Factors Associated With Treatment Adherence and Satisfaction in Type 2 Diabetes Management in Japan: Results From a Web-Based Questionnaire Survey.

INTRODUCTION: To identify factors associated with treatment adherence and satisfaction in patients with type 2 diabetes (T2DM) in Japan. METHODS: A web-based questionnaire survey was conducted from 6 to 17 March 2019 in patients with T2DM aged ≥ 20 years receiving diabetes treatment. Treatment adherence and satisfaction were self-assessed/reported by the patients. A multiple logistic regression model and the chi-square test were used to assess associated factors. RESULTS: Responders (N = 1000) were aged 63.8 (standard deviation 11.9) years, and 739 (73.9%) were male. Adherence to treatment was reported in 941 (94.1%) patients and was significantly associated with higher household income (odds ratio [OR] 2.07, 95% confidence interval [CI] 1.11-3.86), age (OR 1.04, 95% CI 1.02-1.07), employment (OR 0.30, 95% CI 0.15-0.60) and having ≥ 1 impaired basic activity of daily living (BADL) (OR 0.33, 95% CI 0.13-0.82). Satisfaction with treatment was reported by 575 (57.5%) and was significantly associated with receiving/understanding guidance on how pharmacologic therapies are tailored (OR 1.73, 95% CI 1.19-2.51), male sex (OR 1.55, 95% CI 1.10-2.19), higher household income (OR 1.45, 95% CI 1.09-1.94) and age (OR 1.02, 95% CI 1.00-1.03). Treatment adherence was negatively associated with lower household income and having ≥ 1 impaired BADL in patients aged < 65 years, but not in those aged ≥ 65 years. Treatment satisfaction was positively associated with higher household income and receiving/understanding guidance on exercise therapy and the importance of achieving target haemoglobin A1c levels in patients aged ≥ 65 years, but with receiving/understanding guidance on the tailoring of pharmacologic therapies in patients aged < 65 years. CONCLUSION: Lower age, lower household income, employment and impaired BADL may negatively impact treatment adherence in patients with T2DM. Appropriate physician guidance may promote treatment satisfaction. Differences in perspectives between patients aged < 65 and those aged ≥ 65 years should be considered. TRIAL REGISTRATION: Japan Pharmaceutical Information Center, JapicCTI-194636.

Perspectives of patients and physicians regarding hypertensive management from an online survey for excellence: a subanalysis of the PARADOX study by physician categories.

An existing clinical problem in Japan is the high prevalence of uncontrolled hypertension despite the availability of various effective therapies. Here, we analyzed survey data to gain insight into this paradox from physicians' perspectives, with results categorized according to specialty (i.e., with or without certification by the Japanese Society of Hypertension [JSH]), institution type, gender, and age. A web-based survey of typical educational activities for patients regarding hypertension management was conducted in Japan between October 19 and 31, 2017. Differences between physician groups were investigated per category. Survey results from 541 physicians were analyzed: 59 JSH certified (i.e., 'specialist') vs 482 non-JSH certified (i.e., 'nonspecialist') physicians; 192 general practitioners vs 349 hospital physicians; 500 males vs 41 females; and 178 younger (mean age: 40.7 years), 174 middle-aged (52.0 years) or 189 older (61.3 years) physicians. The most statistically significant differences between groups were observed in the category of physician specialty. Compared with nonspecialists, specialist physicians were more conscious of providing education on patient lifestyle modifications, more aware of patient- and physician-derived issues, and understood and followed the treatment guidelines. General practitioners cared more about the patient's burden than did hospital physicians. Younger physicians identified the need to incorporate the patient's perspective into their treatment. This analysis shows that the provision and perceptions of education differ between physician categories. Compared with specialist physicians, nonspecialists were less likely to provide adequate guidance on lifestyle modifications, possibly due to their uncertainty in understanding treatment guideline recommendations. Further education of nonspecialists on hypertension management may be warranted.

Physician and patient perspectives on hypertension management and factors associated with lifestyle modifications in Japan: results from an online survey.

