Prescription Trends for the Antidiabetic Agents Used to Treat Type 2 Diabetes Mellitus in Japan from 2012-2020: a Time-Series Analysis.

In April 2014, sodium-glucose cotransporter 2 inhibitor (SGLT-2i) was introduced in Japan. In May 2015, the prescription limitation for SGLT-2i was lifted. Subsequently, SGLT-2i was shown to reduce cardiovascular events in patients with type 2 diabetes mellitus (T2DM). SGLT-2i prescription is expected to increase and consequently affect the prescription trends for other antidiabetic agents. Therefore, we evaluated the trends for antidiabetic agent prescriptions in Japan from April 2012 to March 2020. In this study, a dynamic cohort consisting of patients with T2DM derived from the Japan Medical Data Center health insurance database and with at least one antidiabetic agent prescription was investigated. The prescription rates were calculated monthly (/1000 person-months) for each class of antidiabetic agent. The eligible cohort comprised 34333 patients. The prescription rate for dipeptidyl peptidase-4 inhibitor increased from 424.0 in April 2012 to 656.3 in May 2015, and slightly decreased to 635.4 in March 2020. The prescription rate for biguanide consistently increased from 347.2 in April 2012 to 500.1 in March 2020. The prescription rate for sulfonylurea consistently decreased from 393.8 in April 2012 to 172.5 in March 2020. The prescription rate for SGLT-2i consistently increased from 4.1 in April 2014 to 363.1 in March 2020. SGLT-2i prescription increased and may affect the prescription trends for dipeptidyl peptidase-4 inhibitor and sulfonylurea after May 2015, when the prescription limitation for SGLT-2i was lifted. Biguanide prescriptions increased regardless of the introduction of SGLT-2i. The treatment of T2DM in Japan is clearly changing, with a focus on SGLT-2i and biguanide.

Impact of breakthrough trials on prescription trends of sodium-glucose cotransporter-2 inhibitors in Japan: An interrupted time-series analysis.

WHAT IS KNOWN AND OBJECTIVE: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have been increasingly prescribed for the treatment of type 2 diabetes mellitus (T2DM). We aimed to investigate the impact of clinical trials presenting remarkable results on the prescription of SGLT-2is and the relationship between the impact and generalisability of the breakthrough trials on SGLT-2is. METHODS: This retrospective cohort study involved 32,949 patients with T2DM who were prescribed at least one antidiabetic agent in the Japan Medical Data Center health insurance database. Prescription rates of SGLT-2is were calculated monthly from April 2014 to March 2020. We evaluated the impact of the EMPA-REG OUTCOME study for an Asian subgroup on the prescription rate of empagliflozin and the impact of the CANVAS/CANVAS-R study on the prescription rate of canagliflozin. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using the quasi-Poisson regression model in the overall population, subgroup with a history of cardiovascular disease (high-risk group), and subgroup without a history and risk factors of cardiovascular disease (low-risk group). RESULTS AND DISCUSSION: The EMPA-REG OUTCOME study for the Asian subgroup led to increased prescription rates of empagliflozin 3 months after its publication in the overall population and high-risk group but not in low-risk group (IRR [95% CI]: 1.40 [1.17-1.66], 1.39 [1.05-1.84], and 1.00 [0.79-1.27], respectively). The increase in high-risk group may be appropriate because this study included patients with a history of cardiovascular disease only. The CANVAS/CANVAS-R study led to increased prescription rates of canagliflozin 3 months after its publication in the overall population, high-risk group, and low-risk group (IRR [95% CI]: 1.52 [1.06-2.19], 1.39 [1.06-1.83], and 1.81 [1.20-2.75], respectively). The increase in low-risk group may not be appropriate because this study did not include patients without a history or risk factors of cardiovascular disease. WHAT IS NEW AND CONCLUSION: The breakthrough trials increased prescription rates not only for patients to whom the trial results could be extrapolated but also for those in whom trial benefits were not certain. Our findings suggest that information about breakthrough trials may need to be provided along with data on trial result generalisability.

Identification of individuals benefiting from the kakaritsuke-yakuzaishi (family pharmacist) system in Japan: a retrospective cohort study using an employment-based health insurance claims database.

