Fragility Fracture Network-Japan: The challenge of establishment of a national hip fracture database and successful achievement of nationwide health system change for hip fracture care in Japan.

BACKGROUND: In April 2022, a new reimbursement scheme for hip fracture was implemented by the Japanese health ministry. Japan is one of the world's most aged societies, facing a significant, rapidly growing burden of osteoporosis and fragility fractures. The incidence of hip fractures is projected to increase from 240,000 in 2020 to 320,000 by 2040. In 2015, Fragility Fracture Network-Japan (FFN-Japan) was formally established as a nonprofit organization in order to create the optimal fragility fracture care system in Japan. METHODS: FFN-Japan launched the Japan National Hip Fracture Database (JNHFD) in 2017, initially with only eight participating hospitals across Japan. The number of patients enrolled from May 2017 to the end of 2020 in the JNHFD from the 16 hospitals registered the patients during this period with amounting to 4271 patients in total. FFN-Japan invited officials from the Ministry of Health, Labor and Welfare (MHLW) to participate in round table meetings to discuss the data collected in the JNHFD and to consider opportunities for nationwide improvement in hip fracture care. RESULTS: The proportion of patients who underwent surgery within 36 h of arrival at hospital was 48.1% in 2018, 58.6% in 2019, and 44.9% in 2020 indicating the delay of surgery. Regarding secondary fracture prevention, initiation of osteoporosis treatment during the in-patients was 60.2% in 2018, 54.0% in 2019, and 64.5% in 2020 indicating the inadequate post fracture care. In April 2022, the Central Social Insurance Medical Council of the Japanese MHLW announced a new reimbursement scheme for hip fracture care including two key components: Early surgery (within 48 h from injury) and Secondary fracture prevention immediately after fracture. DISCUSSION: The new reimbursement scheme of hip fracture care in Japan will catalyze and underpin major improvements on acute multidisciplinary care and post-fracture care with secondary fracture prevention. FFN-Japan played a key role on these policy changes to the health system by means the close collaboration and ongoing communication with the government. CONCLUSION: Within five years of establishment of the JNHFD, FFN-Japan in collaboration with visionary leaders from the Japanese government have successfully achieved a major reform of the Japanese health system's reimbursement of hip fracture care. This reform has laid the foundation for transformation of management of this debilitating and life-threatening injury that currently afflicts almost a quarter of a million older Japanese citizens each year.

Understanding impacts of COVID-19 restrictions on glycemic control for patients with diabetes in Japan.

Objective: This study evaluated the changes in the status of glycemic control and lipid management in patients with diabetes under COVID-19 containment restrictions, in order to better understand the impacts of events causing lifestyle restrictions. Patient characteristics with worsened glycemic control were also assessed. Methods: We conducted a retrospective and observational cohort study using the electronic health records of 5,169 patients with diabetes seeking medical care in two healthcare centers. Laboratory test results including glycemic and lipid goal attainment rates were compared between pre-COVID-19 (January to December 2019) and the first wave of COVID-19 (February to June 2020). Multiple regression models were used to evaluate the association between glycated hemoglobin (HbA1c) at baseline and during the first wave with covariates such as concomitant medications and comorbidities. Results: The HbA1c goal achievement rate improved significantly from 39.0% to 43.1% (p < 0.0001) overall, and more patients reached their glycemic target during COVID-19 restrictions. No significant changes were observed in lipid control. An indexed change in HbA1c level showed that glycemic control improved in 2,230 patients and worsened in 1,619 patients. Administration of insulin, GLP-1, and sulfonylureas were each identified as factors correlated with elevated HbA1c, during the first wave of COVID-19. Conclusion: Although the glycemic control in patients with diabetes improved overall under COVID-19 restrictions, those on insulin, GLP-1, or sulfonylureas worsened. These findings suggest the need to better understand what drives differences in glycemic control to better support people with diabetes for future epidemiological outbreaks. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01302-5.