We conducted a survey to examine the gaps between Japanese physician and patient perspectives on hypertension management and to investigate important factors that may help solve the "hypertension paradox" in Japan. Web-based surveys of patients and physicians were conducted in Japan between October 19 and 31, 2017. The data collected included physician and patient perspectives on hypertension education, adherence to lifestyle modifications and antihypertensive medication, and reasons for treatment adherence/nonadherence. Factors relating to specific patient behaviors (e.g., monitoring their home blood pressure [BP] daily) were analyzed by multivariate logistic regression analysis. Of the 541 physicians and 881 patients included in the analyses, both groups recognized that the extent of lifestyle changes was insufficient. Approximately 80% of physicians reported that they fully or sufficiently provided education to patients about reasons for hypertension treatment and its associated risks, target BP levels, and lifestyle modifications. Only 40-50% of patients considered those topics having been fully or sufficiently discussed. Logistic regression analyses revealed that positive lifestyle modifications (daily home BP monitoring, salt intake <6 g/day, and daily aerobic exercise for ≥30 min) were positively associated with receiving feedback from physicians about specific lifestyle modifications and patient motivation for maintaining their target BP. In conclusion, perception of the amount of education provided by physicians on hypertension management was lower in patients than in physicians. In addition to effective regular follow-up regarding lifestyle modifications, patient motivation by physicians is an important factor for improving lifestyle modifications and achieving effective hypertension management in Japan.

Antihypertensive treatment for hypertensive patients with heart failure using real-world Japanese data: subanalysis of the Retrospective study of antihypertensives for lowering blood pressure (REAL) study.

The number of patients with heart failure (HF) is rapidly increasing. Although hypertension is related to onset of HF, antihypertensive treatment status for these patients has not been fully examined. We conducted a claims-based study to discern the treatment status of Japanese hypertensive patients with HF. Two Japanese databases (2008-2016) from acute care hospitals and health insurance societies were used to analyze prescription rates for antihypertensive drug class or category of diuretics in all hypertensive patients and the subset of patients with HF. Totals of hypertensive patients and those with HF in each database in 2015 were 4,191,666 and 1,404,008 patient-months, and 1,382,732 and 148,194 patient-months, respectively. In the acute care hospitals database, calcium channel blockers (CCBs) (55.0-56.5%) and angiotensin II receptor blockers (49.4-54.7%) were prescribed most. ß-blockers (38.7-48.0%) and diuretics (42.3-45.6%) were prescribed more for hypertensive patients with HF than for all hypertensive patients (21.5-24.8% and 25.5-26.7%, respectively). Loop diuretics were also prescribed more often for hypertensive patients with HF (68.3-76.0% from acute care hospitals and 47.8-55.8% from health insurance societies) than for all hypertensive patients (56.7-61.7% and 16.4-18.3%). The size of medical institution had a greater effect on drug selection than patient age in both patient groups. Given recommendations in guidelines for hypertensive patients with HF, the differences in drug choice in comparison with all hypertensive patients appear reasonable. However, some deviations, such as the high rate of CCBs in frontline and preference for angiotensin II receptor blockers over angiotensin-converting enzyme inhibitors, did not appear to follow guidelines.

Comparison of persistence and adherence between DPP-4 inhibitor administration frequencies in patients with type 2 diabetes mellitus in Japan: a claims-based cohort study.

