Characterizing the role of, and physical and emotional burden on caregivers of patients with heart failure: Results from a cross-sectional survey in Japan.

The aim of this cross-sectional survey was to characterize the role of and burden on caregivers of heart failure (HF) patients in Japan, since such data are limited at present. Data from 126 caregivers whose average age was 63.5 years were analyzed. Helping to prepare meals/cooking was the most frequently reported activity (47% of caregivers); 24% found this the most burdensome. The most frequently reported physical consequence of caregiving was feeling physically tired (44%); emotionally worrying about the patient (62%) was the most frequent psychological consequence. Approximately half of the caregivers reported that caring for patients impacted their lifestyle. Although 40% of caregivers asked questions to physicians regarding diet or lifestyle modifications, 19% did not ask any. Caregivers play a crucial role in the management of HF patients in Japan but experience physical and emotional burden. Solutions are required to reduce the caregiver burden associated with HF.

Slot Blot Analysis of Intracellular Glyceraldehyde-Derived Advanced Glycation End Products Using a Novel Lysis Buffer and Polyvinylidene Difluoride Membrane.

Advanced glycation end products (AGEs) are formed through the reaction/modification of proteins by saccharides (e.g., glucose and fructose) and their intermediate/non-enzymatic products [e.g., methylglyoxal and glyceraldehyde (GA)]. In 2017, Dr. Takanobu Takata et al. developed the novel slot blot method to quantify intracellular GA-derived AGEs (GA-AGEs). Although the original method required nitrocellulose membranes, we hypothesized that the modified proteins contained in the AGEs may be effectively probed on polyvinylidene difluoride (PVDF) membranes. Because commercial lysis buffers are unsuitable for this purpose, Dr. Takata developed the slot blot method using an in-house-prepared lysis buffer containing 2-amino-2-hydromethyl-1,3-propanediol (Tris), urea, thiourea, and 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) that effectively probes AGEs onto PVDF membranes. The slot blot method also entails the calculation of Tris, urea, thiourea, and CHAPS concentrations, as well as protein and mass to be probed onto the PVDF membranes. GA-AGE-modified bovine serum albumin (BSA, GA-AGEs-BSA) is used to draw a standard curve and perform neutralization against a non-specific combination of anti-GA-AGEs antibodies, thereby enabling the quantification of GA-AGEs in cell lysates. This paper presents the detailed protocol for slot blot analysis of intracellular GA-AGE levels in C2C12 cells. Key features • This protocol leverages the idea that advanced glycation end products are modified proteins. • The lysis buffer containing Tris, urea, thiourea, and CHAPS enables probing proteins onto PVDF membranes. • Intracellular GA-AGE levels may be quantified for some cell types using polyclonal anti-GA-AGE antibodies and standard GA-AGE-modified BSA. • The lysis buffer may be simultaneously prepared with the cell lysate. • There is no limit to the type of cultured cells used in the preparation of cell lysate.

Development of a double-crossover markerless gene deletion system in Bifidobacterium longum: functional analysis of the α-galactosidase gene for raffinose assimilation.

Functional analysis of Bifidobacterium genes is essential for understanding host-Bifidobacterium interactions with beneficial effects on human health; however, the lack of an effective targeted gene inactivation system in bifidobacteria has prevented the development of functional genomics in this bacterium. Here, we report the development of a markerless gene deletion system involving a double crossover in Bifidobacterium longum. Incompatible plasmid vectors were used to facilitate a second crossover step. The conditional replication vector pBS423-ΔrepA, which lacks the plasmid replication gene repA, was integrated into the target gene by a first crossover event. Subsequently, the replicative plasmid pTBR101-CM, which harbors repA, was introduced into this integrant to facilitate the second crossover step and subsequent elimination of the excised conditional replication vector from the cells by plasmid incompatibility. The proposed system was confirmed to work as expected in B. longum 105-A using the chromosomal full-length ß-galactosidase gene as a target. Markerless gene deletion was tested using the aga gene, which encodes α-galactosidase, whose substrates include raffinose. Almost all the pTBR101-CM-transformed strains became double-crossover recombinants after subculture, and 4 out of the 270 double-crossover recombinants had lost the ability to assimilate raffinose. Genotype analysis of these strains revealed markerless gene deletion of aga. Carbohydrate assimilation analysis and α-galactosidase activity measurement were conducted using both the representative mutant and a plasmid-based aga-complemented strain. These functional analyses revealed that aga is the only gene encoding a functional α-galactosidase enzyme in B. longum 105-A.

