Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease.

BACKGROUND: The JELIS trial examined the preventive effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemia. Previous investigators have reported that patients with peripheral artery disease (PAD) have a poor prognosis due to the potential risk for CAD. We conducted a subanalysis to examine whether the incidence of CAD was high in patients with PAD and whether EPA prevented the occurrence of CAD. METHODS AND RESULTS: Of 18,645 the Japan EPA lipid intervention study (JELIS) patients, 223 had PAD (control group; complicated (n=77), newly diagnosed (n=29), EPA group; complicated (n=96), newly diagnosed (n=21)). We analyzed the incidence of major coronary events (MCE) in the 2 groups. Cox proportional hazard ratio adjusted for baseline risk factor levels was used to test differences between the 2 groups. The incidence of MCE in the control group was significantly higher in patients complicated with PAD and in those newly diagnosed with PAD than in patients without PAD (complicated: hazard ratio 1.97, P=0.039; newly diagnosed: hazard ratio 2.88, P=0.030). As for patients with PAD, the EPA group had a significantly lower MCE hazard ratio than the control group (hazard ratio 0.44, 95% confidence interval 0.19-0.97, P=0.041). CONCLUSIONS: Subanalysis of the JELIS trial demonstrated that in patients with PAD the incidence of CAD was higher than in controls, and that EPA markedly reduced the occurrence of CAD in those patients.

Usefulness of pravastatin in primary prevention of cardiovascular events in women: analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA study).

BACKGROUND: It is well known that statins reduce the risk of cardiovascular disease. However, the effect of statins in women for the primary prevention of cardiovascular disease has not been determined. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events in women with data from a large-scale primary prevention trial with pravastatin. METHODS AND RESULTS: Patients with hypercholesterolemia (5.7 to 7.0 mmol/L) and no history of coronary heart disease or stroke were randomized to diet or diet plus pravastatin 10 to 20 mg/d and followed up for > or = 5 years. We investigated the effect of diet plus pravastatin treatment on cardiovascular events in 5356 women during the 5-year follow-up. The incidence of cardiovascular events in the women was 2 to 3 times lower than that in men. The occurrence of cardiovascular events was 26% to 37% lower in the diet plus pravastatin treatment group than in the diet alone group. Although these differences did not reach statistical significance, the overall risk reductions were similar to those in men. Notably, women > or = 60 years of age treated with diet plus pravastatin had markedly higher risk reductions for coronary heart disease (45%), coronary heart disease plus cerebral infarction (50%), and stroke (64%) than did women treated with diet alone. CONCLUSIONS: Treatment with pravastatin in women with elevated cholesterol but no history of cardiovascular disease provides a benefit similar to that seen in men, and this benefit is more marked in older women. This treatment should be considered routinely for primary cardiovascular protection in women with elevated cholesterol levels.

Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial.

BACKGROUND AND PURPOSE: The JELIS trial examined the preventive effect of eicosapentaenoic acid (EPA) against coronary artery diseases. Hypercholesterolemic patients received statin only (no EPA group: n=9319) or statin with EPA (EPA group: n=9326) for around 5 years. EPA significantly suppressed the incidence of coronary events in previous analysis. Herein, we investigated the effects of EPA on the primary and secondary prevention of stroke. METHODS: We conducted a subanalysis of JELIS with respect to stroke incidence in the primary and secondary prevention subgroups defined as those without and with a prior history of stroke using Cox proportional hazard ratios, adjusted for baseline risk factor levels. RESULTS: As for primary prevention of stroke, this occurred in 114 (1.3%) of 8862 no EPA group and in 133 (1.5%) of 8841 EPA group. No statistically significant difference in total stroke incidence (Hazard Ratio, 1.08; 95% confidence interval, 0.95 to 1.22) was observed between the no EPA and the EPA groups. In the secondary prevention subgroup, stroke occurred in 48 (10.5%) of 457 no EPA group and in 33 (6.8%) of 485 EPA group, showing a 20% relative reduction in recurrent stroke in the EPA group (Hazard Ratio, 0.80; 95% confidence interval, 0.64 to 0.997). CONCLUSIONS: Administration of highly purified EPA appeared to reduce the risk of recurrent stroke in a Japanese population of hypercholesterolemic patients receiving low-dose statin therapy. Further research is needed to determine whether similar benefits are found in other populations with lower levels of fish intake. The trial is registered at ClinicalTrials.gov (number NCT00231738).

Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.

BACKGROUND: Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids protects against mortality from coronary artery disease. We aimed to test the hypothesis that long-term use of eicosapentaenoic acid (EPA) is effective for prevention of major coronary events in hypercholesterolaemic patients in Japan who consume a large amount of fish. METHODS: 18 645 patients with a total cholesterol of 6.5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999. Patients were randomly assigned to receive either 1800 mg of EPA daily with statin (EPA group; n=9326) or statin only (controls; n=9319) with a 5-year follow-up. The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting. Analysis was by intention-to-treat. The study was registered at ClinicalTrials.gov, number NCT00231738. FINDINGS: At mean follow-up of 4.6 years, we detected the primary endpoint in 262 (2.8%) patients in the EPA group and 324 (3.5%) in controls-a 19% relative reduction in major coronary events (p=0.011). Post-treatment LDL cholesterol concentrations decreased 25%, from 4.7 mmol/L in both groups. Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events. Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group. Sudden cardiac death and coronary death did not differ between groups. In patients with a history of coronary artery disease who were given EPA treatment, major coronary events were reduced by 19% (secondary prevention subgroup: 158 [8.7%] in the EPA group vs 197 [10.7%] in the control group; p=0.048). In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18%, but this finding was not significant (104 [1.4%] in the EPA group vs 127 [1.7%] in the control group; p=0.132). INTERPRETATION: EPA is a promising treatment for prevention of major coronary events, and especially non-fatal coronary events, in Japanese hypercholesterolaemic patients.

Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.

BACKGROUND: Evidence-based treatment for hypercholesterolaemia in Japan has been hindered by the lack of direct evidence in this population. Our aim was to assess whether evidence for treatment with statins derived from western populations can be extrapolated to the Japanese population. METHODS: In this prospective, randomised, open-labelled, blinded study, patients with hypercholesterolaemia (total cholesterol 5.69-6.98 mmol/L) and no history of coronary heart disease or stroke were randomly assigned diet or diet plus 10-20 mg pravastatin daily. The primary endpoint was the first occurrence of coronary heart disease. Statistical analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00211705. FINDINGS: 3966 patients were randomly assigned to the diet group and 3866 to the diet plus pravastatin group. Mean follow-up was 5.3 years. At the end of study, 471 and 522 patients had withdrawn, died, or been lost to follow-up in the diet and diet plus pravastatin groups, respectively. Mean total cholesterol was reduced by 2.1% (from 6.27 mmol/L to 6.13 mmol/L) and 11.5% (from 6.27 mmol/L to 5.55 mmol/L) and mean LDL cholesterol by 3.2% (from 4.05 mmol/L to 3.90 mmol/L) and 18.0% (from 4.05 mmol/L to 3.31 mmol/L) in the diet and the diet plus pravastatin groups, respectively. Coronary heart disease was significantly lower in the diet plus pravastatin group than in the diet alone group (66 events vs 101 events; HR 0.67, 95% CI 0.49-0.91; p=0.01). There was no difference in the incidence of malignant neoplasms or other serious adverse events between the two groups. INTERPRETATION: Treatment with a low dose of pravastatin reduces the risk of coronary heart disease in Japan by much the same amount as higher doses have shown in Europe and the USA.

Risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes mellitus on low-dose simvastatin therapy: implication from Japan Lipid Intervention Trial (J-LIT).

Hypercholesterolemic patients with type 2 diabetes mellitus are at increased risk of coronary heart disease (CHD); however, direct evidence is very limited in Japanese patients. The J-LIT is the first nationwide study conducted to assess the relationship between serum lipid levels and development of coronary events in Japanese hypercholesterolemic patients. We analyzed the coronary events in the J-LIT study subjects by having type 2 diabetes or not. Of the total 41,801 subjects without prior CHD who received open-label simvastatin, 5mg/day, 6554 (male 40.2%, age 57.8+/-7.8) subjects had type 2 diabetes, while 35,247 (male 30.0%, age 57.8+/-7.9) did not. In this analysis, relative coronary event risks based on a 0.26 mmol/l (10mg/dl) increase in low density lipoprotein-cholesterol (LDL-C), were similar between hypercholesterolemic subjects with and without type 2 diabetes (17.3% versus 19.4%). Although all subjects were treated with simvastatin, the subjects with type 2 diabetes have significantly more coronary events compared to the subjects without type 2 diabetes (1.80/1000 and 0.76/1000 patient-years, respectively). Given the results above, to reduce the risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes, careful and strict cholesterol management is needed in addition to the control of blood glucose.