Objective: To explore persistence and adherence with once-daily, twice-daily, or once-weekly DPP-4 inhibitors (DPP-4i) in Japanese patients with type 2 diabetes.Methods: This retrospective, longitudinal, observational cohort study used data from the Japanese nationwide hospital-based Medical Data Vision (MDV) administrative claims database. Data were collected for patients given a new DPP-4i prescription between May 2015 and June 2017 with 1-year follow-up until May 2018. Treatment persistence was defined as the total duration of continuous prescription. Adherence to treatment was measured as the proportion of days covered (PDC).Results: A total of 598,419 patients with a prescription for DPP-4i treatment were identified in the MDV database. Of the 39,826 patients who met the inclusion criteria, 82.4% were receiving once-daily DPP-4i, 15.6% twice-daily DPP-4i, and 2.0% once-weekly DPP-4i. Twelve-month persistence rates with once-daily regimens were 66.3% versus 64.7% with twice-daily (p = .1187), and versus 38.8% with once-weekly, regimens (p < .0001) in the overall population (including untreated [UT] and previously treated [PT] patients); 62.8% with once-daily versus 58.3% with twice-daily (p = .0309), and versus 12.3% with once-weekly regimens (p < .0001) in the UT cohort; and 68.6% with once-daily versus 67.9% with twice-daily (p = .5471), and versus 49.1% with once-weekly regimens (p < .0001) in the PT cohort. In the overall population, 97.8% of patients had a mean PDC of 0.97 with once- and twice-daily, and 65.8% of patients had a mean PDC of 0.74 with once-weekly, DPP-4i regimens.Conclusions: Overall, persistence at 12 months was highest in patients receiving once-daily DPP-4i regimens.

A Randomized Pilot Study of the Effect of Trelagliptin and Alogliptin on Glycemic Variability in Patients with Type 2 Diabetes.

INTRODUCTION: This open-label, parallel-group, exploratory study examined the effects of two dipeptidyl peptidase 4 (DPP4) inhibitors on glycemic variability (GV) in patients with type 2 diabetes. METHODS: Randomized patients with glycated hemoglobin A1c of at least 6.5% to less than 8.5% received trelagliptin 100 mg (n = 13) once weekly or alogliptin 25 mg (n = 14) once daily for 29 days. Continuous glucose monitoring was performed before the start of the treatment period (baseline) and from day 21 to 29, inclusive. The primary endpoint was change from baseline in the standard deviation (SD) of 24-h blood glucose values, measured daily for 7 days (day 22-28) of the treatment period. Secondary and additional efficacy endpoints included changes in glycemic parameters and the rate of DPP4 inhibition, respectively. Adverse events (AEs) were monitored to assess safety. RESULTS: Mean change from baseline in the SD of 24-h blood glucose (95% confidence interval) at day 28 was - 7.35 (- 15.13, 0.44) for trelagliptin and - 11.63 (- 18.67, - 4.59) for alogliptin. In both treatment groups, glycemic parameters improved and the rate of DPP4 inhibition was maintained. Three patients reported AEs; no severe treatment-emergent AEs were reported in either group. CONCLUSION: Once-weekly trelagliptin and once-daily alogliptin improved glycemic control and reduced GV without inducing hypoglycemia. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02771093) and JAPIC (JapicCTI-163250). FUNDING: Takeda Pharmaceutical Company, Ltd.

Analysis of antihypertensive treatment using real-world Japanese data-the retrospective study of antihypertensives for lowering blood pressure (REAL) study.

Hypertension requires strict treatment because it causes diseases that can lead to death. Although various classes of antihypertensive drugs are available, the actual status of antihypertensive drug selection and the transition in prescription patterns over time have not been fully examined. Therefore, we conducted a claims-based study using two claims databases (2008-16) to determine this status in Japan. We examined the prescription rate for each class of antihypertensive drugs in hypertensive patients and compared the patients' ages and the sizes of the medical institutions treating these patients. Among the 1 560 865 and 302 433 hypertensive patients in each database, calcium channel blockers (CCBs) (>60%) and angiotensin II receptor blockers (ARBs) (>55%) were the most frequently prescribed classes. The prescription rate of CCBs increased and ARBs decreased with the patients' ages. Although the Japanese guidelines for management of hypertension in 2014 changed the recommendation and indicated that ß-blockers should not be used as first-line drugs, their prescription status did not change during this study period up to 2016. Use of CCBs and ARBs as first-line drugs differed by the types of patient comorbidities. Although ARBs or angiotensin-converting enzyme inhibitors were recommended for patients with some comorbidities, CCBs were used relatively frequently. In conclusion, the patients' ages and comorbidities and the sizes of the medical institutions affect the selection of antihypertensive drugs. Selection and use of drugs may not always follow the guidelines.

Treatment patterns, persistence and adherence rates in patients with type 2 diabetes mellitus in Japan: a claims-based cohort study.