Cardiovascular safety and effectiveness of vildagliptin in patients with type 2 diabetes mellitus: a 3-year, large-scale post-marketing surveillance in Japan.

Objectives: The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin is indicated for type 2 diabetes mellitus (T2DM). However, the long-term safety, effectiveness, and clinical relationship with cardiovascular events of vildagliptin have not been evaluated in Japan.Methods: The authors conducted post-marketing surveillance (PMS) to evaluate the safety and effectiveness of vildagliptin in more than 3000 Japanese T2DM patients for up to 3 years. Main assessments included demographics, major adverse cardiovascular events (MACE), adverse events (AEs), adverse drug reactions (ADRs), and glycated hemoglobin (HbA1c).Results: In this PMS, 3831 patients (775 sites) were registered in April 2010 - April 2012. The safety analysis population comprised 3769 patients; 2085 patients were aged ≥65 years, and 240, 411, and 114 had renal impairment, hepatic impairment, and heart failure, respectively. The median treatment duration was 2.7 years. The incidence of MACE was 6.04 cases/1000 person-years, mostly attributable to cerebrovascular events (4.27 cases/1000 person-years). The AE and ADR incidences were 26.0% and 5.3%, respectively. The incidence of hypoglycemia was 0.6%. No significant changes in body weight occurred and mean change in HbA1c from baseline at final assessment was -0.74 ± 1.41% (p < 0.0001).Conclusions: In real-world clinical settings, vildagliptin was well tolerated, with similar profiles as previously reported.

Safety and efficacy of vildagliptin: 52-week post-marketing surveillance of Japanese patients with type 2 diabetes in combination with other oral antidiabetics and insulin.

Background: Vildagliptin is a dipeptidyl peptidase-4 inhibitor that reduces glycemia in patients with type 2 diabetes mellitus (T2DM). When approved in 2013, data on vildagliptin combined with >750 mg/day metformin in Japanese patients were limited. There is a need to confirm the safety and efficacy of vildagliptin in combination with oral antidiabetic drugs (OADs).Research design and methods: This 52-week post-marketing surveillance (PMS) observational study in Japanese T2DM patients evaluated the safety and efficacy of vildagliptin in combination with OADs including high-dose metformin or insulin but excluding combination with sulfonylureas alone.Results: During this survey of 3006 Japanese T2DM patients, 13.61% of patients experienced adverse events (AEs) and 2.20% reported a serious AE (SAE). The frequency of AEs/SAEs was similar when in combination with biguanides (12.93%/1.46%), metformin ≥1000 mg/day (12.92%/1.22%), metformin <1000 mg/day (12.62%/1.54%), thiazolidine derivatives (16.71%/2.86%), α-glucosidase inhibitors (13.18%/1.90%), rapid-acting insulin secretagogues  (glinides) (20.41%/5.71%), or insulin (15.87%/2.47%). The mean ± SD changes from baseline at endpoint in glycated hemoglobin and fasting blood glucose were -0.76 ± 1.27% and -23.3 ± 57.3 mg/dL, respectively, and these changes were consistent, regardless of concomitant OAD.Conclusions: Long-term vildagliptin combination therapy is safe and effective in Japanese T2DM patients in real-world settings.

In-hospital resource utilization, worsening heart failure, and factors associated with length of hospital stay in patients with hospitalized heart failure: A Japanese database cohort study.

