Risk reductions for cardiovascular disease with pravastatin treatment by dyslipidemia phenotype: a post hoc analysis of the MEGA Study.

BACKGROUND: The beneficial effect of statins for cardiovascular disease (CVD) prevention has been well established. However, the effectiveness among different phenotypes of dyslipidemia has not been confirmed. OBJECTIVE: We evaluated the effect of pravastatin on the incidence of CVD in relation to the phenotype of dyslipidemia. METHODS: The MEGA Study evaluated the effect of low-dose pravastatin on primary prevention of CVD in 7832 Japanese patients, who were randomized to diet alone or diet plus pravastatin and followed for more than 5 years. These patients were classified into phenotype IIa (n=5589) and IIb (n=2041) based on the electrophoretic pattern for this post hoc analysis. RESULTS: In the diet group there was no significant difference in the incidence of coronary heart disease (CHD), stroke, CVD, and total mortality between the two phenotypes. Phenotype IIb patients, compared to phenotype IIa, had lower levels of high-density lipoprotein cholesterol (HDL-C) and a significantly higher incidence of CVD in relation to a low HDL-C level (<47.5mg/dL; p=0.02). Furthermore, pravastatin decreased the relative risk for each major endpoint in both type IIa and type IIb dyslipidemia. Significant risk reductions were observed for CHD by 38% (p=0.04) and CVD by 31% (p=0.02) in type IIa dyslipidemia but not in phenotype IIb. CONCLUSION: Pravastatin therapy provided significant risk reductions for CHD and CVD in patients with phenotype IIa dyslipidemia, but not in those with phenotype IIb dyslipidemia.

Long-term event monitoring study of fluvastatin in Japanese patients with hypercholesterolemia: Efficacy and incidence of cardiac and other events in elderly patients (≥ 65 years old).

OBJECTIVE: This long-term event monitoring (LEM) study was designed to evaluate the long-term lipid-lowering efficacy and safety of fluvastatin (Lochol®, Novartis A.G.) along with the incidence of cardiac and other events, and safety of fluvastatin in Japanese patients with hypercholesterolemia. METHODS: Patients (n = 21,139) who started fluvastatin between April 1, 2000 and March 31, 2002, across 2563 centers 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 analysis. Levels of low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) decreased significantly in the primary (-27.1% and -18.8%) and secondary (-25.3% and -18.4%) prevention cohorts. Reductions in LDL-C (-22.1 vs. -18.2%, p < 0.0001) and TC (-16.1 vs. -13.1%, p < 0.0001) levels were significantly greater among patients aged ≥ 65 than < 65 years old. Overall, 1.7% (146/8563) and 1.1% (93/8563) of patients aged ≥ 65 years old experienced confirmed cardiac and cerebral events, compared with 1.1% (112/10,517) and 0.3% (28/10,517) of patients aged < 65 years old (p = 0.0002 and < 0.0001, respectively). Incidence of cardiac and cerebral events was lowest in patients aged < 65 years old in the primary prevention cohort and highest among patients aged ≥ 65 years old in the secondary prevention cohort. Adverse events were reported in 7.9% (1501/19,084) of patients. CONCLUSION: This large-scale, prospective, uncontrolled study confirmed the lipid-lowering efficacy and safety of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients aged ≥ 65 years old. The higher incidence of cardiac and cerebral events in patients aged ≥ 65 years old in the secondary prevention cohort reflects a high-risk clinical profile with multiple classic risk factors warranting multifactorial interventions.

Effects of supervised aerobic exercise training on serum adiponectin and parameters of lipid and glucose metabolism in subjects with moderate dyslipidemia.

AIM: To examine the effects of supervised aerobic exercise training on serum adiponectin and lipids, including triglyceride (TG)-rich lipoproteins, in moderate dyslipidemic subjects. METHODS: Twenty-five dyslipidemic patients [mean body mass index (BMI)=24.6 kg/m²; mean age= 39 years; mean total cholesterol=226 mg/dL; mean TG=149 mg/dL] without metabolic syndrome, diabetes, and hypertension underwent supervised aerobic exercise training (60 min/day, 2 to 3 times/week) at an intensity of 60-80% of age-predicted maximal heart rate for 16 weeks. Lipoprotein cholesterol levels were measured by our established anion-exchange HPLC method. RESULTS: Aerobic exercise training significantly decreased BMI, cholesterol levels of LDL- and IDL-, and markedly reduced VLDL-cholesterol at week 8 (-45%) and week 16 (-50%), but changes in TG and HDL-cholesterol were not significant. Adiponectin significantly increased by 51% and HOMA-R was significantly decreased at week 16, although changes in these parameters were not significant at week 8. There was no significant relationship between changes in adiponectin and in VLDL- or IDL- cholesterol, but changes in adiponectin were inversely but insignificantly associated with changes in BMI (r=-0.343, p=0.095). CONCLUSIONS: These results suggest that supervised aerobic exercise training two to three times/week in the presence of body weight loss increases serum adiponectin with an improved lipid profile and insulin sensitivity at week 16 in non-obese moderate dyslipidemic patients, and that VLDL-cholesterol is markedly decreased by supervised aerobic exercise training.