OBJECTIVE: To determine real-world trends in antidiabetic drug use, and persistence and adherence, in Japanese patients with type 2 diabetes mellitus (T2DM). DESIGN: Retrospective evaluation of administrative claims data (2011-2015) using the Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases. SETTING: Analysis of two administrative claims databases for Japanese patients with T2DM. PARTICIPANTS: Adults (aged ≥18 years) with an International Classification of Diseases, 10th Revision code of T2DM and at least one antidiabetic drug prescription. MAIN OUTCOME MEASURES: Treatment patterns in untreated (UT) or previously treated (PT) patients receiving antidiabetic therapy; persistence with treatment at 12 months; adherence to treatment at 12 months. RESULTS: 40 908 and 90 421 patients were included from the JMDC and MDV databases, respectively. The most frequently prescribed therapy at the index (first prescription) date was dipeptidyl peptidase-4 inhibitor (DPP-4i) in UT patients (JMDC: 44.0%, MDV: 54.8%) and combination therapy in PT patients (74.6%, 81.1%). Most common combinations were DPP-4i plus: biguanide (BG; 11.4%, 10.9%), sulfonylurea (SU; 8.4%, 11.0%) or BG+SU (7.8%, 9.1%). In UT or PT patients from either database whose index prescription was for any antidiabetic drug class(es) other than DPP-4i, the most frequent add-on or switch was to DPP-4i. 12-month persistence with index monotherapy was highest with DPP-4i and BG. Adherence was high (≥80%) for all monotherapy schedules, except insulin and glucagon-like peptide-1 agonist, and for the five most frequent two-drug and three-drug combinations. Persistence was greater in elderly UT patients and in those receiving ≤5 medications, but comparatively worse in UT patients with ≥3 index antidiabetic drug classes. CONCLUSIONS: The findings indicate that DPP-4i is the most commonly used antidiabetic drug class in Japanese patients with T2DM, and persistence and adherence to this antidiabetic drug class are high.

Adherence and persistence to hyperlipidemia medications in patients with atherosclerotic cardiovascular disease and those with diabetes mellitus based on administrative claims data in Japan.

BACKGROUND AND AIMS: Real-world data on treatment patterns in Japanese hyperlipidemia patients with diabetes mellitus (DM) or prior atherosclerotic cardiovascular diseases (ASCVD) are lacking. METHODS: This is a retrospective, longitudinal cohort analysis of administrative claims data (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV] databases) for patients prescribed a new hyperlipidemia medication between 2014 and 2015. Patients were followed for ≥12 months. Outcomes included prescribing patterns, persistence (discontinuations), and adherence (proportion of days covered). RESULTS: Data were analyzed for 11,718 and 27,746 DM, and 4101 and 14,356 ASCVD patients from the JMDC and MDV databases, respectively. Among previously-untreated patients, index prescriptions were primarily for moderate statins in the DM (JMDC: 74.7%, MDV: 77.5%) and ASCVD (JMDC: 75.4%, MDV: 78.5%) sub-cohorts. Combinations were rarely prescribed (≤2.5%). Previously-treated patients were most frequently prescribed combinations in the DM (JMDC: 46.7%, MDV: 53.6%) and ASCVD (JMDC: 49.3%, MDV: 53.3%) sub-cohorts. Intensive statins were rarely used by previously-untreated (≤1%) or previously-treated (≤8%) patients in either sub-cohort. Approximately half of previously-untreated patients discontinued hyperlipidemia therapy within 12 months. Adherence was ≥80% across most drug classes. CONCLUSIONS: Many Japanese hyperlipidemia patients with DM or ASCVD are prescribed single-agent lipid-lowering therapy. Use of intensive therapy is lower than expected, and is suggestive of under-treatment. The low persistence rates are concerning, and warrant further study.

Current prescription status of antihypertensive drugs in Japanese patients with hypertension: Analysis by type of comorbidities.