Effects of Nutrition Education Program for the Japan Diet on Serum Phospholipid Fatty Acid Compositions in Patients with Dyslipidemia: Re-analysis of Data from a Previous Randomized Controlled Trial.

AIM: We investigated changes in serum phospholipid fatty acid compositions with intake of the Japan Diet (JD) (higher consumption of fish, soybeans, vegetables, seaweed/mushrooms/konjak, and unrefined cereals with reduced consumption of animal fat, meat and poultry with fat, sweets and alcoholic drinks) recommended by the Japan Atherosclerosis Society. METHODS: A randomized parallel controlled clinical trial on JD intake was conducted on Japanese patients with dyslipidemia. Nutrition education, based on the JD or partial JD (PJD) at baseline and at 3 months, was provided and the participants were followed up for 6 months. Fatty acids comprising serum phospholipids were measured in the JD (n=44) and PJD (n=44) groups. RESULTS: Fatty acid intakes of C20:4, C20:5 and C22:6 increased in the JD group as compared with the PJD group. The percentages of serum phospholipid, C22:1 and C20:5 increased, while those of C18:1, C20:3(n-6) and C20:4(n-6) decreased in the JD as compared with the PJD group at 3 months. Changes in the phospholipid concentrations of C20:5, C22:5 and C22:6 reflected those intake volumes. Serum phospholipid C20:5 and C22:6 showed inverse correlations with C18:1, C18:2, and C20:3(n-6) at baseline and the changes at 3 and 6 months. In contrast, no correlation was observed between C20:4(n-6) and those n-3 fatty acids. The ratios of fatty acid concentrations, C16:1/C16:0 and C18:1/C18:0, decreased, but the ratio of C20:4(n-6)/C20:3(n-6) increased in the JD group. CONCLUSION: Nutrition education on the JD changed serum phospholipid fatty acid profiles in favor to prevent against cardiovascular risk factors in patients with dyslipidemia.

Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey).

BACKGROUND: Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. RESEARCH DESIGN AND METHODS: This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. RESULTS: At 3 years, Kaplan-Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%-2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%-3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79-1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28-0.78; P < 0.05). CONCLUSIONS: Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02285166.

Apolipoprotein D modulates lipid mediators and osteopontin in an anti-inflammatory direction.

BACKGROUND: HDL has been proposed to possess anti-inflammatory properties; however, the detail mechanisms have not been fully elucidated. METHODS: We investigated the roles of Apolipoprotein D (ApoD) in the pathogenesis of inflammation in the mouse model of diet-induced obesity and that of lipopolysaccharide-induced sepsis and the in vitro experiments. Furthermore, we analyzed serum ApoD levels in human subjects. RESULTS: The overexpression of human ApoD decreased the plasma IL-6 and TNF-a levels in both mice models. Lipidomics analyses demonstrated association of ApoD with increase of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, as well as of their metabolites, and of the anti-inflammatory molecule sphingosine 1-phosphate, and decrease of proinflammatory lysophosphatidic acids and lysophosphatidylinositol. ApoD-containing lipoproteins might directly bind eicosapentaenoic acid and docosahexaenoic acid. The modulations of the lysophosphatidic acid and sphingosine 1-phosphate levels resulted from the suppression of autotaxin expression and elevation of apolipoprotein M (ApoM), respectively. Moreover, ApoD negatively regulated osteopontin, a proinflammatory adipokine. The activation of PPARg by ApoD might suppress autotaxin and osteopontin. Serum ApoD levels were negatively correlated with the serum osteopontin and autotaxin levels and, positively with serum ApoM levels. CONCLUSION: ApoD is an anti-inflammatory apolipoprotein, which modulates lipid mediators and osteopontin in an anti-inflammatory direction.

Time-averaged low-density lipoprotein cholesterol lowering with evolocumab: Pooled analysis of phase 2 trials.

