Healthcare resource utilization and healthcare costs in patients with type 2 diabetes mellitus initiating sodium-glucose cotransporter 2 inhibitors vs dipeptidyl peptidase-4 inhibitors in Japan: A real-world administrative database analysis.

AIMS/INTRODUCTION: Healthcare resource utilization (HCRU) and healthcare costs are important factors to consider when selecting appropriate treatment for type 2 diabetes mellitus. We compared the HCRU and healthcare costs of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with type 2 diabetes mellitus in Japan. MATERIALS AND METHODS: This was a Japanese retrospective cohort study conducted using the JMDC Claims Database (January 1, 2015-December 31, 2021). Patients newly treated with an SGLT2i (31,872 patients) or a DPP4i (73,279 patients) were matched 1:1, using propensity score, after excluding patients without continuous SGLT2i or DPP4i prescriptions after the index date. HCRU and healthcare costs were compared between the treatment groups in the full cohort and subcohorts/subgroups of different baseline characteristics, including body mass index (BMI). RESULTS: After matching, patient characteristics were well balanced (17,767 patients each). Patients receiving an SGLT2i vs those receiving a DPP4i had significantly lower numbers of hospitalizations per person per month (PPPM) and outpatient visits PPPM, and had shorter lengths of stay per hospitalization. Healthcare costs, including all-cause overall healthcare costs PPPM and all-cause hospitalization costs PPPM, were generally lower in patients receiving an SGLT2i than those receiving a DPP4i. Similar results were observed among patients with a higher BMI but not among patients with a lower BMI. CONCLUSIONS: SGLT2i were associated with lower HCRU and healthcare costs than DPP4i, suggesting economic benefits with SGLT2i vs DPP4i in type 2 diabetes mellitus management.

Cardiometabolic risk reductions in patients with type 2 diabetes mellitus newly treated with a sodium-glucose cotransporter 2 inhibitor versus a dipeptidyl peptidase-4 inhibitor: A real-world administrative database study in Japan.

AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown beneficial effects on cardiometabolic risk factors (hemoglobin A1c, body mass index, systolic blood pressure) in patients with type 2 diabetes mellitus. We compared combined cardiometabolic effects of SGLT2i on hemoglobin A1c, body mass index and systolic blood pressure versus dipeptidyl peptidase-4 inhibitors (DPP4i) in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: This Japanese retrospective cohort study used the JMDC claims database. Patients newly treated with an SGLT2i (n = 18,936) or DPP4i (n = 55,484) were enrolled (January 2015-March 2020) and matched 1:1 using the propensity score. The primary end-point was the proportion of patients achieving a composite outcome (i.e., simultaneous absolute/percent reduction in hemoglobin A1c ≥0.5%, body mass index ≥3% and systolic blood pressure ≥2 mmHg) 1 year after first SGLT2i or DPP4i prescription; Mantel-Haenszel common risk difference and its 95% confidence interval were estimated. Other end-points included treatment persistence, with the associated hazard ratio calculated using the Cox proportional hazards model. RESULTS: After matching, patient characteristics were balanced (7,302 patients each). The proportion of patients achieving the composite outcome was significantly greater in patients receiving an SGLT2i than those receiving a DPP4i (31.0% [1,279/4,120] vs 12.9% [524/4,070], risk difference 18.6%, 95% confidence interval 16.3, 20.9, P < 0.001). Risk of treatment discontinuation was significantly lower in the SGLT2i group than in the DPP4i group (hazard ratio 0.85, 95% confidence interval 0.81, 0.90, P < 0.001). CONCLUSIONS: In the present study, SGLT2i showed favorable cardiometabolic risk reduction and longer treatment persistence than DPP4i in Japanese patients with type 2 diabetes mellitus.

Demographic and clinical characteristics of patients with type 1 diabetes mellitus initiating sodium-glucose cotransporter 2 inhibitors in Japan: A real-world administrative database analysis.