In 2014, the Japanese Society of Hypertension (JSH) issued revised guidelines for hypertension management. To assess adherence to the guidelines, this retrospective study evaluated the real-world status of antihypertensive drug prescribing for Japanese patients with hypertension, classified by comorbidity: diabetes mellitus, dyslipidemia, gout/hyperuricemia and renal diseases. Data on 59,867 hypertensive patients who received their first prescription for antihypertensive therapy between April 2014 and March 2015, were obtained from a medical insurance claims database for hospitals participating in the Diagnosis Procedure Combination/Per-Diem payment system. The most common drugs prescribed for each comorbidity subgroup were calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs), with prescription rates of around 60-70%. Contrary to JSH recommendations, diuretics and angiotensin-converting enzyme inhibitors were prescribed less often than ß-blockers. Whereas diabetes mellitus is a compelling indication for use of renin-angiotensin system inhibitors, CCBs were commonly prescribed in this subgroup. The treatment pattern for patients with comorbid dyslipidemia closely resembled that for the overall patient population. Loop diuretics were prescribed more frequently for patients with renal diseases or gout/hyperuricemia than for those with diabetes mellitus or dyslipidemia. Although antihypertensive drug prescribing varied by comorbidity, JSH 2014 guidelines appeared not to be incorporated adequately into actual clinical practice.

Treatment patterns and adherence to antihypertensive combination therapies in Japan using a claims database.

Fixed-dose combinations (FDCs) for blood pressure control can simplify prescribing, improve medication adherence, and be cost-effective. In Japan, real-world data about the class effects of antihypertensive drugs on medication adherence are limited. Using the nationwide database of medical health claims from Diagnosis Procedure Combination hospitals, treatment patterns and adherence were analyzed for 47,891 patients prescribed antihypertensive medication between April 2014 and March 2015. Adherence was assessed by the proportion of days covered (expressed as % PDC). Patients were prescribed a mean of 2.0 ± 1.0 antihypertensive drugs and 2.4 ± 1.7 pills for their index prescription. Mean adherence overall was 91.5% PDC and was inversely correlated with the number of antihypertensive drugs or pills prescribed on the index date. Mean % PDC was significantly higher (all P < 0.0001) for CCB + ARB versus ARB + thiazide diuretic combinations and for CCB + ARB + ß-blocker versus CCB + ARB + thiazide diuretic combinations. Adherence was significantly higher (P < 0.0001) for FDC (CCB + ARB) versus corresponding single-drug combinations, but not for other comparisons of FDCs versus single-drug combinations. On the other hand, FDCs were not always used effectively; specifically, FDCs were frequently used concomitantly with a single agent(s) from the same drug class(es) as the FDC. From the results of our study, no clear differences were observed in medication adherence according to the presence or absence of FDC formulations, and there were cases in which FDCs were not being utilized effectively to simplify prescribing.

Comparison of persistence and adherence between fixed-dose combinations and two-pill combinations in Japanese patients with type 2 diabetes.

OBJECTIVE: To compare treatment patterns, persistence and adherence between fixed-dose combinations (FDCs) and two-pill combinations (TPCs) of oral antidiabetic drug (OAD) classes in Japanese patients with type 2 diabetes mellitus (T2DM) using administrative claims databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]). METHODS: This was a retrospective, longitudinal cohort analysis conducted between 2011 and 2015, in patients with T2DM receiving OADs as FDC or TPC. Outcomes included prescribing patterns, treatment persistence and adherence. RESULTS: Data from 3474 and 3066 patients receiving FDCs, and 4325 and 5192 patients receiving TPCs from the JMDC and MDV databases, respectively, was extracted. The most common OAD combination received by over half of all patients was dipeptidyl peptidase-4 inhibitor (DPP-4i) + thiazolidinediones (TZDs) (64.1% [JMDC] and 70.5% [MDV]). Overall, 12-month persistence rates were higher in patients receiving FDCs compared with TPCs (70.4 vs. 66.2% [JMDC], 75.6 vs. 55.7% [MDV]). In the JMDC population receiving FDCs or TPCs, persistence rates were highest with DPP-4i schedules (67.5-83.5%). Median time to discontinuation was significantly longer with biguanide + TZD, and DPP-4i + TZD FDC schedules (p < .05) than TPC; adherence rates were ≥80% across all antidiabetic drug classes in both database populations. CONCLUSIONS: Persistence with and adherence to OADs in Japanese patients with T2DM were greater with FDCs than with TPCs, which may suggest increased patient satisfaction due to reduced treatment burden. Further studies are warranted to investigate the impact of adherence and persistence of FDCs of OADs on glycemic control.