LDL-C is the pivotal risk factor for atherosclerotic cardiovascular disease, and the benefit from LDL-C lowering is proportional to the magnitude of reduction. Clinical trials demonstrate that evolocumab reduces LDL-C levels by approximately 60% when measured at the trough of drug effect, which may underestimate cumulative LDL-C reduction. We obtained a time-averaged estimate of LDL-C lowering that included both peaks and troughs. Pooled analysis of 5 phase 2 trials included patients with hypercholesterolemia who received placebo or evolocumab (140 mg every 2 weeks [Q2W] or 420 mg monthly [QM]). Percent changes from baseline LDL-C and free serum PCSK9 were averaged across weeks 9-12. In 372 patients, time-averaged percent reduction from baseline in LDL-C with evolocumab vs placebo was 67.6% (95% CI: 63.9-71.3) with Q2W dosing and 65.0% (95% CI: 60.7-69.3) with QM dosing. The time-averaged measure yielded LDL-C reductions for evolocumab that exceeded measurements at the end of dosing intervals and may provide a better estimate of cardiovascular benefit during long-term therapy.

Effects of Dietary Education Program for the Japan Diet on Cholesterol Efflux Capacity: A Randomized Controlled Trial.

AIM: Improving cholesterol efflux capacity (CEC) of high-density lipoprotein (HDL) has been regarded as a novel target for preventing cardiovascular disease. HDL reportedly has antioxidant properties which may contribute to its functions. We investigated changes in CEC with intake of the Japan Diet (JD) recommended by the Japan Atherosclerosis Society and the relationship of these changes to serum antioxidant concentrations. METHODS: A randomized parallel controlled clinical trial on JD intake was performed in Japanese patients with dyslipidemia. Ninety-eight participants were randomly divided into the JD (n=49) or the partial JD (PJD) (n=49) group. Nutrition education, based on each diet at baseline and at 3 months, was provided and the participants were followed up for 6 months. RESULTS: Mean CEC was 1.05 in total and correlated positively with HDL-cholesterol (p＜0.001) at baseline. CEC did not change while oxygen radical absorbance capacity (ORAC) was decreased in both groups (p＜0.001). Although serum total carotenoid increased in both groups, serum α-tocopherol decreased in the JD group as compared to the PJD group (p＜0.05). CEC correlated positively with HDL ORAC at baseline (p=0.021) and with serum total carotenoid at 3 and 6 months (p=0.005, 0.035). Changes in CEC correlated positively with changes in HDL ORAC at 3 months and serum total tocopherol at 3 and 6 months (p＜0.001). CONCLUSION: CEC was not changed by JD education in Japanese patients with dyslipidemia who already had normal CEC at baseline. CEC was suggested to be positively associated with serum α- and γ-tocopherol and HDL ORAC.

Abatacept is Efficacious in the Treatment of Older Patients with csDMARD-Refractory Rheumatoid Arthritis: A Prospective, Multicenter, Observational Study.

INTRODUCTION: Abatacept efficacy in older patients with rheumatoid arthritis (RA) has been primarily demonstrated via retrospective comparisons with younger patients. The objective of this study was to compare efficacy of abatacept in older vs. younger patients with RA, and efficacy of abatacept with that of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in both age groups. METHODS: This prospective, multicenter, observational study (UMIN000014913) enrolled csDMARD-refractory patients without previous biological DMARD treatment. Abatacept (A) or csDMARDs (C) were administered at the treating physician's discretion to older (O, ≥ 65 years) and younger (Y, 20-64 years) patients, producing AO, AY, CO, and CY groups. Clinical efficacy after 24 weeks was evaluated using European League Against Rheumatism (EULAR) erythrocyte sedimentation rate response criteria. RESULTS: Overall, 202 patients were evaluated. Compared with the CO group, more patients in the AO group achieved a EULAR good or moderate response (p < 0.0001). Compared with the CY group, more patients in the AY group achieved a EULAR good or moderate response (p < 0.01). Similar proportions of patients in the AO and AY groups achieved a EULAR good response or a good or moderate response. Few adverse events were reported. CONCLUSIONS: This prospective study demonstrated that abatacept is efficacious and safe in older patients with RA and a history of being refractory to csDMARDs. Abatacept was shown to be more efficacious than adding or switching to a new csDMARD in both younger and older csDMARD-refractory patients with RA. TRIAL REGISTRATION: UMIN000014913.