Effects of hypertension and type 2 diabetes mellitus on the risk of total cardiovascular events in Japanese patients with hypercholesterolemia: implications from the Japan Lipid Intervention Trial (J-LIT).

Hyperlipidemia, hypertension, and diabetes mellitus (DM) are well-established risk factors for cardiovascular disease. We analyzed the cardiovascular events in hyperlipidemic patients with or without DM who were administered open-labeled simvastatin in groups stratified by blood pressure level using data from the Japan Lipid Intervention Trial (J-LIT). Hyperlipidemic patients with DM (n=6,288) had significantly more cardiovascular events than those without DM (n=33,933). The incidence rates of total cardiovascular events in the Non-DM and DM groups were 15.40 and 25.76 per 1,000 patients for the 6-year period, respectively. The relative risk of total cardiovascular events in the DM vs. the Non-DM group was 1.68, and the relative risk was significantly higher in the DM than in the Non-DM group. The relative risks of total cardiovascular events were significantly higher in DM and Non-DM patients whose systolic blood pressure (SBP) was greater than or equal to 130 mmHg compared to that of Non-DM patients whose SBP was less than 130 mmHg, and in DM and Non-DM patients whose diastolic blood pressure (DBP) was greater than or equal to 80 mmHg compared to that of Non-DM patients whose DBP was less than 80 mmHg. In all groups stratified by SBP and DBP, relative risks of total cardiovascular events were higher in DM patients than in Non-DM patients. For patients with hypercholesterolemia and DM, blood pressure should be strictly controlled in order to prevent both coronary events and stroke. These results are in good agreement with the JNC 7 and the ESH/ESC guidelines for DM patients, which recommended that the SBP and DBP be less than 130 and 80 mmHg, respectively.

Polymorphisms of apolipoprotein e and methylenetetrahydrofolate reductase in the Japanese population.

AIM: The aim of this study is to analyze the effect of apolipoprotein E (apo E) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms on serum lipid and homocysteine levels in the general Japanese population. METHODS: We analyzed the polymorphisms in individuals randomly selected from among participants of Serum Lipid Survey 2000. RESULTS: The frequency of the epsilon2, epsilon3, and epsilon4 alleles of APOE was 4.2, 85.3, and 10.5%, respectively. Individuals with the genotype epsilon4/epsilon4 had the highest total and low-density lipoprotein (LDL) cholesterol levels, while those with epsilon2/epsilon2 had the lowest. Individuals with the epsilon2/epsilon2 and epsilon2/epsilon4 genotypes had higher remnant-like particles (RLP)-cholesterol levels than those with epsilon2epsilon3, epsilon3epsilon3, and epsilon3epsilon4. There was a trend for individuals with the epsilon2/epsilon4 and epsilon2/epsilon2 genotypes to have higher triglyceride levels, although the difference was not significant. The presence of the T allele in a MTHFR polymorphism (C667T) was associated with higher homocysteine levels, which is more prominent in men than in women. CONCLUSION: Thus in our large-scale analysis we have shown that RLP-cholesterol is better associated with, APOE genotype than triglyceride and the effect of the T allele on MTHFR polymorphism (C667T) homocysteine levels is more prominent in men than in women among Japanese.

Efficacy and Safety of Long-term Coadministration of Fenofibrate and Ezetimibe in Patients with Combined Hyperlipidemia: Results of the EFECTL Study.

