in this study. Longitudinal data for eligible populations were used to identify patients who displayed CVS symptoms throughout the follow-up period. Due to the lack of a specific diagnosis code for CVS in 2017, the Rome IV criteria were applied to identify CVS cases in the pediatric and adult populations. The prevalence was standardized to the 2017 Japanese census and extrapolated to estimate the number of CVS cases. A total of 2,093 patients with CVS were identified from 3,506,144 individuals. The overall age-and-sex-standardized prevalence was 0.32 per 1,000 population (95% confidence interval [CI]: 0.30-0.34), projected to approximately 49,000 patients with CVS across Japan. The pediatric age-and-sex-standardized prevalence was 2.10 per 1,000 population (95% CI: 2.01-2.19), and the adult prevalence was 0.05 per 1,000 population (95% CI: 0.04-0.06). Marked sex differences were observed before and after 12 years of age. Thus our study provides the first large-population-based estimates of CVS prevalence and incidence in Japan, and currently, the only estimates for adult CVS in Japan.

Impact of oral corticosteroid use for idiopathic osteonecrosis of the femoral head: a nationwide multicenter case-control study in Japan.

BACKGROUND: Previous studies on corticosteroid use and idiopathic osteonecrosis of the femoral head (ONF) have been conducted involving patients with systemic lupus erythematosus and renal transplantation, among other disorders, which make it possible only to compare high- and low-dose corticosteroids. The main objective here was to estimate the impact of oral corticosteroid use for idiopathic ONF compared to nonuse of corticosteroids. In addition, we investigated the relations between underlying medical conditions and idiopathic ONF. METHODS: A nationwide multicenter case-control study was conducted in Japan. Cases were defined as patients who visited the cooperative orthopedic department after January 2002 and received a diagnosis of idiopathic ONF after the visit. For each case, up to five matched controls were selected from among patients without idiopathic ONF who consulted the same orthopedic department after the visit of the identified case. The matching conditions were sex, age (5-year age groups), and ethnicity. The subjects' demographic and anthropometric data and histories of medications, diseases, alcohol consumption, and smoking were collected by a structured self-administered questionnaire. A conditional logistic regression model was used to obtain the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 73 cases and 250 matched controls completed the questionnaire. After adjustment for the potential confounders, the multivariate OR of oral corticosteroid use compared to nonuse was 20.3 (95% CI 6.73-61.5). Furthermore, a positive association of liver disease with idiopathic ONF was observed with marginal significance (multivariate OR 3.53, 95% CI 0.88-14.1) regardless of oral corticosteroid use, alcohol consumption, and smoking. CONCLUSIONS: The current findings first revealed the impact of oral corticosteroid use for idiopathic ONF compared to nonuse. However, because the regimen of corticosteroid therapy (dose and duration) could not be assessed, further study is required. An independent role of liver disease was also suggested.

Incidence and causes of mildly to moderately elevated aminotransferase in Japanese patients with type 2 diabetes.

OBJECTIVES: To identify the association of type 2 diabetes (T2DM) and liver disease with elevated ALT and factors associated with increased ALT in patients with and without T2DM. DESIGN AND SETTING: We performed a retrospective study in adults with ≥ 2 claims for blood tests recorded in the Medical Data Vision claims database between 2010 and 2016. PARTICIPANTS: Patients were entered into T2DM and non-DM groups based on diagnosis and medication claim codes. PRIMARY OUTCOME MEASURE: The primary endpoint was the first follow-up ALT elevation over three times the normal value, and etiologies were categorized by subsequent diagnoses. We estimated the ALT elevation incidence and association with T2DM using Poisson regression and Cox proportional hazard models. RESULTS: We identified 3161 cases of elevated ALT in 104,903 patients (follow-up, 280,659 patient-years). The age- and sex-adjusted incidence of elevated ALT in the T2DM group (13.47 per 1000 patient-years; 95% confidence interval (CI) 12.53-14.48) was significantly higher than that in the non-DM group (8.43 per 1000 patient-years; 95% CI 7.72-9.20, p < 0.0001). Compared to the non-DM group, the T2DM group had an approximately 3.5 times higher risk of fatty liver-related ALT elevation (adjusted hazard ratio (HR), 3.54; 95% CI 1.90-6.58). T2DM was not associated with an increased incidence of jointly elevated ALT and total bilirubin (adjusted HR, 0.94; 95% CI 0.77-1.15). CONCLUSION: T2DM is strongly associated with increased liver enzymes secondary to fatty liver. The causes of liver enzyme abnormalities were not fully characterized due to a high proportion of unexplained ALT elevation.

