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Aims: The study aimed to investigate low-density lipoprotein cholesterol (LDL-C) goal achievement rates in patients receiving LDL-C-lowering therapy using recent real-world data, following the 2017 revision of the Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases (JAS GL2017)., Methods: Patients with documented LDL-C test results were extracted from the Medical Data Vision claims database between July 2018 and June 2021 and divided into three groups according to JAS GL2017: primary prevention high risk (Group I, LDL-C goal ＜120 mg/dL), secondary prevention (Group II, LDL-C goal ＜100 mg/dL), and secondary prevention high risk (Group III, LDL-C goal ＜70 mg/dL)., Results: The mean LDL-C value was 108.7 mg/dL (n=125,235), 94.4 mg/dL (n=57,910), and 90.6 mg/dL (n=33,850) in Groups I, II, and III, respectively. Intensive statin monotherapy (pitavastatin, rosuvastatin, or atorvastatin) was the most frequently prescribed lipid-lowering treatment (21.6%, 30.8%, and 42.7% in Groups I, II, and III, respectively), followed by ezetimibe (2.5%, 7.1%, and 8.5% in Groups I, II, and III, respectively). LDL-C goals were achieved by 65.5%, 60.6%, and 25.4% of patients overall in Groups I, II, and III, respectively. Achievement rates were 83.9%, 75.3%, and 29.5% in patients prescribed intensive statin monotherapy and 82.3%, 86.4%, and 46.4% in those prescribed statin and ezetimibe combinations in Groups I, II, and III, respectively. In Group III, the proportion of patients with familial hypercholesterolemia prescribed statin and ezetimibe combinations achieving LDL-C goals was low (32.5%)., Conclusions: The proportion of patients achieving LDL-C goals for secondary prevention in the high-risk group remains low even with statin and ezetimibe combination therapy.

Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein (LDL)-cholesterol (LDL-C), tendon and skin xanthomas, and premature coronary artery disease (CAD). In Japan, detailed information on the current status of drug therapies for patients with FH has not been reported so far, and their efficacy and safety have not been clarified. After the introduction of ezetimibe, which can further reduce serum LDL-C levels on top of statins, the changes of management for FH patients with these drugs are of particular interest. The current study aimed to evaluate the clinical status of FH heterozygotes and homozygotes, especially focusing on the real-world lipid-lowering drug therapy, attained serum LDL-C levels, and cardiovascular events at registration and during the follow-up., Methods: The FAME Study enrolled 762 heterozygous (including 17 newly diagnosed cases) and 7 homozygous FH patients from hospitals and clinics nationwide. Diagnosis of FH was based upon the criteria defined in the Study Report in 2008 of the Research Committee on Primary Hyperlipidemia supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare. Data analysis was primarily carried on heterozygous FH patients., Results: Xanthoma or thickening of the Achilles tendon was observed in more than 80% of the patients. CAD was recorded in 23% of patients. Patients with parental and sibling CAD accounted for 47% and 24%, respectively. At baseline, patients without CAD who had LDL-C ＜100 mg/dL accounted for 12.3% and those with CAD who had attained the target (LDL-C ＜70 mg/dL) in the secondary prevention accounted for only 1.8%. In the multiple logistic analysis, male sex, age ＞40, heterozygous FH score ＞20, hypertension, and sibling CAD were significantly and positively associated with prevalent CAD, whereas serum HDL-cholesterol levels showed a significant inverse association with CAD. Patients treated with statin alone, statin＋ezetimibe, statin＋resin, or statin＋probucol accounted for 31.1%, 26.3%, 4.0%, and 3.7%, respectively. Patients treated with three-drug combination (statin＋ezetimibe＋resin or statin＋ezetimibe＋probucol) accounted for 7.5%. Statins and ezetimibe were used in 88.0% and 48.0% at the baseline, respectively. Although high-intensity statins were mainly prescribed, statin doses were much lower than those reported in Western countries. The addition of ezetimibe resulted in ~20% reduction in serum LDL-C. CAD was diagnosed in 17 patients with 21 episodes during follow-up. The Cox hazard model analysis demonstrated that male sex, CAD at the baseline, and parental CAD were related to the development of atherosclerotic cardiovascular disease (ASCVD) events. Furthermore, an increase in serum HDL-C was associated with a significant reduction of ASCVD events, while serum LDL-C and triglyceride levels were not related to ASCVD events., Conclusion: The prevalence of CAD in Japanese patients with heterozygous FH is still very high. In most of the cases, the target level of serum LDL-C was not achieved for primary and secondary prevention of CAD, suggesting that a more aggressive LDL-C lowering and appropriate management of residual risks are necessary.