BACKGROUND: The kakaritsuke-yakuzaishi system (henceforth, the family pharmacist system) which provides more health services than those by general pharmaceutical practice, was implemented in Japan in April 2016. To distribute medical resources and medical care expenditures appropriately, identifying the possible major beneficiaries of this system is essential. By analyzing administrative claims data through this retrospective cohort study, we identified modifiers of the potential benefits of the system. Further, we integrated the identified modifiers into a scoring system that indicates the possible benefitting subpopulations. METHODS: We obtained data about individuals under 75 years old routinely using community pharmacies in Japan from the JMDC database. We classified the individuals as users or non-users. We used claims related to "choufukutouyaku-sougosayoutou-boushi-kasan (additional therapeutic duplication and drug interaction [TDDI] prevention fees)" filed between April 2018 and March 2020, which indicate that individuals' prescriptions were modified to adjust leftover drugs or to avoid TDDI as indicators of potential benefit. We estimated adjusted absolute risk differences and 95% confidence intervals for product terms using multiple generalized linear regression models. We included the factors whose 95% confidence interval lower limits did not reach 0 in the multiple logistic regression models for developing a scoring system. RESULTS: The eligible cohort included 162,340 individuals (1,214 users and 161,126 non-users). The leftover drugs adjustment significantly increased for individuals prescribed antidepressants. However, as only one modifier was identified, we did not develop a scoring system for the leftover drugs adjustment. For TDDI prevention, the following factors were included in the scoring system: being female, being prescribed ≥ 6 drug types, using ≥ 2 medical institutions, and being prescribed proton pump inhibitors, antibiotics, probiotics, or traditional Japanese herbal medicines. The developed scoring system for TDDI prevention scored "female" and "traditional Japanese herbal medicines prescription" factors higher than other factors. CONCLUSIONS: Individuals who are female or prescribed traditional Japanese herbal medicines, or antidepressants may benefit significantly from the family pharmacist system.

Efficacy and safety of atypical antipsychotics for psychosis in Parkinson's disease: A systematic review and Bayesian network meta-analysis.

INTRODUCTION: We performed a systematic review and Bayesian network meta-analysis to clarify the relative efficacy and safety of pimavanserin compared to atypical antipsychotics for psychosis in Parkinson's disease (PD). METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, and Japana Centra Revuo Medicina Web were searched for relevant articles until October 31, 2019. Eligible randomized controlled trials were synthesized for efficacy (Brief Psychiatry Rating Scale [BPRS] and Clinical Global Impression Scale [CGI-S]) and safety (Unified Parkinson's Disease Rating Scale part III [UPDRS-III] and dropouts due to adverse events). The mean differences (BPRS, CGI-S, and UPDRS-III) or odds ratios (dropouts due to adverse events) between each active drug and placebo were estimated and summarized as means and 95% credible intervals, respectively. RESULTS: We identified 17 relevant trials. Clozapine showed significant efficacy (BPRS, -5.6 [-8.4 to -2.7] and CGI-S, -1.2 [-1.7 to -0.7]), with low impact on motor functions (UPDRS-III, -1.1 [-3.8 to 1.5]), but an increase in dropouts due to adverse events (2.9 [0.9 to 9.6]) as compared to placebo. Pimavanserin also showed significant efficacy (CGI-S, -0.5 [-0.9 to -0.2]) and similar impact on motor functions (UPDRS-III, 0.2 [-1.4 to 1.9]), but a tendency of increase in dropouts due to adverse events (2.2 [0.5 to 12.4]) as compared to placebo. CONCLUSIONS: Clozapine showed an efficacy with low impact on motor functions that was consistent with previous reports. Although the efficacy of pimavanserin may be inferior to that of clozapine, it had a favorable profile for the treatment of psychosis in PD.

Risk stratification for physical morbidity using factors associated with atypical antipsychotic treatment in Parkinson's disease: A retrospective observational study using administrative claims data.