The relationship between the effect of pravastatin and risk factors for coronary heart disease in Japanese patients with hypercholesterolemia.

BACKGROUND: Several epidemiologic studies in Japan have shown the risk factors for coronary heart disease (CHD) in the general population. The present analysis determined the risk factors for CHD in the MEGA Study, a large primary prevention trial with pravastatin in Japanese with hypercholesterolemia. METHODS AND RESULTS: The relationship between each baseline characteristic and the risk of CHD for the 5-year study period were evaluated using the Cox proportional hazard model. The multivariable predictors of CHD were sex, age, high-density lipoprotein-cholesterol (HDL-C), diabetes mellitus (DM), hypertension (HT), and history of smoking. Serum total and low-density lipoprotein-cholesterol were not independent risk factors for CHD in the current analysis. In addition, the effect of pravastatin was evaluated by subgroups in each risk factor using the interaction in a Cox model. Diet plus pravastatin treatment reduced CHD risk by 14-43% compared with diet alone, regardless of the presence or absence of risk factors. CONCLUSIONS: The risk factors for CHD were sex, age, DM, HT, smoking, and low HDL-C in the MEGA Study. The pravastatin treatment was effective for reducing the risk of CHD, regardless of the presence of risk factors.

Influences of age, sex, and LDL-C change on cardiovascular risk reduction with pravastatin treatment in elderly Japanese patients: A post hoc analysis of data from the Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE).

BACKGROUND: The Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) found that the prevalence of cardiovascular events (CVEs) was significantly lower with standard-dose (10-20 mg/d) pravastatin treatment compared with low-dose (5 mg/d) pravastatin treatment in elderly (aged ⩾ 60 years) Japanese patients with hypercholesterolemia. Small differences in on-treatment total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels between the 2 dose groups in the PATE study were associated with significant differences in CVE prevalence. However, the reasons for these differences have not been determined. How sex and age differences influence the effectiveness of pravastatin also remains unclear. OBJECTIVES: The aims of this study were to determine the relationship between reduction in LDL-C level and CVE risk reduction in the PATE study and to assess the effects of sex and age on the effectiveness of pravastatin treatment (assessed using CVE risk reduction). METHODS: In this post hoc analysis, Cox regression analysis was performed to study the relationship between on-treatment (pravastatin 5-20 mg/d) LDL-C level and CVE risk reduction using age, sex, smoking status, presence of diabetes mellitus and/or hypertension, history of cardiovascular disease (CVD), and high-density lipoprotein cholesterol level as adjustment factors. To explore risk reduction due to unspecified mechanisms other than LDLrC reduction, an estimated Kaplan-Meier curve from the Cox regression analysis was calculated and compared with the empirical (observed) Kaplan-Meier curve. RESULTS: A total of 665 patients (527 women, 138 men; mean [SD] age, 72.8 [5.7] years) were enrolled in PATE and were followed up for a mean of 3.9 years (range, 3-5 years). Of those patients, 50 men and 173 women were ⩾75 years of age. Data from 619 patients were included in the present analysis. In the calculation of model-based Kaplan-Meier curves, data from an additional 32 patients were excluded from the LDL-C analysis because there were no data on pretreatment LDL levels; hence, the data from 587 patients were analyzed. A reduction in LDL-C level of 20 mg/dL was associated with an estimated CVE risk reduction of 24.7% (hazard ratio [HR] = 0.753; 95% CI, 0.625-0.907; P = 0.003). Risk was reduced by 22.2% in patients aged <75 years (HR = 0.778; 95% CI, 0.598-1.013; P = NS) and 29.9% in patients aged ⩾75 years (HR = 0.701; 95% CI, 0.526-0.934; P = 0.015). The risk reductions were 19.8% in women (HR = 0.802; 95% CI, 0.645-0.996; P = 0.046) and 35.8% in men (HR = 0.642; 95% CI, 0.453-0.911; P = 0.013). The risk reduction was 32.4% in patients without a history of CVD at enrollment (HR = 0.676; 95% CI, 0.525-0.870; P = 0.002) and 15.1% in those with a history of CVD (HR = 0.849; 95% CI, 0.630-1.143; P= NS). The estimated Kaplan-Meier curve strongly suggested that the effects of pravastatin were only partially associated with changes in LDLrC level. CONCLUSIONS: The results from this post hoc analysis suggest that pravastatin 5 to 20 mg/d might elicit CVE risk reduction by mechanisms other than cholesterol-lowering effects alone. They also suggest that pravastatin treatment might be effective in reducing the risk for CVEs in both female and male patients aged ⩾75 years.