Background: Controversy remains regarding the influence of lipid-lowering therapy on the eicosapentaenoic acid/arachidonic acid ratio., Objective: This study aimed to clarify the effects of lipid-lowering therapy on the eicosapentaenoic acid/arachidonic acid ratio in patients with acute coronary syndrome (ACS)., Methods: This was a post hoc sub-analysis of the Heart Institute of Japan-PRoper level of lipid-lowering with pitavastatin and ezetimibe in ACS study. We compared the eicosapentaenoic acid/arachidonic acid ratio changes from baseline to the 3-month follow-up after contemporary lipid-lowering therapy with pitavastatin + ezetimibe therapy and pitavastatin mono-therapy., Results: Among patients with ACS and dyslipidemia, the eicosapentaenoic acid/arachidonic acid increased significantly in the pitavastatin mono-therapy group (0.40 ± 0.26 to 0.46 ± 0.34, P < .0001) but did not increase in the pitavastatin + ezetimibe group (0.37 ± 0.22 to 0.38 ± 0.27, P = .18). When the analysis was limited to patients who received 2 mg/day of pitavastatin during the follow-up period, these trends in changes of the eicosapentaenoic acid/arachidonic acid ratio remained unchanged. Multivariate analysis showed that ezetimibe use ( P = .005; β = 0.09), ST-elevation myocardial infarction ( P = .04; β = -0.01), and baseline low-density lipoprotein cholesterol (LDL-C) level ( P = .0003; β = 0.12) were independent predictors of the percentage change in the eicosapentaenoic acid/arachidonic acid ratio. These trends were similar even when the analysis was limited to patients who did not take statins at enrollment., Conclusion: Standard lipid-lowering therapy with pitavastatin mono-therapy improved the eicosapentaenoic acid/arachidonic acid ratio for patients with ACS. Intensive lipid-lowering therapy with pitavastatin + ezetimibe did not improve the eicosapentaenoic acid/arachidonic acid ratio, although LDL-C decreased significantly. Inhibition of the improvement in the eicosapentaenoic acid/arachidonic acid ratio by adding ezetimibe may affect cardiovascular disease prognosis.

Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients., Methods: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke., Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P =0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P =0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P =0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups., Conclusions: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Background and Aims: We aimed to examine the effect of serum sitosterol, a cholesterol absorption marker, on clinical outcomes in acute coronary syndrome patients with dyslipidaemia., Methods: This is a sub-analysis of the HIJ-PROPER trial that assesses the effect of aggressive low-density lipoprotein cholesterol (LDL-C) lowering treatment with pitavastatin + ezetimibe in 1734 acute coronary syndrome (ACS) patients with dyslipidaemia. Patients were divided into two groups based on sitosterol level at enrolment (cut-off value was 2.2 μg/mL; a median of baseline sitosterol level), and clinical outcomes were examined., Results: The mean LDL-C level after 3 years in the low sitosterol group was 84.8 ± 20.1 mg/dL with pitavastatin-monotherapy and 64.6 ± 20.3 mg/dL with pitavastatin + ezetimibe, while corresponding values in the high sitosterol group were 91.0 ± 22.9 mg/dL and 71.1 ± 23.3 mg/dL, respectively. In the high sitosterol group, the Kaplan-Meier event rate for the primary endpoint at 3 years was 26.0% in the pitavastatin + ezetimibe group, as compared with 34.3% in the pitavastatin-monotherapy group (hazard ratio, 0.71; 95% confidence interval, 0.56-0.91; p = 0.006, p-value for interaction = 0.010). However, in the low sitosterol group, there was no significant reduction of the primary endpoint by pitavastatin + ezetimibe therapy., Conclusions: Aggressive lipid-lowering treatment with ezetimibe had a positive effect on clinical outcomes in the high sitosterol subset of ACS patients with dyslipidaemia, but not in the low sitosterol subset. This effect was independent of LDL-C reduction and suggests that sitosterol measurement on admission in ACS patients might contribute to a "personalised" lipid-lowering approach., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: This study examined treatment patterns, possible statin intolerance, and incidence of cardiovascular events (CVEs) in 2 cohorts of patients with high cardiovascular risk (i.e., patients with atherosclerotic cardiovascular disease [ASCVD] and patients with diabetes mellitus).Methods and Results:A retrospective cohort study examined adults initiating either a statin or ezetimibe from 1 January 2006 to 31 May 2014 in the Japan Medical Data Center database. The first observed statin or ezetimibe prescription defined the index date. Patients had ≥12 months of pre- and post-index date plan enrollment. Two high-risk cohorts, the ASCVD cohort and diabetes cohort, were created based on diagnoses observed during the 12 months' pre-index date. Treatment patterns, possible statin intolerance, and incidence of CVEs were reported. In the ASCVD cohort (n=5,302), 32.9% discontinued therapy, 7.7% switched to a non-index statin or non-statin lipid-lowering therapy, and 11.2% augmented index therapy in the 12 months' post-index date; only 0.3% were using high-intensity statins and 10% had possible statin intolerance. Also, 8.1% had any new CVE during the follow-up period. Treatment patterns and incidence of CVEs among the diabetes cohort were similar to those of the ASCVD cohort., Conclusions: High cardiovascular risk Japanese patients had frequent treatment modifications, although use of high-intensity statin doses was rare. These patterns may indicate that alternative therapies for lipid lowering are needed.