Comparison of the Japan Society of Clinical Chemistry reference method and CDC method for HDL and LDL cholesterol measurements using fresh sera.

OBJECTIVES: In 2009, the Japan Society of Clinical Chemistry (JSCC) recommended a reference method for the measurement of serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. This automated method uses cholesterol esterase-cholesterol dehydrogenase to measure cholesterol levels in fractions obtained after ultracentrifugation and dextran sulfate/magnesium chloride precipitation. In the present study, using fresh samples, we compared the LDL-C and HDL-C levels measured using this method with those measured using the traditional Centers for Disease Control and Prevention (CDC)-beta-quantification (BQ) method. DESIGN: and methods: Using both the JSCC and CDC-BQ methods, LDL-C/HDL-C levels were measured in 47 non-diseased and 126 diseased subjects, whose triglyceride levels were lower than 11.29 â€‹mmol/L (1000 â€‹mg/dL). RESULTS: For LDL-C, the equation of the line representing the correlation between the two methods was y â€‹= â€‹0.991x + 0.009 â€‹mmol/L; r â€‹= â€‹0.999; and Sy/x â€‹= â€‹0.025 â€‹mmol/L, where x is the mean LDL-C level measured using the CDC-BQ method. Similarly, for HDL-C, the equation of the line representing the correlation between the two methods was y â€‹= â€‹0.988x + 0.041 â€‹mmol/L, r â€‹= â€‹0.999, and Sy/x â€‹= â€‹0.019 â€‹mmol/L, where x is the mean HDL-C level measured using the CDC-BQ method. CONCLUSIONS: The JSCC method agreed with the CDC-BQ method in cases of both non-diseased and diseased subjects, including those with dyslipidemia.

Effects of Nutrition Education Program for the Japan Diet on Serum LDL-Cholesterol Concentration in Patients with Dyslipidemia: A Randomized Controlled Trial.

AIM: The Japan Diet (JD) recommended by the Japan Atherosclerosis Society based on the traditional Japanese diet is presumably favorable for preventing atherosclerotic cardiovascular diseases, but few high-quality controlled clinical trials have examined its benefits as compared with other diets. We studied effects of nutrition education for JD intake as compared with partial JD (PJD) intake on serum lipids and inflammatory parameters in subjects with dyslipidemia. METHODS: A randomized parallel controlled clinical trial was conducted on outpatients with dyslipidemia. Participants were randomly divided into the JD or the PJD group. Face-to-face nutrition education based on each diet at baseline and at 3 months, as well as monthly counseling by mail during the intervening 3-month period, were provided and participants practiced up to 6 months. Both groups were advised to reduce consumptions of animal fat/ fatty meat/poultry, confections, and alcoholic drinks. Additionally, the JD group participants were recommended to consume more fish, soybean products especially natto, vegetables, and seaweed/mushrooms/konjak, and to switch from refined to unrefined cereals or barley. RESULTS: Mean LDL-cholesterol was 125 +/- 29 mg/dL at baseline, and the JD group ( n=49) showed a greater mean LDL-cholesterol decrease than the PJD group (n=49) [- 8 mg/dL in JD vs 1 mg/dL in PJD, difference, -9 mg/dL (95%CI, -17 to 0) p=0.043)], and triglyceride (p=0.023) and insulin (p=0.033) reductions were larger in the JD group than in the PJD group at 6 months. CONCLUSION: Nutrition education for JD intake was suggested to improve serum lipid and metabolic parameters in patients with dyslipidemia.