BACKGROUND: Our objective was to characterize cases of hospitalized heart failure (HHF) focusing on in-hospital resource utilization (particularly furosemide doses) and worsening heart failure (WHF), and identify which factors are associated with the length of stay (LOS). METHODS: Cases of HHF (≥20 years), excluding those undergoing surgical procedures and in-hospital deaths, were retrieved from the Japanese Diagnosis Procedure Combination database (April 2012 to March 2016). WHF was defined using eight components, including up-titration of intravenous drugs and non-pharmacological management. RESULTS: The mean age of 78,953 cases of HHF was 79 years and 51% were male. The median LOS was 17 days. The maximum daily dose and cumulative dose of furosemide (mean ± standard deviation) were 43.3 ± 56.0 mg and 215.6 ± 450.6 mg, respectively, for intravenous furosemide, and 44.0 ± 37.3 mg and 523.3 ± 675.4 mg, respectively, for oral furosemide. The incidence of WHF was 36.1% during hospitalization and 19.3% from 6th hospital day to discharge. The mean number of WHF components was 1.4 ± 0.7 during hospitalization and 1.3 ± 0.6 from 6th hospital day. Regression analyses showed that the number of WHF components from 6th hospital day, pneumonia, and hyponatremia were strongly associated with longer LOS. CONCLUSIONS: These findings in patients with HHF could be vital to focus future efforts to improve the therapeutic strategies for heart failure.

Burden of Heart Failure on Patient Daily Life and Patient-Physician Discordance in Disease Management　- Results From a Cross-Sectional Survey in Japan.

Background: We investigated the impact of heart failure (HF) on daily life and satisfaction with current HF medication from the patient perspective in a real-world study in Japan. Methods and Results: A cross-sectional survey of 154 HF patients treated by 58 cardiologists was conducted in Japan using patient self-completed questionnaires about their daily life and satisfaction with HF medication, as well as patient record forms completed by their physicians capturing corresponding data. The mean age of patients was 72.7 years. The proportion of patients within New York Heart Association Class I, II, III, and IV was 39%, 44%, 16%, and 1%, respectively. Symptoms reported by patients included dyspnea when active (46%), nocturia (43%), anxiety (18%), and depression (6%). There was a discordance between physician- and patient-reported symptoms, especially for nocturia and inability to sleep. The most frequent lifestyle recommendation from physicians was 'reduce salt/sodium intake', but only 51% of patients receiving this recommendation followed the advice. In all, 44% of patients reported dissatisfaction with their current medication; according to the patients, 27% reported no discussion with their physicians about their prescribed medication, while physicians reported the opposite. Conclusions: HF negatively impacts patient daily life. There is discordance between patients and physicians in symptom reporting, lifestyle modification advice and adherence, and reported medication decision making. Gaps in patient-physician communication exist.

Treatment patterns of drug-naive patients with type 2 diabetes mellitus: a retrospective cohort study using a Japanese hospital database.

BACKGROUND: Guidelines for Type 2 diabetes mellitus (T2DM) management in Japan provide physicians the discretion to select treatment options based on patient pathophysiology of the disease. There exists a wide variation of preference for initial antidiabetes drugs (AD). The current database analysis aimed to understand the real world treatment patterns in drug-naive patients with T2DM in Japan. METHODS: We analyzed data of patients (≥ 18 years) diagnosed with T2DM between October 2012 and September 2016 from the Medical Data Vision, a Diagnosis Procedure Combination database. The primary objective was to determine the proportion of T2DM patients receiving each type of treatment as first-line therapy among the drug-naive cohort. RESULTS: Of the 436,546 drug-naive patients, 224,761 received their first-line T2DM treatment in the outpatient setting. The mean age of the patient population was 65.6 years at index date. Dipeptidyl peptidase-4 (DPP-4) inhibitor was the most prescribed (56.8%) outpatient AD monotherapy, followed by metformin (15.4%). DPP-4 inhibitors were prescribed over metformin in patients with renal disease (odds ratio [OR]: 4.20; p < 0.0001), coronary heart disease and stroke (OR: 2.22; p < 0.0001). Male (OR: 1.03; p = 0.0026), presence of diabetic complications [retinopathy (OR: 1.33; p < 0.0001), neuropathy (OR: 1.05; p = 0.0037), nephropathy (OR: 1.08; p < 0.0001)] and a high baseline HbA1c (OR: 1.45; p < 0.0001) received treatment intensification during 180 days. CONCLUSION: DPP-4 inhibitors were the most prevalent first-line T2DM treatment followed by metformin in Japan. The findings from this retrospective analysis also support the previously published web survey results and can help understand the real world utilization of T2DM treatment.Trial registration Retrospectively registered.