Pharmacokinetics and Safety After a Single Dose of Imarikiren in Subjects with Renal or Hepatic Impairment.

BACKGROUND AND OBJECTIVE: Imarikiren hydrochloride (TAK-272; SCO-272) is a novel direct renin inhibitor. The objective of this study was to determine the effects of renal impairment (RI) or hepatic impairment (HI) on the pharmacokinetics and safety of imarikiren. METHODS: This phase I, open-label, parallel-group comparative study evaluated the pharmacokinetics and safety of a single 40 mg oral dose of imarikiren in RI [mild, moderate, severe, or end-stage renal disease (ESRD), and on hemodialysis] or HI (mild or moderate) subjects compared with subjects with normal renal or hepatic function. RESULTS: Following administration of a single 40 mg oral imarikiren dose, the geometric mean imarikiren area under the plasma concentration-time curve from time zero to infinity (AUC∞) and maximum observed plasma concentration (Cmax) in subjects with mild, moderate, and severe RI (including non-hemodialysis and ESRD), and hemodialysis subjects compared with normal renal function subjects were approximately 0.5-, 1.2-, 2.7-, and 1.8-fold, respectively, for AUC∞; and approximately 0.6-, 0.8-, 2.1-, and 1.4-fold, respectively, for Cmax. The mean fraction of excretion of imarikiren in dialysate was ~ 3% during the 4 h dialysis period. The geometric mean imarikiren AUC∞ and Cmax in mild and moderate HI subjects compared with normal hepatic function subjects were approximately 1.0- and 1.4-fold, respectively, for AUC∞, and approximately 0.9- and 1.3-fold, respectively, for Cmax. No deaths or serious adverse events were observed; all adverse events were mild or moderate in intensity. CONCLUSIONS: RI and HI are associated with limited changes in imarikiren pharmacokinetics. Imarikiren was safe and well-tolerated, regardless of the severity of RI or HI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02367872.

Treatment patterns in hyperlipidaemia patients based on administrative claim databases in Japan.

BACKGROUND AND AIMS: Real-world evidence on treatment of hyperlipidaemia (HLD) in Japan is limited. We aimed to describe treatment patterns, persistence with, and adherence to treatment in Japanese patients with HLD. METHODS: Retrospective analyses of adult HLD patients receiving drug therapy in 2014-2015 were conducted using the Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases. Depending on their HLD treatment history, individuals were categorised as untreated (UT) or previously treated (PT), and were followed for at least 12 months. Outcomes of interest included prescribing patterns of HLD drug classes, persistence with treatment at 12 months, and adherence to treatment. RESULTS: Data for 49,582 and 53,865 patients from the JMDC and MDV databases, respectively, were analysed. First-line HLD prescriptions for UT patients were predominantly for moderate statins (JMDC: 75.9%, MDV: 77.0%). PT patients most commonly received combination therapy (JMDC: 43.9%, MDV: 52.6%). Approximately half of the UT patients discontinued treatment during observation. Within each cohort, persistence rates were lower in UT patients than in PT patients (JMDC: 45.0% vs. 77.5%; MDV: 51.9% vs. 85.3%). Adherence was ≥80% across almost all HLD drug classes, and was slightly lower in the JMDC cohort than MDV cohort. CONCLUSIONS: Most common prescriptions were moderate statins in UT patients and combination therapy in PT patients. The high discontinuation rate of HLD therapy in UT patients warrants further investigation and identification of methods to encourage and support long-term persistence.

Current use of antihypertensive drugs in Japanese patients with hypertension: Analysis by age group.