The Prevalence and Diagnostic Ratio of Familial Hypercholesterolemia (FH) and Proportion of Acute Coronary Syndrome in Japanese FH Patients in a Healthcare Record Database Study.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C). Because of underdiagnosis, acute coronary syndrome (ACS) is often the first clinical manifestation of FH. In Japan, there are few reports on the prevalence and diagnostic ratios of FH and the proportion of ACS among FH patients in clinical settings. METHODS: This retrospective, observational study used anonymized data from electronic healthcare databases between April 2001 and March 2015 of patients who had ≥2 LDL-C measurements recorded after April 2009. The index date was defined as the date of the first LDL-C measurement after April 2009. The primary endpoint was the prevalence of definite or suspected FH; secondary endpoints included the proportion of FH patients hospitalized for ACS, the proportion of patients using lipid-lowering drugs (LLDs), and LDL-C levels. RESULTS: Of the 187,781 patients screened, 1547 had definite or suspected FH (0.8%) based on data from the entire period; 832 patients with definite (n = 299, 0.16%) or suspected FH (n = 533, 0.28%) before the index date were identified in the main analysis cohort. LLDs were used in 214 definite FH patients (71.6%) and 137 suspected FH patients (25.7%). Among definite or suspected FH patients with ACS (n = 84) and without ACS (n = 748), 32.1% and 30.1% with definite FH and 3.2% and 2.4% with suspected FH had LDL-C levels < 2.6 mmol/L (<100 mg/dL), respectively. Sixty patients (7.2%) were hospitalized due to ACS at the index date. CONCLUSIONS: The prevalence of FH in this Japanese cohort of patients with ≥2 LDL-C measurements at hospitals was 0.8%, which is higher than that currently reported in epidemiological studies (0.2-0.5%). Patients with suspected FH, with or without ACS, had poorly controlled LDL-C levels and were undertreated. The proportion of FH patients who were hospitalized due to ACS was 7.2%.

Discrepancy Between Fasting Flow-Mediated Dilation and Parameter of Lipids in Blood: A Randomized Exploratory Study of the Effect of Omega-3 Fatty Acid Ethyl Esters on Vascular Endothelial Function in Patients With Hyperlipidemia.

INTRODUCTION: Omega-3 fatty acid ethyl esters (omega-3), an eicosapentaenoic acid and docosahexaenoic acid preparation (Lotriga®, Takeda Pharmaceutical Company Limited), are approved in Japan to treat triglyceridemia. We investigated the effects of omega-3 on vascular endothelial function, measured by flow-mediated dilation (FMD). METHODS: Patients with dyslipidemia receiving 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors were randomized 1:1 to receive omega-3 at 2 g (QD) or 4 g (2 g BID) for 8 weeks. The primary end point was the change from baseline of fasting  %FMD in each treatment group. Secondary end points included the 4-h postprandial  %FMD and 4-h postprandial triglyceride (TG) level. RESULTS: Thirty-seven patients were randomized to receive omega-3 at 2 g (n = 18) or 4 g (n = 19). Mean fasting %FMD did not increase from baseline to week 8 in the 2-g group (- 1.2%) or 4-g group (- 1.3%). Mean 4-h postprandial %FMD did not change from baseline to week 8 in the 2-g group (0.0%), but increased in the 4-g group (1.0%). Mean 4-h postprandial TG level decreased by 34.7 mg/dl from baseline over week 8 in the 2-g group, with a significantly larger decrease in the 4-g group of 75.9 mg/dl (p < 0.001). No new safety concerns were identified. CONCLUSIONS: Fasting %FMD did not improve after 8 weeks of omega-3 treatment at 2 g or 4 g. After 8 weeks, 4-h postprandial TG levels showed improvement at both doses, with a greater reduction in the 4-g group. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02824432.