Evidence shows that atypical antipsychotics (AAPs), a treatment of psychosis in Parkinson's disease (PD), are associated with factors reflecting the severity of the disease. Therefore, we evaluated the applicability of these factors in risk stratification for physical morbidity in PD patients requiring AAPs. We implemented a nested case-control analysis using administrative claims data derived from PD inpatients in 143 National Hospitals in Japan between April 2012 and March 2017. The analysis compared PD patients exposed to AAPs with unexposed matched controls using conditional logistic regression. The cases were then stratified by the weighted score using the partial regression coefficients of extracted factors or the number of factors that they had. Physical morbidity was evaluated using length of stay (LOS) and readmission. After comparing the cases (n = 829) with the matched controls (n = 3316), 10 factors were extracted. The cases were stratified into four level groups using the weighted score, or five level groups using the number of factors. LOS was prolonged with increasing score (49.7; 58.5; 72.7; and 83.3 days) and number of factors (52.1; 52.9; 63.9; 80.7; and 79.1 days). Readmission within 30 days increased along with increasing score (5.7; 10.2; 10.2 and 12.9%) and number of factors (5.9; 9.3; 8.9; 11.3; and 14.3%). We confirmed two stratification manners for physical morbidity in PD patients requiring AAPs. These manners would be useful for considering management plan for these patients.

Prevention of Acute Upper Respiratory Infections by Consumption of Catechins in Healthcare Workers: A Randomized, Placebo-Controlled Trial.

Catechins, phytochemicals contained mainly in green tea, exhibit antiviral activity against various acute infectious diseases experimentally. Clinical evidence supporting these effects, however, is not conclusive. We performed a placebo-controlled, single-blind, randomized control trial to evaluate the clinical effectiveness of consumption of catechins-containing beverage for preventing acute upper respiratory tract infections (URTIs). Two hundred and seventy healthcare workers were randomly allocated to high-catechin (three daily doses of 57 mg catechins and 100 mg xanthan gum), low-catechin (one daily dose of 57 mg catechins and 100 mg xanthan gum), or placebo (0 mg catechins and 100 mg xanthan gum) group. Subjects consumed a beverage with or without catechins for 12 weeks from December 2017 through February 2018. The primary endpoint was incidence of URTIs compared among groups using a time-to-event analysis. A total of 255 subjects were analyzed (placebo group n = 86, low-catechin group n = 85, high catechin group n = 84). The URTI incidence rate was 26.7% in the placebo group, 28.2% in the low-catechin group, and 13.1% in the high-catechin group (log rank test, p = 0.042). The hazard ratio (95% confidence interval (CI)) with reference to the placebo group was 1.09 (0.61-1.92) in the low-catechin group and 0.46 (0.23-0.95) in the high-catechin group. These findings suggest that catechins combined with xanthan gum protect against URTIs.

Comparison of the association of risperidone and quetiapine with deteriorating performance in walking and dressing in subjects with Parkinson's disease: a retrospective cohort study using administrative claims data.

This retrospective cohort study was performed to investigate the association between risperidone and deteriorating performance in walking and dressing in subjects with Parkinson's disease using the Japanese Diagnosis Procedure Combination data. These data include inpatient claims including information from the time of admission to discharge from 89 acute phase National Hospitals in Japan. The data were evaluated by implementing the inverse probability of treatment weighting, using propensity scores estimated from the clinical characteristics of subjects prescribed risperidone or quetiapine. The generalized estimation equation was used to estimate the adjusted risk ratios (aRRs) and 95% confidence intervals (CIs). In total, 304 subjects were eligible for participation, and were hospitalized between April 2012 and March 2017 (108 and 196 for risperidone and quetiapine groups, respectively). The performance of walking deteriorated at discharge, with 22.2% and 10.2% recorded at admission for the risperidone and quetiapine groups (aRR, 1.7; 95% CI, 0.9 to 3.4), respectively. The performance of dressing also deteriorated: 24.1% and 10.7% in the risperidone and quetiapine groups (aRR, 1.9; 95% CI, 1.04 to 3.7), respectively. These results suggest an association between risperidone and deteriorating performance in dressing in subjects with Parkinson's disease in comparison with quetiapine.