AIMS: To investigate the baseline demographic and clinical characteristics of patients with type 1 diabetes mellitus (T1DM) newly treated with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) as an add-on to insulin, or treated with insulin alone or in combination with oral anti-diabetic drugs other than an SGLT2i. METHODS: Retrospective study using data from the JMDC database (December 21, 2018, to October 31, 2020). Included patients with T1DM treated with an SGLT2i (add-on to insulin) (n = 1027) or with insulin (n = 4320). Baseline demographic and clinical characteristics were summarized, and change in insulin dose and efficacy outcomes, including hemoglobin A1c (HbA1c) and body mass index (BMI), before and after the first SGLT2i or insulin prescription were evaluated. RESULTS: The SGLT2i add-on group had higher HbA1c and BMI than the insulin group. Daily insulin doses decreased from immediately before to after the first SGLT2i prescription. HbA1c and BMI improved from baseline to after the first SGLT2i prescription. CONCLUSIONS: This large real-world study reported the baseline demographic and clinical characteristics of patients with T1DM newly treated with an SGLT2i in Japan. The findings may guide the appropriate use of SGLT2i and support large-scale database studies in T1DM research.

Reduction in cardiovascular disease events in patients with type 2 diabetes mellitus treated with a sodium-glucose cotransporter 2 inhibitor versus a dipeptidyl peptidase-4 inhibitor: A real-world retrospective administrative database analysis in Japan.

AIMS/INTRODUCTION: To evaluate the benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) in reducing cardiovascular disease (CVD) events in patients with type 2 diabetes mellitus with and without a CVD history. MATERIALS AND METHODS: This retrospective cohort study used Japanese hospital administrative data from the Medical Data Vision database (January 2015 to April 2020). Patients with type 2 diabetes mellitus (n = 625,739) who were new users of an SGLT2i (n = 57,070; 9.1%) or DPP4i (n = 568,669; 90.9%) were included. Outcomes included hospitalization for heart failure (hHF), all-cause death (ACD) and the composite of hHF or ACD. Hazard ratios (HR) were calculated using the inverse probability weighting Cox proportional hazards model to compare CVD event risks between treatment groups. RESULTS: Compared with DPP4i, SGLT2i was associated with a significant reduction in hHF risk among patients without a CVD history (HR 0.507, 95% confidence interval 0.283-0.907), but not in the full cohort or those with a CVD history. SGLT2i was associated with a significant risk reduction of ACD (HR 0.592, 95% confidence interval 0.481-0.729) and the composite of hHF or ACD (HR 0.712, 95% confidence interval 0.613-0.826), compared with DPP4i in the full cohort; similar results were observed among patients with and without a CVD history. CONCLUSIONS: In this real-world study, SGLT2i versus DPP4i was associated with a significant reduction in hHF, ACD and hHF or ACD events in patients with type 2 diabetes mellitus without a CVD history.

[A cross-sectional analysis of the health-related quality of life and work productivity in Japanese subjects with self-reported chronic constipation using the National Health and Wellness Survey 2017].

BACKGROUND: Chronic constipation (CC) is associated with lower health-related quality of life (HR-QoL) and work productivity in Western countries;however, limited data in Japanese subjects are available. METHODS: This retrospective, cross-sectional analysis used the data from the National Health and Wellness Survey (NHWS), a web-based questionnaire survey conducted in 2017 for the Japanese general population. Subjects were allocated to the self-reported CC group when they answered "yes" to the question "Did you have chronic constipation in the past 12 months?". Other subjects were allocated to the non-CC group. Self-reported CC population was sub-categorized as per the abdominal symptoms. The HR-QoL was assessed using the Medical Outcomes Study 12-Item Short-Form Health Survey version 2 using the Mental Component Summary (MCS), Physical Component Summary (PCS), and Role/Social Component Summary (RCS) scores (3-component method). Work productivity was assessed using the Work Productivity and Activity Impairment:General Health version 2.0 for absenteeism, presenteeism, work productivity loss, and activity impairment. RESULTS: Of the 30001 respondents, 3373 had self-reported CC (895 with abdominal symptoms, 2478 without abdominal symptoms) and 26628 did not report CC. The differences in the summary scores [95% confidence interval (CI) ] adjusted for potential confounders between self-reported CC and non-CC (self-reported CC - non-CC) were -1.60 (-1.98, -1.22) in MCS, -0.78 (-1.19, -0.37) in PCS, and -2.09 (-2.57, -1.61) in RCS;the differences in the adjusted summary scores (95% CI) between self-reported CC with and without abdominal symptoms (self-reported CC with abdominal symptoms - without abdominal symptoms) were -0.95 (-1.77, -0.14) in MCS, -1.67 (-2.66, -0.68) in PCS, and -2.05 (-3.55, -0.55) in RCS. All the summary scores were lower in those with self-reported CC and abdominal symptoms than in those with self-reported CC without abdominal symptoms;all the adjusted differences between the summary scores were statistically significant. The adjusted risk ratio (95% CI) of each outcome of self-reported CC relative to non-CC was 1.34 (1.04, 1.73) in absenteeism, 1.21 (1.12, 1.31) in presenteeism, 1.20 (1.11, 1.29) in work productivity loss, and 1.21 (1.15, 1.27) in activity impairment. In terms of statistics, the risk of decreased work productivity for all the outcomes was significantly higher in those with than in those without self-reported CC, indicating decreased work productivity in those with self-reported CC. CONCLUSION: HR-QoL and work productivity were lower in those with self-reported CC than in those who did not report CC, suggesting that CC negatively affects the HR-QoL and work productivity.