AIM: We investigated the safety and efficacy of a long-term combination therapy with fenofibrate and ezetimibe in Japanese patients with combined hyperlipidemia, in comparison with fenofibrate or ezetimibe alone. METHODS: The study was a three-arm parallel-group, open-label randomized trial. Eligible patients were assigned to a combination therapy with fenofibrate (200 mg/day in capsule form or 160 mg/day in tablet form) and ezetimibe (10 mg/day), the fenofibrate monotherapy, or the ezetimibe monotherapy, which lasted for 52 weeks. The changes in serum low-density lipoprotein (LDL) cholesterol and triglycerides were the primary outcomes. RESULTS: A total of 236 patients were assigned to one of the three treatments, and the number of patients included in the final analysis was 107 in the combination therapy, 52 in the fenofibrate monotherapy, and 51 in the ezetimibe monotherapy. Mean±SD changes in LDL cholesterol were -24.2%±14.7% with combination therapy, -16.0%±16.0% with fenofibrate alone, and -17.4%± 10.1% with ezetimibe alone. The combination therapy resulted in a significantly greater reduction in LDL cholesterol as compared with each monotherapy (p＜0.01 for each). The corresponding values for triglycerides were -40.0%±29.5%, -40.1%±28.7%, and -3.4%±32.6%, respectively. Fenofibrate use was associated with some changes in laboratory measurements, but there was no differential adverse effect between the combination therapy and fenofibrate monotherapy. CONCLUSION: The combination therapy with fenofibrate and ezetimibe substantially reduces concentrations of LDL cholesterol and triglycerides and is safe in a long-term treatment in Japanese patients with combined hyperlipidemia.

Prevalence of metabolic syndrome in the general Japanese population in 2000.

To determine the prevalence of metabolic syndrome in the Japanese general population, we analyzed data from a nationwide survey conducted in 2000. According to the Japanese new diagnostic criteria for metabolic syndrome in 2005, we analyzed 3,264 people aged from 20 to 79 (men, 1,917; women, 1,347) from the total participants. The incidence of metabolic syndrome was 7.8%. Men had a higher incidence (12.1%) than women (1.7%). Most of the women satisfying the criteria were 50 years old or over, while the incidence in men started to rise from their 30s. When we applied the criteria of Adult Treatment Panel III, the incidence was about 3-fold higher. In this population visceral obesity was associated with metabolic abnormalities, such as higher LDL-cholesterol, triglyceride, glucose, and blood pressure and lower HDL-cholesterol. Thus we determined the incidence of metabolic syndrome and each metabolic abnormality in the Japanese general population in 2000 and found an association of visceral obesity with metabolic abnormalities. Intervention to reduce the incidence of metabolic syndrome in Japan is necessary to reduce the risk of cardiovascular disease.

Effects of diacylglycerol oil on adiposity in obese children: initial communication.

Several studies have shown that diacylglycerol (DAG) oil may suppress accumulation of body fat in adults compared to triacylglycerol (TAG) oil. In this study, we investigated the effect of DAG oil as part of dietetic therapy in obese children. The participants were 11 male and female obese children who were under treatment at the outpatient clinic (four boys, seven girls, age: 7-17 years old). Daily-use cooking oil was changed to DAG oil, and the effects on abdominal fat areas, adipocytokines, and serum lipids were investigated. The total and subcutaneous fat areas significantly decreased in the 5th month after ingestion of DAG oil. Leptin was significantly lower than the initial level after ingestion of DAG oil. The ingestion of DAG oil decreased both the abdominal fat area and leptin in obese children, suggesting that DAG oil prevents obesity in children as well as in adults.

The risk of cardiovascular events in Japanese hypertensive patients with hypercholesterolemia: sub-analysis of the Japan Lipid Intervention Trial (J-LIT) Study, a large-scale observational cohort study.

Coronary events and stroke are leading causes of death in Japan. However, the effects of hypertension on the risk of coronary events and stroke have not been well established in Japanese hypercholesterolemic patients. This study aimed to determine the relationship between the risk of coronary events or stroke and blood pressure and cholesterol levels during low-dose simvastatin treatment using data from the Japan Lipid Intervention Trial (J-LIT) study (a large scale nationwide cohort study). In the present study, 47,294 hypercholesterolemic patients were treated with open-labeled simvastatin (5 to 10 mg/day) for 6 years by a large number of physicians in a clinical setting. The adjusted incidence rates of coronary events in males and females were 8.9 and 2.3 and those of stroke were 17.6 and 11.3/1000 patients during the 6-year period, respectively. The incidence rate of stroke was higher than that of coronary events in both males and females. An obvious sex difference was observed in terms of the incidence of coronary events. The risk of coronary events, stroke, and total cardiovascular events were increased, with elevations in blood pressure observed in patients treated for hypercholesterolemia. The risk of total cardiovascular events in the groups exhibiting less lipid control increased, with lower blood pressure levels than those of the well-controlled group. For patients with hypercholesterolemia and hypertension, blood pressure should be strictly controlled in order to prevent both coronary events and stroke, and the serum total cholesterol levels should be maintained at low levels as well.

Serum lipid survey and its recent trend in the general Japanese population in 2000.