Introduction: The present study is the largest registry study ever conducted in Japan exploring the prevalence of familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS). Our study aims to (1) evaluate the status of lipid management and the subsequent risk of major cardiovascular events following hospitalisation of Japanese patients with ACS in real-world clinical practice; (2) determine the proportion of Japanese patients with ACS who achieve the lipid management goal and have a reduction of event risks with strict lipid management (low-density lipoprotein-cholesterol <1.81 mmol/L); (3) determine the prevalence of FH and (4) investigate the clinical significance of proprotein convertase subtilisin kexin 9 (PCSK9) level., Methods and Analysis: We will conduct a multicentre, prospective, observational study of approximately 2000 Japanese patients with ACS with/without FH hospitalised between April 2015 and August 2016. The primary end point is the incidence of major adverse cardiovascular events (MACEs) after initial hospitalisation. The secondary end points are (1) MACE developed from visit 1 to visit 2 (day 30); (2) MACE developed from visit 2 (day 30) to visit 5 (day 730); (3) treatment rate by lipid-lowering therapies (any statin or intensive, PCSK9 inhibitor, fibrates and ezetimibe); (4) incidence of events by the addition of the following outcomes to the primary end point: coronary revascularisation due to myocardial ischaemia, revascularisation other than coronary artery, inpatient treatment for occurrence or exacerbation of heart failure, transient ischaemic attack, acute arterial occlusion, central retinal artery occlusion and other adverse events prolonging or requiring hospitalisation and (5) proportion of subjects achieving target lipid levels., Ethics and Dissemination: The study protocol was submitted to the ethical review committee of each participating centre for approval. Participation in the study is voluntary and anonymous. The study findings will be disseminated in international peer-reviewed journals and presented at relevant conferences., Clinical Trial Registration: UMIN000018946., Competing Interests: Competing interests: KU is an employee of Sanofi. MN, AH, JA, AN, HA and MH-S have received consultation fees from Sanofi., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aim: Cholesterol absorption has been suggested to be an independent risk factor for cerebral and cardiovascular events. We studied the clinical efficacy of ezetimibe in Japanese patients with type 2 diabetes mellitus complicated by dyslipidemia, in whom increased cholesterol absorption had been reported., Subjects and Methods: Ninety-six patients with type 2 diabetes complicated by dyslipidemia received ezetimibe at 10 mg/day for 12 weeks. The lipid profile, a cholesterol synthesis marker (lathosterol), and cholesterol absorption markers (cholestanol, sitosterol, and campesterol) were measured before and after the therapy to evaluate the clinical efficacy of ezetimibe., Results: Serum low-density lipoprotein-cholesterol (LDL-C) levels were positively associated with cholesterol absorption markers but not associated with a cholesterol synthesis marker, suggesting that serum LDL-C levels are more strongly related to cholesterol absorption than synthesis. During the 12-week ezetimibe treatment period, cholesterol absorption markers significantly decreased, and serum lipid profiles, including LDL-C levels, significantly improved. The LDL-C-lowering rate was greater in those patients who had been receiving statin therapy and were newly started on ezetimibe additionally than in the ezetimibe monotherapy group (-31.4% vs. -18.4%; P<0.001)., Conclusions: It is suggested that ezetimibe improves the lipid profile in Japanese type 2 diabetes patients with dyslipidemia through the substantial reduction of cholesterol absorption.