Apolipoprotein E Gene Polymorphisms Affect the Efficacy of Thiazolidinediones for Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Although several studies have evaluated the efficacy of thiazolidinediones (TZD) for the treatment of Alzheimer's disease (AD), investigation of the impact of apolipoprotein E (ApoE) gene polymorphisms on the efficacy of TZD remains insufficient. We investigated the impact by conducting a systematic review and meta-analysis. MEDLINE, Cochrane Library, and Japana Centra Revuo Medicina were searched to identify relevant studies based on eligibility criteria. Mean differences (MD) of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score with 95% confidence intervals (CI) were calculated for subgroups stratified by ApoE genotype. To evaluate the impact of ApoE gene polymorphisms, meta-regression analysis was also conducted to calculate the regression coefficient (Coef) of ApoE expression status with 95% CI. Three randomized controlled studies comparing rosiglitazone and placebo, with a total of 2381 subjects met the eligibility criteria. ApoE expression status was reported in 983 individuals (ApoE4-positive, 141; ApoE4-negative, 842). When compared to placebo, rosiglitazone significantly decreased ADAS-Cog score in ApoE4-negative individuals (MD, -1.37; 95% CI, -2.09 to -0.65), but significantly increased ADAS-Cog score in ApoE4-positive individuals (MD, 2.18; 95% CI, 0.52 to 3.85). The meta-regression analysis showed a significant association between efficacy and ApoE expression status (Coef, 3.55; 95% CI, 1.42 to 5.68). Although the present results should be interpreted with caution because of the limited number of studies, our findings suggest that ApoE gene polymorphisms impact the efficacy of rosiglitazone for AD patients. This finding would provide useful information for the development of new agents for AD.

Comparative Utility of Atypical Antipsychotics for the Treatment of Psychosis in Parkinson's Disease: A Systematic Review and Bayesian Network Meta-analysis.

We performed a systematic review and Bayesian network meta-analysis to determine atypical antipsychotics that are effective and safe for the treatment of psychosis in Parkinson's disease (PD). We conducted a comprehensive literature search using PubMed/MEDLINE, Cochrane Library, and Japana Centra Revuo Medicina (Ichu-shi Web). We used randomized controlled trials evaluating the utility of atypical antipsychotics for the treatment of psychosis in PD using the Brief Psychiatric Rating Scale (BPRS) and the Unified PD rating Scale parts III (UPDRS-III) as the endpoints. Posterior distributions of mean differences between each treatment and placebo were estimated using Bayesian network meta-analysis. The distributions describing each treatment effect were expressed as means (95% credible intervals). Ten trials involving any two treatment arms using clozapine (64 subjects in four trials), olanzapine (99 subjects in three trials), quetiapine (79 subjects in five trials), risperidone (five subjects in one trial), or placebo (156 subjects in seven trials) were finally included in the present study. Pooled estimates of each posterior distribution based on the BPRS were as follows: clozapine, -2.0 (-6.7 to 2.7); olanzapine, 0.5 (-2.3 to 3.4); quetiapine, 0.3 (-3.9 to 4.5); and risperidone, -4.7 (-57.4 to 53.3). Based on the UPDRS-III, the pooled estimates were clozapine, 0.7 (-3.8 to 4.3); olanzapine, 2.8 (0.8 to 5.1); quetiapine, 3.3 (-0.7 to 5.8); and risperidone, 4.5 (-57.7 to 63.4). Although clozapine had an effective and relatively safe profile, all atypical antipsychotics included in the present study may be unsafe, as they may worsen motor function when compared to placebo.

Behaviors in Response to Adverse Events Associated with Health Food Use: Internet Survey of Consumers, Physicians and Pharmacists.

Adverse events associated with health food use appear to be quite common. Nevertheless, even though severe adverse events should be reported to the Japanese government via public health centers, the number of cases reported is relatively small. To clarify this discrepancy and to understand how consumers and physicians act when they or their patients develop adverse events due to health food use, we conducted an internet questionnaire with consumers (preliminary survey: n=44,649; full survey: n=3,000), physicians (n=500), and pharmacists (n=500). During 2016, 17% of consumers who used health foods developed adverse events. However, only 11% of them reported their adverse events to public health centers. Most physicians and pharmacists did not report these cases to public health centers because they were unable to establish a clear cause-and-effect relationship. It is important to encourage not only consumers, but also physicians and pharmacists to report adverse events to public health centers.

Safety Profile of Telaprevir-Based Triple Therapy in Elderly Patients: A Real-World Retrospective Cohort Study.