Relationship of patient background with macro- and microvascular complications: a 2-year post-marketing surveillance of vildagliptin in nearly 20,000 Japanese diabetic patients.

BACKGROUND: Vildagliptin is indicated for type 2 diabetes mellitus (T2DM); however, the onset and exacerbation of diabetic complications in Japanese T2DM patients treated with vildagliptin is unknown. RESEARCH DESIGN AND METHODS: This 2-year post-marketing surveillance (PMS) assessed the real-world safety and efficacy of vildagliptin therapy in 19,218 Japanese T2DM patients. The relationship between the incidence of macro- and microvascular complications with patient characteristics and changes in glycemic control (HbA1c) were evaluated. RESULTS: The incidences of macro- and microvascular diseases were 1.14% and 3.09%, respectively. Patients with HbA1c ≥8.4% had a higher odds ratio (OR) for micro- and macrovascular disease (OR: 2.02 and 1.90) compared with patients with HbA1c <6.9%. Patient characteristics (OR, 95% CI) associated with macrovascular disease were age (1.04, 1.01-1.07) and a history of macrovascular disease (3.38, 1.98-5.75). Microvascular disease was associated with a final HbA1c level ≥7.0% (1.48, 1.11-1.98) and previous diabetic nephropathy (1.42, 1.05-1.93). The mean (SD) HbA1c decreased from 7.89% (1.46%) to 7.05% (0.99%) after 24 months. CONCLUSIONS: Vildagliptin elicited no increases/exacerbations of diabetic complications; this PMS suggested that the incidence of diabetic complications tends to be low in subjects with good HbA1c control.

Relationship between diet/exercise and pharmacotherapy to enhance the GLP-1 levels in type 2 diabetes.

The rapid rise in the prevalence of type 2 diabetes mellitus (T2DM) poses a huge healthcare burden across the world. Although there are several antihyperglycaemic agents (AHAs) available including addition of new drug classes to the treatment algorithm, more than 50% of patients with T2DM do not achieve glycaemic targets, suggesting an urgent need for treatment strategies focusing on prevention and progression of T2DM and its long-term complications. Lifestyle changes including implementation of healthy diet and physical activity are cornerstones for the management of T2DM. The positive effects of diet and exercise on incretin hormones such as glucagon-like peptide-1 (GLP-1) have been reported. We hypothesize an IDEP concept (Interaction between Diet/Exercise and Pharmacotherapy) aimed at modifying the diet and lifestyle, along with pharmacotherapy to enhance the GLP-1 levels, would result in good glycaemic control in patients with T2DM. Consuming protein-rich food, avoiding saturated fatty acids and making small changes in eating habits such as eating slowly with longer mastication time can have a positive impact on the GLP-1 secretion and insulin levels. Further the type of physical activity (aerobic/resistance training), intensity of exercise, duration, time and frequency of exercise have shown to improve GLP-1 levels. Apart from AHAs, a few antihypertensive drugs and lipid-lowering drugs have also shown to increase endogenous GLP-1 levels, however, due to quick degradation of GLP-1 by dipeptidyl peptidase-4 (DPP-4) enzyme, treatment with DPP-4 inhibitors would protect GLP-1 from degradation and prolong its activity. Thus, IDEP concept can be a promising treatment strategy, which positively influences the GLP-1 levels and provide additive benefits in terms of improving metabolic parameters in patients with T2DM and slowing the progression of T2DM and its associated complications.