Cost-effectiveness analysis of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in Japan.

BACKGROUND: The cost of treating Clostridioides difficile infection (CDI), particularly recurrent disease, is high. In clinical trials, fidaxomicin has been associated with significantly lower recurrence rates and higher sustained cure rates versus vancomycin. The high acquisition cost of fidaxomicin has limited its acceptance into clinical practice. OBJECTIVE: To evaluate the cost-effectiveness of fidaxomicin versus vancomycin in patients with CDI after failure of metronidazole in the Japanese healthcare setting. METHODS: Clinical results from three phase III trials and inputs based on assumptions validated by clinical experts in Japan were used in a semi-Markov model with 1-year time horizon. Incremental cost-effectiveness ratios (ICERs) for fidaxomicin versus vancomycin were expressed as cost per quality-adjusted life year (QALY) and interpreted using willingness-to-pay thresholds of JPY 5,000,000 (primary) and JPY 7,500,000 (secondary) per QALY gained in Japan. Probabilistic sensitivity analyses and scenario analyses were performed. RESULTS: Higher drug acquisition costs for fidaxomicin were partially offset by lower hospitalization costs driven by fewer recurrences, lower costs of complications, and fewer general practitioner visits versus vancomycin. The ICER for fidaxomicin versus vancomycin was estimated at JPY 5,715,183 per QALY gained. Sensitivity analyses showed a 46% probability of fidaxomicin being cost-effective versus vancomycin at a willingness-to-pay threshold of JPY 5,000,000 per QALY gained. At a threshold of JPY 7,500,000, there was a 54% probability of fidaxomicin being cost-effective. CONCLUSIONS: Fidaxomicin treatment in patients with CDI following failure of metronidazole improves health outcomes with partial offset of higher drug acquisition costs versus vancomycin.

Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis.

We conducted a systematic review of the literature and network meta-analysis (NMA) to compare the relative effectiveness of antibiotic treatments for Clostridioides (Clostridium) difficile infection (CDI) including vancomycin (VCM), metronidazole (MTZ) and fidaxomicin (FDX). Eligible studies were randomised controlled trials (RCTs) including adults with any severity of CDI that was treated with VCM, MTZ or FDX. The NMA was performed using a Bayesian framework, using a fixed-effects model. The searches identified seven publications for inclusion, which provided five RCTs for VCM versus MTZ, and three RCTs for FDX versus VCM. The NMA showed that for clinical cure rate, there was no difference for FDX versus VCM, and there was a significant difference in favour of FDX versus MTZ (odds ratio [OR]: 1.77; 95% credible interval [CrI] 1.11, 2.83]). For recurrence rate, there was a significant difference in favour of FDX versus both VCM (OR: 0.50; 95% CrI: 0.37, 0.68) and MTZ (OR: 0.44; 95% CrI: 0.27, 0.72). For sustained cure (clinical cure without recurrence), there was a significant difference in favour of FDX versus VCM (OR: 1.61; 95% CrI: 1.27, 2.05) and MTZ (OR: 2.39; 95% CrI: 1.65, 3.47). These findings suggest that FDX and VCM are effective first-line treatments for mild or moderate CDI, whereas MTZ is not, and FDX may be more effective at preventing CDI recurrence than VCM.