To compare the rate of treatment discontinuation due to adverse events for telaprevir-based triple (T/PR) and pegylated interferon-alfa-2b and ribavirin (PR) therapy for the treatment of hepatitis C virus (HCV) infection in patients over the age of 65 years, in Japan. Retrospective analysis of the health data of patients over the age of 65 years treated for a HCV infection genotype 1 using T/PR or PR therapy, from 38 prefectures in Japan. The primary outcome was the rate of treatment discontinuation due to adverse events for T/PR and PR. The secondary outcome was to evaluate the prevalence and type of adverse events during the treatment period that resulted in treatment discontinuation for both therapies. For comparison, the T/PR and PR populations were matched using the propensity score method, and adjusted odds ratios (ORs) for treatment discontinuation calculated by multivariate logistic regression analysis. The study group included 1330 patients, 328 in the T/PR group and 1002 in the PR group. The rate of treatment discontinuation due to adverse events in the matched population was lower for T/PR (19.82%) than PR (35.98%) therapy, (adjusted OR, 0.418; 95% confidence interval, 0.292-0.599; p<0.01). Malaise was the principal cause of treatment discontinuation in both groups (T/PR, 30.77%, and PR, 42.37%). Using real-world health data of elderly individuals in Japan, we identified a lower rate of treatment discontinuation for T/PR than PR. Our outcomes provide information for a segment of the population that is generally excluded for clinical trials.

Risk Factors for Treatment Discontinuation Caused by Adverse Events When Using Telaprevir, Peginterferon, and Ribavirin to Treat Chronic Hepatitis C: A Real-World Retrospective Cohort Study.

In this study, a nationwide database was used to identify the risk factors for treatment discontinuation due to adverse events during telaprevir, peginterferon, and ribavirin (T/PR) treatment, and estimate the increase in the occurrence of adverse events when patients have multiple risk factors at the same time. The risk factors were identified using univariate logistic regression analysis, and a Cochran-Armitage trend test was used to analyze the correlation between the number of risk factors and treatment discontinuation due to adverse events. Of the 25989 individuals registered in the database, 1668 (age, mean±standard deviation (S.D.): 58.0±9.9) were included in the study. Of these, 188 (11.3%) discontinued T/PR therapy due to adverse events. In the univariate logistic regression analysis, sex, age, aspartate aminotransferase (AST) level, and platelet count were found to significantly affect the incidence of T/PR treatment discontinuation (p<0.05). Furthermore, the incidence of treatment discontinuation gradually increased from 4.6 to 27.2% as the number of risk factors increased from 0 to 4, and the Cochran-Armitage trend test showed a significant correlation (p<0.001). In conclusion, this study not only revealed the risk factors for treatment discontinuation but also showed that patients with multiple risk factors are more likely to discontinue treatment due to adverse events compared to patients with fewer risk factors.

The Safety Profile of Telaprevir-Based Triple Therapy in Clinical Practice: A Retrospective Cohort Study.

This study was designed to evaluate the safety profile of adding telaprevir to therapy using pegylated interferon-alfa-2b and ribavirin (PR) using real world patient data obtained from a nationwide Japanese interferon database. This retrospective cohort study compared telaprevir-based triple therapy (T/PR) with PR therapy. The study population comprised patients with genotype 1 chronic hepatitis C represented in the database between December 2009 and August 2015. The primary endpoint was dropout from treatment due to adverse events during the relevant standard treatment duration based on guidelines from the Japan Society of Hepatology. The dropout odds ratio (OR) and 95% confidence interval (95% CI) were calculated using univariate logistic regression analysis. Covariates were detected using a stepwise logistic regression analysis, and the adjusted OR and 95% CI were calculated. A total of 25989 patients were registered, and 4619 patients (T/PR: 1334, PR: 3285) were appropriate for primary endpoint analysis. The dropout rate due to adverse events was lower in the T/PR group (13.4%) than in the PR group (22.6%) (OR: 0.530; 95% CI, 0.444-0.633). After adjustment for the covariates detected by stepwise selection, the OR was 0.529 (95% CI, 0.441-0.634). Our study showed that there was a difference in dropout rate between real world T/PR and PR therapy in Japan. Although the addition of telaprevir to PR therapy may improve treatment continuity under the care of hepatologists, this study could not fully determine which therapy was safer or the factors influencing this result. Therefore, additional research will be required to confirm this.