Choice of Treatment Regimen as Add-On to Insulin in Japanese Patients with Type 2 Diabetes Mellitus: Physicians' Perspective in a Real-World Setting, Insight from a Web Survey.

INTRODUCTION: The Japanese guidelines emphasize treatment individualization and intensification with oral anti-diabetes drugs and glucagon-like peptide-1 receptor agonists (OADGs) as add-on therapy to insulin in the management of type 2 diabetes mellitus (T2DM). However, a step-wise treatment algorithm is not clearly defined in the Japanese guidelines. This study explores the treatment factors and patient characteristics for selecting the OADGs as add-on therapy to insulin from physicians' perspectives in a real-world setting in Japan. METHODS: This web-based survey comprised a questionnaire designed for physicians (diabetologists with board certification and general physicians without board certification) across Japan. The primary endpoint was the proportion of treatment factors and patient characteristics influencing the selection of OADGs as add-on therapy to insulin by the physicians. RESULTS: In total, 549 physicians participated. The mean number of patients treated with insulin by diabetologists (102.2 ± 91.2) in the past 6 months was higher than the number by general physicians (35.1 ± 44.3). The dipeptidyl peptidase-4 (DPP-4) inhibitors were the most frequently prescribed OADGs as add-on therapy to insulin types among the physicians (75.4-88.2%), followed by metformin (65.2-76.3%). The treatment factors influencing the choice of a DPP-4 inhibitor were glycated hemoglobin (HbA1c) and postprandial glucose (PPG) lowering effect, frequency of administration, effect on glucagon, and ease of use in patients with renal or liver impairment. For metformin, cost-effectiveness was the key deciding factor. The patient characteristics for the choice of DPP-4 inhibitors among diabetologists were predominantly PPG, concern about hypoglycemia, diabetes complications, and adherence to diet and exercise. For metformin, it was age, body mass index (BMI), insulin resistance, renal and liver function, and economic status of the patients. CONCLUSION: DPP-4 inhibitors, followed by metformin, were the most frequently prescribed OADGs in combination with insulin in a real-world setting in Japan. The diabetologists considered more drug characteristics for DPP-4 inhibitor or metformin-insulin combinations. The treatment factors and patient characteristics for the choice of DPP-4 inhibitors and metformin were comparable across different insulin types. FUNDING: Novartis Pharma K.K.

Factors Influencing the Prescribing Preferences of Physicians for Drug-Naive Patients with Type 2 Diabetes Mellitus in the Real-World Setting in Japan: Insight from a Web Survey.

INTRODUCTION: The Japanese guidelines for type 2 diabetes mellitus (T2DM) emphasize individualization of treatment based on patient need and encourage physicians to select an appropriate oral antidiabetes drug (OAD). However, limited evidence is available on the factors influencing the selection by physicians (diabetes specialists and nonspecialists) of the first-line OAD to treat drug-naive patients with T2DM. A survey was designed to explore the treatment factors and patient characteristics that influence physicians when they choose an initial OAD to prescribe to a drug-naive patient with T2DM in a real-world setting in Japan. METHODS: The 25-min web-based online survey consisted of simple and focused multiple-choice questions, and was circulated to physicians across eight selected regions in Japan. The primary endpoints were the proportions of physicians who considered particular treatment factors and patient characteristics when selecting the appropriate treatment for drug-naive T2DM patients. RESULTS: A total of 491 physicians participated in the survey. Dipeptidyl peptidase-4 inhibitors (DPP-4is) were the most-preferred first-line OADs, followed by metformin, of both specialists (69% vs. 60%) and nonspecialists (73% vs. 47%). The most influential factors when a DPP-4i was selected were found to be glycated hemoglobin (HbA1c), postprandial glucose (PPG)-lowering effect, and a low risk of hypoglycemia, which were considered by > 80% of physicians, whereas the key factors when metformin was selected were improvement in insulin resistance, low cost, low risk of hypoglycemia, and PPG- and HbA1c-lowering effects, which were considered by > 85% of physicians. Regression analysis revealed that the dominant reason for choosing DPP-4is over metformin was their ease of use in patients with renal impairment, whereas the dominant reasons for choosing metformin over DPP-4is were improvement in insulin resistance and low cost. The key patient characteristics driving the choice of DPP-4is or metformin as the first-line OAD by physicians were similar to those that influenced the treatment intensification decision (DPP-4is: PPG and renal function; metformin: age, BMI, insulin resistance, and renal function). CONCLUSION: In Japan, DPP-4is are the preferred first-line OADs, followed by metformin. The key treatment factors and patient characteristics considered when selecting DPP-4is or metformin are similar for both specialists and nonspecialists. These results may prompt further discussion of the differences in T2DM treatment between Japan and other counties. FUNDING: Novartis.