Acute lethal crush-injured rats can be successfully rescued by a single injection of high-dose dexamethasone through a pathway involving PI3K-Akt-eNOS signaling.

BACKGROUND: Crush syndrome (CS) is characterized by ischemia/reperfusion-induced rhabdomyolysis and the subsequent onset of systemic inflammation. CS is associated with a high mortality, even when patients are treated with conventional therapy. We hypothesized that treatment of lethal CS rat model with dexamethasone (DEX) have therapeutic effects on the laboratory findings and clinical course and outcome. METHODS: To create a CS model, anesthetized rats were subjected to bilateral hind limb compression with rubber tourniquets for 5 hours and randomly divided into three groups as follows: saline-treated CS group, CS groups treated with low (0.1 mg/kg) and high doses (5.0 mg/kg) of DEX. Saline for the CS group or DEX for the DEX-treated CS groups was intravenously administered immediately before reperfusion. Under continuous monitoring and recording of arterial blood pressures, blood and tissue samples were collected for histologic and biochemical analysis at designated period before and after reperfusion. RESULTS: Ischemic compression of rat hind limbs reduced the nitrite content in the crushed muscle, and the subsequent reperfusion induced reactive oxygen species-mediated circulatory collapse and systemic inflammation, finally resulting in a mortality rate of 76% by 48 hours after reperfusion. A single injection of high-dose DEX immediately before reperfusion activated endothelial nitric oxide synthase (eNOS) by sequential phosphorylation through the nongenomic phosphoinositide 3-kinase (PI3K)-Akt-eNOS signaling pathway. DEX also exhibited anti-inflammatory effects by modulating proinflammatory and anti-inflammatory mediators, consequently suppressing myeloperoxidase activities and subsequent systemic inflammation, showing a complete recovery of the rats from lethal CS. CONCLUSION: These results indicate that high-dose DEX reduces systemic inflammation and contributes to the improved survival rate in a rat CS model.

[Insomnia in diabetes].

Previous studies have shown that several physiological and psychological conditions, such as hyperglycemia, diabetic neuropathy, sleep apnea syndrome and depression, may cause sleep disturbances, insomnia in diabetic patients. On the other hand, epidemiological evidences are indicating that chronic partial sleep loss may increase the risk of diabetes. Laboratory studies have shown that sleep restriction is associated with an increase in sympathetic nervous activity and a decrease in insulin sensitivity without adequate compensation in beta-cell function, resulting in an impact on glucose homeostasis and an elevated risk of diabetes. Sleep curtailment is also associated with a dysregulation of the neuroendocrine control of appetite, with a reduction of the satiety factor, leptin, and an increase in hunger-promoting hormone, ghrelin. The adverse impact of sleep deprivation on energy homeostasis is likely to be driven by increased activity of neuronal populations expressing in orexin system that promotes waking, feeding and energy-expenditure.

Lack of association of interleukin-18 gene polymorphisms with susceptibility of Japanese populations to Graves' disease or Graves' ophthalmopathy.

OBJECTIVE: To investigate whether polymorphisms of interleukin (IL)-18 gene confer susceptibility to Graves' disease (GD) and Graves' ophthalmopathy (GO). DESIGN: We performed a case control study on polymorphisms of IL-18 gene in Japanese patients with GD (n = 435), and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 255). The C-4675G, C-607A, and G-137C polymorphisms in the promoter region and A105C (exon 5) polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using restriction enzymes, sequence-specific PCR, and PCR-direct sequencing methods. RESULTS: None of the polymorphisms in the IL-18 gene were associated with development of Graves' disease. The CC genotype and C allele frequencies of IL-18 gene G-137C polymorphism tended to be greater in patients with ophthalmopathy than in patients without evident ophthalmopathy. However, the differences were not statistically significant. Although there were three major haplotypes, none of the haplotypes were statistically associated with susceptibility to GD or ophthalmopathy. CONCLUSIONS: These results suggest that IL-18 gene polymorphisms are not major genetic factors for susceptibility to GD in a Japanese population. Further studies with adequate sized data set in the subset analyses for GO are needed.