Comparison of Food and Nutrient Intakes between Japanese Dyslipidemic Patients with and without Low-Density Lipoprotein Cholesterol Lowering Drug Therapy: A Cross-Sectional Study.

AIM: We aimed to clarify actual food and nutrient intakes in Japanese patients with dyslipidemia. We also compared food and nutrient intakes between patients with and without low-density lipoprotein cholesterol (LDL-C) lowering drug therapy. METHODS: Food and nutrient intakes were assessed employing 3-day weighted dietary records in this cross-sectional study of 104 Japanese outpatients with dyslipidemia, age 30-65 years, not given dietary counseling. Anthropometric and biochemical parameters were measured after an overnight fast. Food and nutrient intakes were compared between patients with versus without LDL-C lowering drug prescriptions. Stepwise multiple regression analysis was performed to identify relationships between the serum LDL-C concentrations and food intakes. RESULTS: Of the 104 patients, 43.3% were prescribed LDL-C lowering drugs, primarily statins. Of the total patients, 83% had lipid intakes over 25% of total energy consumption (%E), exceeding the recommendation for dyslipidemia by the Japan Atherosclerosis Society. Similarly, 77% had saturated fatty acid intakes over 7%E, and 88% had cholesterol intakes over 200 mg per day. Dietary fiber consumption was low (＜25 g) in 97% of patients. Those taking LDL-C lowering drugs consumed less "meat, poultry and processed meat products" and "cereals", and more "fish", "fruits" and "nuts", than patients not taking these drugs (p＜0.05). Food intakes correlating with LDL-C concentrations independently of drug therapy differed between patients taking versus not taking these medications. CONCLUSION: Our results support the necessity of diet therapy for patients with dyslipidemia regardless of whether LDL-C lowering drugs are prescribed.The clinical trial registration number: UMIN000022955.

"Japan Diet" and Health-The Present and Future.

Japan achieved remarkable economic development after World War II, which has led remarkable changes in risk factors of atherosclerotic diseases and led to epidemiological transition in Japan. Nowadays, obesity is pandemic around world, which is same case in Japan. BMI of Japanese population, especially young adult men increased gradually since the 1960s associated with increase in intake of fat as well as decrease in intake of rice, which has been revealed by the annual report of the Ministry of Health, Labour and Welfare. Such changes suggest the change of dietary habit from Japanese style to westernized style. In recent years such changes in lifestyle has been accompanied by a gradual increase in serum cholesterol in the Japanese population, which is associated with increase in the incidence of cardiovascular diseases (CVD). Japanese guidelines recommend "The Japan diet" to prevent CVD, because there are several epidemiological data to show the cardio-preventive effect of fish, soy bean, and vegetables, which are the major component of "The Japan Diet". It is very important to recognize the diet habit is one of culture and that rice plays a pivotal role in "The Japan Diet".

Pharmacokinetics and exploratory efficacy biomarkers of bococizumab, an anti-PCSK9 monoclonal antibody, in hypercholesterolemic Japanese subjects
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OBJECTIVE: Bococizumab, a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, has been shown to reduce low-density lipoprotein cholesterol (LDL-C). Here, we describe the pharmacokinetics and pharmacodynamics of bococizumab and its effect on lipoprotein particle composition and other biomarkers, based on a double-blind, placebo-controlled, randomized, dose-ranging study. MATERIALS AND METHODS: The study consisted of two populations: Japanese subjects with uncontrolled LDL-C (LDL-C ≥ 100 mg/dL) despite treatment with atorvastatin (n = 121) and Japanese subjects naïve to lipid-lowering agents with LDL-C ≥ 130 mg/dL (n = 97). Subjects were randomized to receive either bococizumab 50, 100, or 150 mg or placebo, every 2 weeks. One arm of subjects in the ator-vastatin-treated population received ezetimibe 10 mg instead of bococizumab. RESULTS: In both populations, bococizumab exposure increased with increasing dose, and subjects with lower body weights tended to have higher exposures. Bococizumab treatment was associated with a dose-dependent reduction in LDL particles and a small increase in total high-density lipoprotein (HDL) particles. Significant reductions in lipoprotein-associated phospholipase A2 (Lp-PLA2) were observed for bococizumab-treated subjects but not for subjects treated with placebo or ezetimibe. CONCLUSION: Increased bococizumab dosage resulted in increased exposure. Levels of LDL and HDL particles and biomarkers such as Lp-PLA2 were also altered with bococizumab treatment. (ClinicalTrials.gov identifier: NCT02055976).
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Long-Term Treatment With Evolocumab Among Japanese Patients　- Final Report of the OSLER Open-Label Extension Studies.