Effect of baseline renal and hepatic function on the incidence of adverse drug events: the Japan Adverse Drug Events study.

Background The impact of renal and hepatic dysfunction on the morbidity and mortality of inpatients with adverse drug events (ADEs) is uncertain in daily clinical practice. The objective of this study was to investigate the effect of renal and hepatic function on ADEs and inpatients' morbidity and mortality. Methods The Japan Adverse Drug Events (JADE) study was a prospective cohort study carried out at three tertiary-care teaching hospitals in Japan. Participants were consecutive inpatients (n=3459) aged 15 years or older. We evaluated the effect of renal and hepatic function on the occurrence of ADEs, and assessed how they affected length of hospital stay (LOS) and in-hospital mortality. We used the estimated glomerular filtration rate to quantify renal function and categorized patients into three groups (normal, ≥60 mL/min/1.73 mm; moderate, ≥30 and <60 mL/min/1.73 mm; severe, <30 mL/min/1.73 mm). We defined patients as having hepatic dysfunction when at least one data point (total bilirubin, aspartate aminotransferase, alanine aminotransferase, or gamma glutamyltransferase) was beyond a cutoff value. Results We analyzed the laboratory data of 2508 patients. There was a significant difference in the occurrence of ADEs among the three GFR categories (normal, 20%; moderate, 26%; severe, 22%; p=0.02). More ADEs occurred in patients with hepatic dysfunction (25% vs. 20%, p=0.01). LOS was significantly longer in those with ADEs stratified either by renal or by hepatic dysfunction (p<0.0001). ADEs were independently associated with in-hospital mortality, adjusting for renal and hepatic function (p<0.0001). Conclusions Inpatients' organ dysfunction increased ADEs, and ADEs were associated with both LOS and in-hospital mortality independently, irrespective of renal and hepatic function.

Improving the assessment of adverse drug reactions using the Naranjo Algorithm in daily practice: The Japan Adverse Drug Events Study.

It is difficult to determine adverse drug reactions (ADRs) in daily complicated clinical practice in which many kinds of drugs are prescribed. We evaluated how well the Naranjo Algorithm (NA) categorized ADRs among suspected ADRs. The Japan Adverse Drug Events (JADE) study was a prospective cohort study of 3459 inpatients. After all suspected ADRs were reported from research assistants, a single physician reviewer independently assigned an NA score to each. After all NA score of suspected ADRs were scored, two physician reviewers discussed and determined ADRs based on the literature. We investigated the sensitivity and specificity of NA and each component to categorize ADRs among suspected ADRs. A total of 1579 suspected ADRs were reported in 962 patients. Physician reviewers determined 997 ADRs. The percentage of ADRs was 94% if the total NA score reached 5. The modified NA consisted of 5 components that showed high classification abilities; its area under the curve (AUC) was 0.92 for categorizing ADRs, the same as the original. When we set the total NA score cut-off value to 5, specificity was 0.95 and sensitivity was 0.59. When we reclassified NA components as binary variables, the specificity increased to 0.98 with a cut-off value of 4 and yielded an AUC of 0.93. In conclusion, we showed that both NA and modified NA could categorize ADRs among suspected ADRs with a high likelihood in daily clinical practice.