Interleukin-13 gene polymorphisms confer the susceptibility of Japanese populations to Graves' disease.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. IL-13 is an important mediator of antiinflammatory immune responses and is expressed in the thyroid and orbit. The aim of the present study was to investigate whether IL-13 gene polymorphisms are associated with the development of GD. IL-13 gene polymorphisms were studied in Japanese GD patients (n = 310) and healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders (n = 244). A C/T polymorphism at position -1112 of the promoter region was measured using the direct sequencing method, and an Arg(130)Gln (G2044A) polymorphism in exon 4 was examined using the PCR-restriction fragment length polymorphism method. There was a significant decrease in -1112T allele frequency in GD patients compared with controls (16% vs. 23%; P = 0.0019). The frequency of the 2044A allele on exon 4 also appeared lower in GD patients compared with controls. Haplotype analysis showed a significant decrease in the -1112T/2044A haplotype in GD patients. There was no association between IL-13 gene polymorphisms and ophthalmopathy, severity, or serum IgE levels. In conclusion, IL-13 gene polymorphisms are associated with GD susceptibility in Japan.

Immunohistochemical analysis of bcl-2, Bax and Bak expression in thyroid glands from patients with Graves' disease.

In order to clarify the role of apoptosis and the expression of Bcl-2 family proteins in the pathology of Graves' disease (GD), we evaluated the apoptosis by in situ end-labeling of fragmented DNA and the expression of Bcl-2, Bax and Bak by immunohistochemistry in thyroid tissues from 20 patients with GD and in normal thyroid tissues from 6 patients with follicular adenoma (N). Apoptotic nuclei were found in thyrocytes and in germinal center of lymphoid follicles. Bcl-2 was strongly expressed in both GD and N thyrocytes. Bax was not expressed in either GD or N thyrocytes. Bak was expressed in thyrocytes from 5 of 20 patients with GD, while it was detected in all N thyrocytes. In lymphoid follicles Bcl-2 was expressed in the mantle zone, while Bax and Bak were both expressed in the germinal center. The percentage of apoptotic nuclei in GD thyrocytes was low (0~3.6%), and negatively correlated with the weight of the thyroid glands resected (rs = -0.43, P<0.05). It was greater in Bak-positive GD thyrocytes than in Bak-negative ones (mean +/- SD; 1.7 +/- 0.7% vs. 0.7 +/- 0.9%, P<0.05). These findings suggest that the differential expression of Bcl-2 family proteins in both thyrocytes and lymphoid follicles may be involved in the pathology of GD.

A polymorphism of interferon-gamma gene associated with changes of anti-thyrotropin receptor antibodies induced by antithyroid drug treatment for Graves' disease in Japanese patients.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. Interferon-gamma (IFN-gamma) is an important mediator of inflammatory and immune responses. The aim of the present study was to investigate whether the polymorphism of IFN-gamma gene is associated with the development of GD or with clinical course during the antithyroid drug therapy. We have studied the CA repeat polymorphisms in the first intron of IFN gamma gene in Japanese patients with GD (n = 162) and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 133). There was no difference in allele frequency of IFN-gamma gene polymorphism between patients with GD and control subjects. However, the allele 4 (15 CA repeats) frequency was significantly greater in patients whose antithyrotropin receptor antibody (TRAb) became negative within 3 years by antithyroid drug treatment than those with consistently positive TRAb for more than 3 years (34.1% vs. 15.7%, chi2 = 8.545, p = 0.0035, pc = 0.049). The in vitro production of IFN-gamma by concanavalin A-stimulated peripheral blood mononuclear cells was significantly smaller in control subjects with the allele 4 compared to those with the other alleles. In conclusions, the CA repeat polymorphism of the IFN-gamma gene might be associated with the outcome of anti-thyroid drug treatment.