BACKGROUND: Treatment with evolocumab reduces mean low-density lipoprotein cholesterol (LDL-C) up to 75% and cardiovascular events by 16% in the first year and 25% thereafter. Methods and Results: Japanese patients with hypercholesterolemia enrolled in the parent YUKAWA-1-2 studies could enroll, once eligible, in the OSLER studies (n=556). OSLER re-randomized patients 2:1 to evolocumab plus standard of care (SOC; evolocumab+SOC) or SOC alone for 1 year; after year 1, patients could enter the all-evolocumab+SOC open-label extension of OSLER. Patients received evolocumab+SOC from the 2nd year through up to 5 years. Long-term efficacy and safety, including antidrug antibodies, were evaluated. Of 556 patients, 532 continued to the all-evolocumab+SOC extension: mean (standard deviation [SD]) age 61 (10) years, 39% female. A total of 91% of 532 patients completed the studies. Mean (SD) LDL-C change from parent-study baseline with evolocumab from a mean (SD) baseline of 142.3 (21.3) and 105.0 (31.1) mg/dL in OSLER-1 and OSLER-2, respectively, was maintained through the end of the study: -58.0% (19.1%) at year 5 in OSLER-1, -62.7% (25.6%) at year 3 in OSLER-2. The overall safety profile of the evolocumab+SOC periods was similar to that of the year-1 controlled period. Antidrug antibodies were detected transiently in 3 patients. No neutralizing antibodies were detected. CONCLUSIONS: Japanese patients who continued evolocumab+SOC for up to 5 years experienced sustained high LDL-C level reduction. Long-term evolocumab+SOC exposure showed no new safety signals.

Influence of blood pressure on the effects of low-dose asprin in elderly patients with multiple atherosclerotic risks.

OBJECTIVE: We examined whether the efficacy of low-dose acetylsalicylic acid (aspirin) for primary prevention of cardiovascular events is influenced by blood pressure (BP) using data from patients aged 60-85 years with hypertension, dyslipidemia, and/or diabetes, but without cardiovascular disease of the Japanese Primary Prevention Project. METHODS: All patients had received aspirin (100 mg/day) or no aspirin. BP subgroups were defined as low (average SBP from the baseline to the year of the events <130 mmHg), moderate (≥130 and <140 mmHg), and high (≥140 mmHg). The mean duration of follow-up was 5.02 years. RESULTS: In hypertensive patients (n = 12 278) aspirin had no significant impact on the primary outcome of death from cardiovascular disease, nonfatal stroke, and nonfatal myocardial infarction. On the other hand, aspirin increased the incidence of serious extracranial hemorrhage [hazard ratio, 1.81; 95% confidence interval (CI), 1.18-2.77; P = 0.0064] and tended to increase hemorrhagic stroke (hazard ratio, 1.75; CI, 0.99-3.07; P = 0.053). Aspirin had no effect on the primary outcome in any of the BP subgroups, and was associated with increased hemorrhagic stroke in the high BP group (hazard ratio, 3.51; CI, 1.29-9.51; P = 0.014); serious extracranial hemorrhage was elevated or tended to elevate in the moderate (hazard ratio, 2.53; CI, 1.18-5.45; P = 0.017) and high (hazard ratio, 2.14; CI, 1.00-4.56; P = 0.050) BP groups. CONCLUSION: In aged Japanese hypertensive patients, these data demonstrated no overall benefit of low-dose aspirin therapy although treatment was associated with an elevated risk of hemorrhagic events.