Increased risk for cardiovascular outcomes and effect of cholesterol-lowering pravastatin therapy in patients with diabetes mellitus in the pravastatin anti-atherosclerosis trial in the elderly (PATE).

BACKGROUND: The Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) was the first large-scale, prospective clinical trial to show that cholesterol-lowering therapy with pravastatin is effective in reducing the risk for cardiovascular events (CVEs) in elderly (aged ≥60 years) patients with hypercholesterolemia. PATE also included a subgroup of patients with diabetes mellitus (DM). OBJECTIVE: The aim of this post hoc analysis was to assess the effects of lon-gtermpravastatin therapy on cardiovascular outcomes in the subgroup of patients with DM compared with a subgroup without it. METHODS: PATE was conducted at 50 hospitals, universities, and clinics acrossJapan. Patients were randomly allocated to 1 of 2 treatment groups: low-dose pravastatin (5 mg PO QD; L group) or standard-lose pravastatin (in Japan, 10 mg PO QD; S group). Treatment was given for 3 to 5 years. Serum cholesterol levels were measured and the prevalence of CVEs was determined. The primary end point of the study was the S:L risk ratio for fatal or nonfatal CVEs. The secondary end point was the effect of diabetic patients' glycemic control on CVEs. RESULTS: A total of 665 patients (527 women, 138 men; mean [SD] age, 72.8[5.7] years) were followed up for a mean of 3.9 years (range, 3-5 years). Among these, 199 patients had DM; 104 patients with DM were allocated to the L group and 95 to the S group. Four hundred sixty-six patients did not have DM (L group, 230 patients; S group, 236 patients). Overall, between 3 months and 3 years after the initiation of treatment, patients in the L group (mean dose, 4.5 mg/d) experienced reductions from baseline total cholesterol level of 11% to 13%. Those in the S group (mean dose, 8.3 mg/d) experienced reductions from baseline of 15% to 17%. Decreases in low-density lipoprotein cholesterol (LDL-C) levels were 17% to 20% and 23% to 26% in the L and S groups, respectively. Statistically similar reductions were noted between patients with DM and those without it in response to either dose. The DM subgroup experienced 32 CVEs (L group, 17; S group, 15) compared with 39 CVEs (L group, 25; S group, 14) in the subgroup without DM. The S:L CVE risk ratio (primary end point) was 0.94 (95% Cl, 0.46-1.92) in patients with DM and 0.54 (95% Cl, 0.28-1.05) in those without DM; the differences between the treatment groups were not statistically significant. The risk for CVEs in patients with DM whose glycosylated hemoglobin concentrations were <8.0% and ≥8.0% were, respectively, 1.87-fold (95% Cl, 1.09-3.20; P = 0.02) and 3.79-fold (95% Cl, 1.92-7.48; P < 0.01) higher than that in patients without DM. CONCLUSIONS: In this post hoc analysis of the effects of long-term cholesterol-loweringtherapy (low- and standard-dose pravastatin) on cardiovascular outcomes in elderly patients with DM, dose had no effect on the risk for CVEs in these patients as it did in those without DM. Poorer glycemic control in patients with DM was related to a higher risk for CVEs. The lack of pravastatin efficacy found in the subgroup with DM may have been attributable to the small differences in LDL-C levels found between the 2 treatment groups and/or the small sample size of the study.

Decrease in plasma low-density lipoprotein cholesterol, apolipoprotein B, cholesteryl ester transfer protein, and oxidized low-density lipoprotein by plant stanol ester-containing spread: a randomized, placebo-controlled trial.