AIM: To analyze the current use of antihypertensive drug classes in Japanese hypertensive patients stratified by age, highlighting differences between older and younger patients. METHODS: A nationwide medical database was used to evaluate antihypertensive use in patients (aged ≥20 years) who had received a prescription for one or more antihypertensive drug as an outpatient from April 2014 to March 2015. Patients (n = 59 867) were age-stratified into three groups: <65 years (28.7%), 65-74 years (33.1%) and ≥75 years (38.2%). RESULTS: The mean number of antihypertensive drugs prescribed for patients in the overall population was 1.9 ± 1.0, with no appreciable differences between age groups. The most commonly prescribed drug classes for all ages were calcium channel blockers (CCB) and angiotensin II receptor blockers (ARB). CCB were prescribed more often than ARB in the 65-74 years (66.9% vs 60.5%) and ≥75 years (70.4% vs 56.8%) years age groups, and ARB were prescribed more often than CCB in patients aged <65 years (63.1% vs 61.9%). There were minimal differences by age in prescription rates for ß-blockers, angiotensin-converting enzyme inhibitors and thiazide diuretics. ARB prescription rates were lower in patients aged ≥75 years with diabetes mellitus or renal disease than in younger age groups. Prescription rates for loop diuretics were higher in patients aged ≥75 years than in younger age groups, especially among those with renal disease. CONCLUSIONS: Antihypertensive drugs selected for patients aged ≥75 years differed from those selected for younger patients, in particular CCB and loop diuretics (prescribed more often), and ARB (prescribed less often). Geriatr Gerontol Int 2018; 18: 899-906.

Analysis of second- and third-line antihypertensive treatments after initial therapy with an angiotensin II receptor blocker using real-world Japanese data.

Combination therapy using two or three classes of drugs is often required to treat hypertension to prevent cardiovascular disease. In this study, we examined combination therapies administered following initial therapy with an angiotensin II receptor blocker (ARB) in hypertensive Japanese patients. To determine which classes of antihypertensives are being prescribed as second- or third-line treatments for patients who were initially treated with a single ARB, we analyzed prescription claims data from two Japanese health-care databases for 2008 to 2015. Among the 26 998 patients who were initially treated with a single ARB (from one database), calcium channel blockers (CCBs) were the most frequently prescribed second-line antihypertensive, as these medicines were added for >20% of patients within 1 year of ARB prescription initiation. The addition rates of CCBs as a second-line therapy differed depending on the initial ARB type. In contrast, <10% of patients received a diuretic as a second-line antihypertensive. Among the 48 813 patients who were prescribed an ARB in combination with a CCB (as shown in the other database), diuretics were prescribed as third-line antihypertensives more frequently than increased doses of CCBs or ARBs. Diuretics were added for 8% of patients within 2 years of CCB addition, and the addition rates differed based on the CCB dose used for combination therapy. We also found that the addition rates of diuretics differed depending on patient clinical histories among ARB and CCB recipients.

Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics.

RATIONALE: Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear. OBJECTIVE: To determine how mitochondria impact endothelial cell function. METHODS AND RESULTS: We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochondrial uncoupling protein 2 (UCP2). Analysis in silico indicated increased UCP2 expression is common in highly proliferative cell types, including cancer cells. Upregulation of UCP2 was critical for controlling mitochondrial membrane potential (Δψ) and superoxide production. In the absence of UCP2, endothelial growth stimulation provoked mitochondrial network fragmentation and premature senescence via a mechanism involving superoxide-mediated p53 activation. Mitochondrial network fragmentation was both necessary and sufficient for the impact of UCP2 on endothelial cell phenotype. CONCLUSIONS: These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2.

The effects of long-term smoking on endothelial nitric oxide synthase mRNA expression in human platelets as detected with real-time quantitative RT-PCR.