To determine the recent serum lipid levels and other serum variables in the general Japanese population and trends in their changes over the past 40 years, a nationwide survey of serum lipid levels was conducted in 36 institutes from various districts around Japan in 2000. The total number of subjects was 12,839, aged 4 through 99 years. The mean total cholesterol level was 201 mg/dl; 202 mg/dl in men and 200 mg/dl in women. The mean HDL-cholesterol level was 59 mg/dl; 55 mg/dl in men and 65 mg/dl in women. The mean LDL-cholesterol level was 118 mg/dl; 121 mg/dl in men and 115 mg/dl in women. The mean triglyceride level was 118 mg/dl; 136 mg/dl in men and 92 mg/dl in women. The total cholesterol level slightly increased by 5 mg/dl in 10 years. Although the triglyceride level in women did not change, the triglyceride level in men increased over 10 years, especially in the 30s through 70s age bracket, indicating a possible increase in metabolic syndromes in the future. The present results will become the standard serum lipid level data for the Japanese people, and succeeding 10-year surveys will clarify the trends of lipid levels in this country.

Polymorphisms in four genes related to triglyceride and HDL-cholesterol levels in the general Japanese population in 2000.

We studied the association of six common polymorphisms of four genes related to lipid metabolism with serum lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the genes for cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic lipase (LIPC), and apolipoprotein CIII (APOC3), and studied 2267 individuals randomly selected from the participants of Serum Lipid Survey 2000. There was a significant association of CETP polymorphism (D442G, Int14 +1 G --> A, and TaqIB), LPL polymorphism (S447X), and LIPC polymorphism (-514 --> CT) with HDL-cholesterol levels. We also found a significant association of LPL polymorphism (S447X) and APOC3 polymorphism (SstI) with triglyceride levels. This is the largest database showing the association of common genetic variants in lipid metabolism with serum lipid levels in the general Japanese population. Further study is necessary to elucidate the role of these gene polymorphisms in cardiovascular events.

A randomized, double-blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia.

Pitavastatin (p-INN) is a novel and fully synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, with a cholesterol-lowering action stronger than that of other statins currently in use. A 12-week, multi-center, randomized, double-blind, controlled study was conducted to confirm the efficacy and safety of pitavastatin compared with pravastatin, an agent for using to reduce low density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. Patients were recruited at 43 institutes in Japan. Following more than 4 weeks run-in period, 240 patients were randomized to receive 2 mg of pitavastatin or 10 mg of pravastatin daily. At 12 weeks post-randomization, the pitavastatin group showed significantly lower LDL-C levels by -37.6% from baseline compared with -18.4% in the pravastatin group (P<0.05). Pitavastatin also significantly lowered total cholesterol (TC) by -28.2% compared with -14.0% of pravastatin (P<0.05). The LDL-C target level of <140 mg/dl was attained in 75% of the patients treated with pitavastatin, compared with 36% of those in the pravastatin group (P<0.05). Pitavastatin also significantly reduced triglycerides (TG), apo B, C-II and C-III, compared with pravastatin, and increased HDL-C, apo A-I and A-II, to the same extent of pravastatin. Safety was assessed by monitoring adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. These results indicated that pitavastatin was more effective than pravastatin, and both drugs were well-tolerated in the treatment of hypercholesterolemia.

Primary cardiovascular events and serum lipid levels in elderly Japanese with hypercholesterolemia undergoing 6-year simvastatin treatment: a subanalysis of the Japan lipid intervention trial.