OBJECTIVE: The ester of plant stanols significantly reduces plasma levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in Western people. Effects of plant stanol ester-containing spread on plasma levels of TC, LDL-C, and apolipoprotein B (apoB) were studied in a randomized, placebo-controlled trial in Japanese subjects whose diet is low in fat and cholesterol. The effects of plant stanol ester on plasma levels of arteriosclerosis-promoting factors, namely remnants of triacylglycerol (TG)-rich lipoproteins, cholesteryl ester transfer protein (CETP), and oxidized LDL (Ox-LDL), were also studied. The assessment of safety was also made. METHODS: One hundred and five healthy volunteers were assigned randomly to one of three groups: placebo spread (n = 35), 2 g/d of plant stanol (3.4 g of stanol ester; n = 34), and 3 g/d of plant stanol (5.1 g of stanol ester; n = 36). Plasma levels of lipids were measured at start of the study, at 2 and 4 wk (end of trial), and at 8 wk (+4 wk). Plasma apoproteins, cholesterol in remnant-like particles which are equivalent to remnants of TG-rich lipoproteins (RLP-C), CETP mass, and Ox-LDL were measured at the beginning and the end of the trial. Plasma levels of plant steroids and fat-soluble vitamins were also measured for the assessment of safety. RESULTS: Background and dietary composition did not differ among groups. Plasma levels of TC, LDL-C, apoB, apoE, CETP mass, and Ox-LDL were reduced significantly by 6.5%, 9.6%, 8.3%, 4.5%, 6.1%, and 20%, respectively, in the 2 g/d plant stanol group. Plasma levels of TC, LDL-C, apoB, CETP mass, and Ox-LDL were decreased significantly by 5.5%, 7.3%, 5.6%, 3.3%, and 19%, respectively, in the 3 g/d plant stanol group. Plasma levels of plant stanols, plant sterols, retinol, beta-carotene, and alpha-tocopherol did not change in any group, but levels of campestanol increased and alpha-tocopherol decreased slightly in the sitostanol groups. CONCLUSION: Plasma levels of TC and LDL-C were significantly reduced by the plant stanol ester-containing spread. The smaller reduction than in Western studies and the lack of dose dependency in this study might be due to the different basal diets. We concluded that plant stanol ester-containing spread is efficacious in reducing plasma LDL-C, apoB, CETP, and Ox-LDL and that 2 g/d plant stanol is adequate for Japanese people. No significant side effects were observed in any group.

Sweet elements of Siraitia grosvenori inhibit oxidative modification of low-density lipoprotein.

This study examined the ability of sweet elements extracted from Siraitia grosvenori (SG) to inhibit the oxidation of LDL. We monitored the formation of conjugated diene during copper-mediated LDL oxidation in the presence or absence of sweet elements of whole extract of SG (SG extract) or cucurbitane glycosides (CGs) purified from SG extract as sweet elements. CGs consist of Mogroside IV (Mog.IV), Mogroside V (Mog.V), 11-Oxo-mogroside V (11-Oxo-mog.V), and Siamenoside I (Sia.I). In addition, the effect of these elements on human umbilical vein endothelial cell (HUVEC)- mediated LDL oxidation was tested by measuring production of lipid peroxides. SG extract inhibited copper-mediated LDL oxidation in a dose-dependent fashion, but neither glucose nor erythritol suppressed the oxidation. Among CGs, 11-Oxo-mog.V significantly inhibited LDL oxidation, and prolongation of the lag time during LDL oxidation by 11-Oxo-mog.V was dose-dependent. The lag time (119.7 +/- 8.9 min) in the presence of 200 microM 11-Oxo-mog.V was significantly longer than that (76.8 +/- 5.5 min) of control (p < 0.01). In addition, SG extract and 11-Oxo-mog.V inhibited HUVEC-mediated LDL oxidation in a dose-dependent manner. These results demonstrate that SG extract can inhibit LDL oxidation and that 11-Oxo-mog.V, a sweet element of SG extract, provides the anti-oxidative property of SG which might reduce the atherogenic potential of LDL.

Influence of apolipoprotein E phenotype on metabolism of lipids and apolipoproteins after plant stanol ester ingestion in Japanese subjects.

OBJECTIVE: We investigated the effect of apolipoprotein E phenotype on changes in plasma levels of lipids and apoproteins by plant stanol ester (PSE) ingestion in Japanese subjects whose diet is low in fat and cholesterol. METHODS AND RESULTS: The effect of PSE-containing spread was studied in a randomized, placebo-controlled trial. One hundred five healthy volunteers were enrolled for this study. Apolipoprotein E phenotyping was done in 96 of 105 subjects. We compared plasma levels at the start and end of the test period (4 wk). The daily ingestion of 2 g of plant stanols from the PSE spread significantly reduced plasma levels of low-density lipoprotein cholesterol by 8.9 +/- 6.6% (mean +/- standard deviation) in the E(3) group and 10.4 +/- 8.0% in the E(4) group. The daily ingestion of 2 g of plant stanols from the PSE spread significantly decreased plasma levels of apoprotein B by 5.4 +/- 7.9% in the E(3) group and 8.9 +/- 7.0% in the E(4) group. No further reductions of low-density lipoprotein cholesterol and apoprotein B were observed with 3 g/d of plant stanols from the PSE spread. CONCLUSION: The ingestion of PSE spread significantly reduced plasma levels of total cholesterol, low-density lipoprotein cholesterol, and apoprotein B. However, the response to PSE ingestion was not influenced by apolipoprotein E phenotype.