The incidence of medically-attended norovirus gastro-enteritis in Japan: Modelling using a medical care insurance claims database.

BACKGROUND: The burden of medically-attended acute gastro-enteritis (MA-AGE) that can be attributed to norovirus is not well established in Japan. Using a nationwide database of medical care insurance claims, we estimated the incidence of medically-attended norovirus-attributable gastroenteritis (MA-NGE) in Japan. METHODS: The incidences of MA-NGE outpatient consultations or hospitalization in Japan were modelled on seasonal patterns of MA-AGE for unspecified causes derived from the Japan Medical Data Center (JMDC) database for the period July 2007 to June 2015. RESULTS: Mean age-adjusted annual incidence rates (per 10,000 person-years) of MA-NGE associated with outpatient care or hospitalization were 389 (95% CI 269-558) and 13 (95% CI 9-20), respectively. Highest rates were in children under 5 years of age: 1,569 (95% CI 1,325-1,792) for outpatient consultations and 48 (95% CI 39-56) for hospitalizations. Of all gastroenteritis episodes associated with outpatient care or hospitalization, 29% and 31% were attributed to norovirus, respectively. Norovirus was estimated to be responsible for 4,964,000 outpatient visits (95% CI 3,435,000-7,123,000) and 171,000 hospitalizations (95% CI 110,000-251,000) per year across Japan. CONCLUSIONS: Incidence rates of MA-AGE are high in Japan, and norovirus-attributable disease is at least as high as in some other developed countries.

Association between therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors and risk of ileus: a cohort study.

BACKGROUND: Three cases of ileus have been published among dipeptidyl peptidase-4 (DPP-4) inhibitor users in Japan. The purpose of this study was to estimate and compare incidence rates of ileus among alogliptin users and users of other DPP-4 inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and voglibose. METHODS: We used the Medical Data Vision database in Japan to conduct a retrospective cohort study among type 2 diabetes mellitus (T2DM) patients who were new users of alogliptin, other DPP-4 inhibitors, GLP-1 receptor agonists, or voglibose between 1 April 2010 and 30 April 2014. The primary outcome was an incident diagnosis of ileus. Kaplan-Meier survival curves were used to estimate ileus events over time. Adjusted Poisson regression models were used to estimate incidence rate ratios (IRR) for ileus and 95 % confidence intervals (CI) by comparing alogliptin users to users of the other study drugs. RESULTS: We identified 82,386 patients with T2DM. In the adjusted model, there was no difference in risk of ileus among patients exposed to alogliptin compared with patients exposed to other DPP-4 inhibitors (IRR 1.15, 95 % CI 0.75-1.75) or GLP-1 receptor agonists (IRR 0.42, 95 % CI 0.14-1.20). The risk of ileus was significantly lower among patients exposed to alogliptin compared with patients exposed to voglibose (IRR 0.55, 95 % CI 0.35-0.88). CONCLUSIONS: The independent risk of ileus among new users of alogliptin did not significantly differ compared with new users of other DPP-4 inhibitors or GLP-1 receptor agonists but was significantly lower than new users of voglibose.

Quantitative Evaluation of Compliance with Recommendation for Sulfonylurea Dose Co-Administered with DPP-4 Inhibitors in Japan.

After the launch of dipeptidyl peptidase-4 (DPP-4), a new oral hypoglycemic drug (OHD), in December 2009, severe hypoglycemia cases were reported in Japan. Although the definite cause was unknown, co-administration with sulfonylureas (SU) was suspected as one of the potential risk factors. The Japan Association for Diabetes Education and Care (JADEC) released a recommendation in April 2010 to lower the dose of three major SUs (glimepiride, glibenclamide, and gliclazide) when adding a DPP-4 inhibitor. To evaluate the effectiveness of this risk minimization action along with labeling changes, dispensing records for 114,263 patients prescribed OHDs between December 2008 and December 2010 were identified in the Nihon-Chouzai pharmacy claims database. The adherence to the recommended dosing of SU co-prescribed with DPP-4 inhibitors increased from 46.3% before to 63.8% after the JADEC recommendation (p < 0.01 by time-series analysis), while no change was found in those for SU monotherapy and SU with other OHD co-prescriptions. The adherence was significantly worse for those receiving a glibenclamide prescription. The JADEC recommendation, along with labeling changes, appeared to have a favorable effect on the risk minimization action in Japan. In these instances, a pharmacy claims database can be a useful tool to evaluate risk minimization actions.