OBJECTIVES: To determine the relationship between serum lipid levels and the incidence of coronary events in older Japanese hypercholesterolemic patients without prior coronary heart disease (CHD). DESIGN: Post hoc subanalysis of the results in the Japan Lipid Intervention Trial. SETTING: A large-scale cohort observational study conducted throughout Japan. PARTICIPANTS: Men aged 35 to 70 and postmenopausal women younger than 70 with serum total cholesterol (TC) level of 220 mg/dL or greater treated for 6 years with low-dose simvastatin (52,421 total patients). After exclusion of 5,127 patients because of prior CHD and 4,934 patients because of incomplete data, 42,360 patients were divided into an older (9,860 patients, aged 65-70, mean age 67.1) and younger (32,500 patients, younger than 65, mean age 54.9) group and analyzed. MEASUREMENTS: Fasting serum lipid levels were measured every 6 months. Major coronary events, including fatal or nonfatal myocardial infarction, and sudden cardiac death as the primary endpoint and other cardiovascular diseases, including onset of angina pectoris, cerebrovascular events, and any causes of death, as the secondary endpoints were monitored. RESULTS: Simvastatin treatment in older patients was as safe and effective as in younger patients. Incident rates of major coronary events were 1.30 per 1,000 patient-years in the older group and 0.80 per 1,000 patient-years in the younger group. The incidence of a major coronary event was correlated to serum TC and low-density lipoprotein cholesterol (LDL-C) levels in both groups. The absolute risk of major coronary events in the older group was higher than in the younger group at any level of LDL-C, whereas the relative risk increased by 1.7% with an elevation of each 1 mg/dL LDL-C level in both groups. In the older group, the risk of major coronary events also increased as triglyceride level increased, whereas the risk decreased as high-density lipoprotein cholesterol level increased above 60 md/dL. CONCLUSION: The LDL-C level-dependent increase of relative risk of CHD was similar in elderly and younger patients, whereas the absolute risk at any LDL-C level in elderly patients was higher than in younger patients.

A retrospective meta-analysis of the efficacy and tolerability of fenofibrate 300 mg/d on high-density lipoprotein cholesterol levels in randomized, double-blind, comparative studies conducted in Japan.

BACKGROUND: Low levels of plasma high-density lipoprotein cholesterol (HDL-C) represent an important risk factor for coronary heart disease (CHD). Increasing HDL-C by 1 mg/dL decreases the incidence of CHD by 2% to 3%. Fenofibrate increases HDL-C by ∼23%, to ≥40 mg/dL, and may be effective in preventing CHD. OBJECTIVE: The aim of this study was to assess the effects of fenofibrate on HDL-C in patients treated for 12 weeks in 3 randomized, double-blind, comparative studies conducted in Japan. Changes in total cholesterol (TC) and triglycerides (TG), effects on HDL-C and apolipoprotein (apo) A-I and A-II by TG level, and effects on serum lipid levels by type of hyperlipidemia were the secondary end points. METHODS: Changes in HDL-C levels, as well as TC and TG levels, were analyzed in patients who received fenofibrate 300 mg/d for 12 weeks. Patients aged 20 to 80 years with mean TC ≥220 mg/dL (hypercholesterolemia), TG ≥150 mg/dL (hypertriglyceridemia), or both (combined hyperlipidemia) were considered assessable. RESULTS: In this retrospective meta-analysis conducted at Grelan Pharmaceutical Co. Ltd. (Tokyo, Japan), data from 263 patients (137 women, 126 men; mean [SD] age, 56.0 [10.8] years; range, 25-79 years) were included. The mean (SD) HDL-C level increased significantly, from 46.1 (0.9) mg/dL to 55.9 (1.0) mg/dL after 12 weeks of treatment with fenofibrate (P<0.001). Serum TC and TG decreased significantly (both P<0.001). HDL-C elevation was greater in patients with TG ≥150 mg/dL than in patients with TG<150 mg/dL, although apo A-I and A-II changes were the same in both groups. HDL-C increased in every type of hyperlipidemia, 14.9% in hypercholesterolemia, 22.0% in hypertriglyceridemia, and 33.5% in combined hyperlipidemia. Baseline HDL-C levels were <40 mg/dL in 93 patients (group 1) and ≥40 mg/dL in 170 patients (group 2). Mean HDL-C levels increased significantly in both groups during the treatment period, from 32.6 (0.6) mg/dL to 42.6 (1.0) mg/dL in group 1 and from 53.5 (0.9) mg/dL to 63.1 (1.1) mg/dL in group 2 (both P<0.001). One patient (0.3%) of the 331 included in the tolerability analysis experienced a serious adverse effect (jaundice). CONCLUSION: In this study of patients with hypercholesterolemia, hypertriglyceridemia, or combined hyperlipidemia, 12-week treatment with fenofibrate 300 mg/d was effective and generally well tolerated, with the possible exception of transient changes in aminotransferases. HDL-C was increased in all patients to ∼40 mg/dL, the target level.

[Hypertriglyceridemia as a cause of atherosclerosis].