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.

12-Week Effectiveness and Safety of Low-Density Lipoprotein Cholesterol-Lowering Therapy by Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition in Patients With Familial Hypercholesterolemia and Hypercholesterolemia　- Data From a Real-World Observational Study of Evolocumab in Japan.

Background: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) approved in Japan for the treatment of patients with familial hypercholesterolemia (FH) and hypercholesterolemia (HC). This study assessed the 12-week effectiveness and safety of low-density lipoprotein cholesterol (LDL-C)-lowering therapy by PCSK9 inhibition in patients with FH (homozygous [HoFH] or heterozygous [HeFH]) and HC by analyzing evolocumab data collected in the real-world setting in Japan. Methods and Results: Overall, 427 patients (mean±SD age, 61.6±13.8 years; female, 38.4%; 28 HoFH, 320 HeFH, 79 HC), enrolled from 299 clinical sites, were included in the safety analysis set. The major cardiovascular risk factors were coronary artery disease (77.3%), diabetes mellitus/impaired glucose tolerance (38.6%), and hypertension (65.1%). Median follow-up duration was 85.0 days. After 12 weeks of evolocumab treatment, the mean±SD percent change from baseline in LDL-C was -45.5%±27.0% (n=23) in HoFH (P<0.001 vs. baseline; t-test), -54.2%±29.0% (n=280) in HeFH (P<0.001), and -64.6%±22.4% (n=72) in HC (P<0.001) patients. The incidence of adverse drug reactions was 5.4% (23/427). Conclusions: Results suggest that patients receiving evolocumab treatment in the real-world setting were predominantly those with FH and HC in the secondary prevention group. LDL-C-lowering effectiveness with evolocumab was observed in FH (both HoFH and HeFH) and HC patients.

Efficacy and Safety of Alirocumab in Japanese Patients with Diabetes Mellitus: Post-hoc Subanalysis of ODYSSEY Japan.

AIM: To examine the efficacy and safety of alirocumab in Japanese patients with dyslipidemia with or without diabetes mellitus (DM). METHODS: Patients (n=216) with heterozygous familial hypercholesterolemia (heFH), non-FH at high cardiovascular risk with coronary artery disease (CAD), or category III (primary prevention) were enrolled; 148 (68.5%) patients had a diagnosis of DM at baseline. Patients were randomized (2:1), with stratification factor (heFH, non-FH), to alirocumab (75 mg every 2 weeks [Q2W] with increase to 150 mg if week 8 LDL-C was above predefined limits) or placebo subcutaneously for 52 weeks on top of stable statin therapy. RESULTS: At Week 24, least square (LS) mean±standard error changes in low-density lipoprotein cholesterol (LDL-C) concentration from baseline in alirocumab-treated patients were －63.1±1.6% and －60.8±2.7% in those with and without DM. These LDL-C reductions were maintained to Week 52: －63.0±1.6% (LS mean difference vs placebo －62.4±3.0%; P＜0.0001) with DM and －61.3±2.8% (LS mean difference vs placebo －53.4±4.0%; P＜0.0001) without DM. The most common adverse events in the alirocumab group were nasopharyngitis, back pain, injection site reaction, and fall. No particular safety signals or concerns were noted between DM and non-DM groups at 52 weeks. A dose-increase in alirocumab from 75 to 150 mg Q2W was necessary in two heFH patients, neither of whom had DM. CONCLUSIONS: In high-cardiovascular-risk Japanese patients with hypercholesterolemia on stable statin therapy, alirocumab produced substantial and sustained LDL-C reductions throughout the 52-week study regardless of DM status at baseline, with a similar safety profile to placebo.