Endothelium-derived nitric oxide (NO) plays an important role in the prevention of platelet aggregation and adhesion to the vascular wall. Endothelial nitric oxide synthase (eNOS) and L-arginine/NO pathway are both present in human platelets. Platelet-derived NO inhibits excessive activation and aggregation of platelets. However, the expression level of the eNOS gene in human platelets has yet to be elucidated. The current study investigates the individual expression level of platelet eNOS mRNA using the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) detection method. eNOS mRNA expression was examined in platelets isolated from 50 subjects: 11 male smokers, 15 male nonsmokers, and 24 female non-smokers. After extraction of platelet total RNA, eNOS (target) and GAPDH (internal control) mRNA expression levels were quantitated using real-time RT-PCR. The expression levels of eNOS mRNA (relative copy numbers) were significantly lower in male smokers (59+/-17) than in male nonsmokers (195+/-71, P < .03), and higher in female nonsmokers (285+/-60) than in the male nonsmokers (195+/-71, P < .03). By multiple linear regression analysis, cigarette smoking (P = .008) and diabetes mellitus (P = .047) were found to be significantly negative predictors, and antioxidant (vitamin E) treatment (P = .01) was a significantly positive predictor of platelet eNOS mRNA expression. Age, other medications, and other risk factors for coronary artery disease were not significant. Using this method, eNOS mRNA abundance in human platelets was detected and quantitated in real-time. The intraplatelet eNOS mRNA expression levels were significantly decreased in cigarette smokers. Low platelet NO synthesis in smokers may result in the augmentation of platelet aggregation and thrombus formation, developing into acute coronary syndromes.

Synergistic interaction of T-786-->C polymorphism in the endothelial nitric oxide synthase gene and smoking for an enhanced risk for coronary spasm.

OBJECTIVE: We previously reported that a T-786-->C polymorphism in the 5'-flanking region of the endothelial nitric oxide synthase gene and smoking were independently associated with coronary spasm; however, the interaction between this polymorphism and smoking remains to be elucidated. METHODS: We analyzed 209 men and 238 women who were admitted consecutively at our institution; all subjects received an intracoronary injection of acetylcholine (ACh) while undergoing coronary angiography for evaluation of chest pain: all subjects had no significant coronary stenosis. We divided these subjects into four groups: non-smokers with T/T genotype (Control Group A); non-smokers with C/T or C/C genotype (Group B); smokers with T/T genotype (Group C); and smokers with C/T or C/C genotype (Group D). We further examined quantitative coronary angiographies of the left anterior descending coronary artery in a subset of 54 consecutive men and 53 consecutive women. RESULTS: The frequencies of coronary spasm in Group B (male: 61%, female: 78%), Group C (62%, 59%) and Group D (91%, 92%) were significantly higher than in Group A (30%, 38%). In the males, ACh-induced vasoconstriction was greatest in Group D, and the change was weakest in Group A. In the females, ACh-induced vasoconstrictions were significantly greater in Groups B, C and D than in Group A. The T-786-->C polymorphism and smoking combine to increase the risk of coronary spasm.

Inhibitory effect of natriuretic peptides on aldosterone synthase gene expression in cultured neonatal rat cardiocytes.

BACKGROUND: Although previously thought to be synthesized solely in adrenal cortex, we have recently showed that aldosterone is also produced in and the expression of CYP11B2 mRNA was induced in the failing or hypertensive human ventricle. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones with wide biological effects, including inhibition of renin and aldosterone production. We hypothesized that natriuretic peptides reduce the expression of CYP11B2 mRNA in the heart. METHODS AND RESULTS: To test this hypothesis, we examined whether endogenous or exogenous natriuretic peptides reduce the expression of CYP11B2 mRNA using real-time reverse transcription-polymerase chain reaction. By using HS 142-1, a functional guanylyl cyclase-A type receptor antagonist, we showed that angiotensin II (AngII) pretreated with HS 142-1 increased CYP11B2 mRNA expression (1.62+/-0.12-fold, HS 142-1+AngII 10(-7) mol/L versus AngII 10(-7) mol/L alone, P<0.0001). The treatment with exogenous (10(-6) mol/L) ANP and BNP reduced CYP11B2 mRNA expression (ANP, P=0.0042; BNP, P=0.0012). CONCLUSIONS: We showed that endogenous and exogenous natriuretic peptides reduced CYP11B2 mRNA expression in cultured neonatal rat cardiocytes. This may inhibit the cardiac renin-angiotensin-aldosterone system by suppressing the gene expression of CYP11B2 and restraining cardiac hypertrophy and fibrosis.