Many observational studies have investigated whether elevated levels of serum triglyceride are associated with increased risk of coronary heart disease. The results of these studies have been inconsistent. Recently, however, evidences are accumulating to suggest that hypertriglyceridemia is an independent risk factor for coronary heart disease. Elevated levels of serum triglyceride are associated with four pathogenic conditions which are considered to accelerate atherosclerosis. These are decreased serum HDL cholesterol levels, increased remnant lipoproteins, increased small dense LDLs, and increased thrombogenic conditions. The results of primary and secondary prevention studies support the concept that some types of hypertriglyceridemia will be the cause of atherosclerosis.

Risk factors for cardiovascular events in Japanese patients treated with fluvastatin from the long-term event monitoring (LEM) study.

OBJECTIVE: The long-term event monitoring (LEM) study evaluated the lipid-lowering efficacy and safety of fluvastatin in Japanese patients with hypercholesterolemia. The present sub-analysis focused on the impact of risk factors on event prevention. METHODS: In the LEM study, patients (n=21,139) who started fluvastatin between 2000/4/1 and 2002/3/31 in Japan were prospectively registered and followed up for 3 years (secondary prevention cohort) or 5 years (primary prevention cohort). RESULTS: Of the patients registered, 19,084 were included in this sub-analysis. The secondary prevention group, demonstrated 8.27- and 2.89-fold higher incidence in cardiac events and cerebral events, respectively compared with the primary prevention group (P < 0.001). Complications of cerebrovascular disease demonstrated a 2.22- and 5.29-fold higher incidence in cardiac events and cerebral events (P < 0.01 and P < 0.001, respectively). Presence of diabetes mellitus (DM) in patients without complication significantly increased the incidence in both cardiac events (2.37) and cerebral events (2.15) as compared with non-DM patients for primary prevention (P < 0.001 and P < 0.01, respectively). For the secondary prevention, DM patients with complication of cardiac disease showed a significantly higher incidence in both cardiac events (1.59) and cerebral events (3.79) compared with non-DM patients (P < 0.05 and P < 0.01, respectively). In contrast, DM patients with complications of cerebrovascular disease showed a significantly higher incidence in cerebral events (2.58, P < 0.05), but not cardiac events compared with non-DM patients. Similarly, the presence of hypertension significantly increased the incidence in both cardiac (1.64) and cerebral events (1.81) for primary prevention (P < 0.01 and P < 0.05, respectively). For secondary prevention, hypertension in patients with complication of cardiac or cerebrovascular disease did not affect incidence in both cardiac and cerebral events. In the patients without complication, high triglycerides and low high density lipoprotein cholesterol (HDL-C), but not low density lipoprotein cholesterol (LDL-C), increased cerebral events, while only LDL-C significantly increased cardiac events. For secondary prevention, high triglycerides or low HDL-C, but not LDL-C, significantly increased the relative risk of cardiac events in the patients with complication of cardiac disease. CONCLUSIONS: The LEM study, a large-scale prospective study of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients, demonstrated high impact of complications such as DM and hypertension as well as high triglycerides or low HDL-C on cardiac and cerebral events. After long-term statin treatment, the control of other factors rather than LDL-C alone might be important to avoid vascular events.

The effect of low-dose pravastatin in metabolic syndrome for primary prevention of cardiovascular disease in Japan: a post hoc analysis of the MEGA study.

The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study demonstrated the beneficial effect of low-dose pravastatin treatment (10-20 mg/d) on cardiovascular disease (CVD) in Japanese patients with mild-to-moderate hypercholesterolemia. However, it is not known whether mild lipid modification is effective even for patients at high risk. In this study, we evaluated low-dose pravastatin treatment in patients with metabolic syndrome in the MEGA Study. Metabolic syndrome (MetSyn) was defined according to the modified US National Cholesterol Education Program criteria. There were 72 coronary heart disease (CHD) events and 130 CVD events in 2636 patients with MetSyn, and 70 CHD events and 125 CVD events in 5196 patients without MetSyn (hazard ratios 1.85 and 1.90, respectively). No significant risk reduction in CHD was found in the diet plus pravastatin group compared with the diet group patients with MetSyn (hazard ratio .78, P = .29). On the other hand, there was a significant 36% CVD risk reduction (P = .01) in the diet plus pravastatin group compared with the diet group patients with MetSyn, with a small number needed to treat (45). These results indicate that low-dose pravastatin provides a substantial beneficial effect for the prevention of CVD in Japanese patients with MetSyn without known CVD, a population at proportionally high risk in primary prevention.