Effect of lovastatin on lipoprotein fluidity in patients with hypercholesterolaemia.

Lovastatin was administered to six hypercholesterolaemic patients (mean plasma cholesterol 450 mg dl-1). Plasma lipoproteins (VLDL, LDL, and HDL) were separated before and following 7 and 12 weeks treatment with lovastatin. Fluidity was quantified by fluorescence polarization measurements using 1,6-diphenyl 1,3,5 hexatriene (DPH) as the fluorescent probe. Lovastatin treatment resulted in a significant reduction of total plasma cholesterol, LDL cholesterol and VLDL cholesterol (-41%, -44%, -68%, respectively). Fluidity measurements showed significant (p < 0.01) increase in LDL fluidity by 11% and 21% after 7 and 12 weeks of lovastatin treatment, whereas, VLDL fluidity was increased by 27% after 12 weeks of therapy. HDL fluidity was not altered. These alterations in the fluidity of the atherogenic lipoproteins (LDL and VLDL) in hypercholesterolaemic patients may prove to be of significance in reducing the risk of atherosclerosis.     

Plasma lipoprotein changes after treatment with pravastatin and gemfibrozil in patients with familial hypercholesterolemia

The ability of pravastatin, a new hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, to lower plasma lipid levels and modify lipoprotein patterns was compared with that of gemfibrozil in 18 patients with familial hypercholesterolemia who participated in a 16-week, double-blind, parallel trial. Pravastatin proved better than gemfibrozil in lowering total and low-density lipoprotein (LDL) cholesterolemia: -23.6% and -28.2% versus -18.1% and -21.4%, respectively. A significant positive correlation was found between the starting level of serum cholesterol (both total and LDL) and the gemfibrozil-induced reduction (r = 0.72 and 0.69), whereas the hypocholesterolemic effect of pravastatin was apparently independent from pretreatment levels (r = 0.32 and 0.10). Apolipoprotein B concentrations were lowered by 25.4% (pravastatin) and 22.0% (gemfibrozil). Pravastatin and gemfibrozil reduced triglyceride levels by 13.9% and 49.4%, respectively. Both drugs increased the level of high density lipoprotein (HDL) cholesterol, but this change was significant only with gemfibrozil (p less than 0.05). The HDL subfraction structure and distribution were not modified by pravastatin treatment. Gemfibrozil, in contrast, increased HDL3 cholesterol level by 9% because of an enrichment of HDL3 particles in both free cholesterol and cholesteryl esters and lowered the flotation rate of HDL3 (p less than 0.05). LDL particles became smaller after gemfibrozil treatment (diameter: 25.4 +/- 0.3 nm vs 26.1 +/- 0.4 nm, p less than 0.01) and were not modified by pravastatin. This comparison shows a more pronounced efficacy of the HMG CoA reductase inhibitor on total and LDL cholesterol levels, also indicating that pravastatin acts by a single major mechanism, reducing the number of circulating LDL particles. Gemfibrozil may exert additional activities, possibly consequent to the stimulation of very low density lipoprotein catabolism.     

Efficacy of three statins at lower maintenance doses

The purpose of this study was to determine whether patients who are receiving lovastatin 20 mg daily can be switched to daily regimens of lovastatin 10 mg, pravastatin 10 mg, or simvastatin 5 mg without loss of lipid control or an increase in side effects. One hundred five patients were identified whose lipid levels were clinically stable on a regimen of lovastatin 20 mg/d; these patients were randomly allocated to a group that continued to receive lovastatin 20 mg/d (the control group) or a group receiving 1 of the 3 alternative regimens. Patients were evaluated after 6 and 12 weeks of treatment for side effects and changes in liver and muscle enzymes and lipid levels compared with baseline. Of the 105 patients enrolled, 5 withdrew because of side effects, 4 did not return for follow up, and 3 were excluded. Ninety-three patients completed the 12-week study. When baseline values were compared to those at week 12 for each group, the proportions of patients meeting treatment goals for LDL cholesterol, as defined by the National Cholesterol Education Program, were as follows: control group, 30.8% improved; lovastatin 10 mg, 16.7% worsened; pravastatin 10 mg, 27.3% improved; and simvastatin 5 mg, no change. Patients who were switched from lovastatin 20 mg daily to pravastatin 10 mg or simvastatin 5 mg daily did not experience statistically significant changes in mean total cholesterol levels. Patients who were switched from 20 to 10 mg/d of lovastatin experienced increases in mean total cholesterol levels (from 195 mg/dL +/-5 mg/dL at baseline to 200 mg/dL +/-5 mg/dL at 12 weeks; P<0.05). There were no differences in side effects or in elevations in liver or muscle enzymes. Thus patients who are stable on 20 mg/d lovastatin can be switched to a regimen of 10 mg/d pravastatin or 5 mg/d simvastatin.     

Gemfibrozil in familial combined hyperlipidaemia: effect of added low-dose cholestyramine on plasma and biliary lipids

Gemfibrozil is frequently used for lipid-lowering in familial combined hyperlipidaemia (FCHL) and in other forms of combined hyperlipidaemia. This therapy increases biliary cholesterol saturation, enhancing the risk for gallstone formation. Furthermore, in hypertriglyceridaemia, LDL cholesterol levels often tend to rise. We have explored the possibility that addition of a low dose of cholestyramine to gemfibrozil therapy obliterates these phenomena. Eighteen gallstone-free patients with definite (n = 5) or probable (n = 10) FCHL, or combined hyperlipoproteinaemia (n = 3) were randomized to a 6 week treatment with gemfibrozil, 600 mg b.i.d., or gemfibrozil 600 mg b.i.d. plus 4 g cholestyramine o.d. After 6 weeks the patients were crossed over to the alternative treatment. Plasma lipoproteins and biliary lipids were determined at baseline and at the end of each period. Institution of gemfibrozil treatment resulted in a decrease in plasma cholesterol by 15% (P less than 0.05) and in plasma triglycerides by 47% (P less than 0.05); HDL cholesterol increased by 18% (P less than 0.05). Addition of cholestyramine further decreased plasma and LDL total cholesterol by 9% (P less than 0.05). Total triglycerides and HDL cholesterol did not change. Gemfibrozil treatment was associated with a rise in the relative biliary concentration of cholesterol from 5.6 +/- 0.4 to 6.9 +/- 0.5 molar percent (P less than 0.01), and a parallel decrease in the relative concentration of bile acids, resulting in an increased cholesterol saturation of the bile, from 77 +/- 5 to 90 +/- 6% (P less than 0.05). This change was not observed during the combined therapy (mean cholesterol saturation, 82 +/- 4%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low‐density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia: A case report

A 49 years old woman (weight 68 kg, BMI 27.3 kg/m²) with heterozygous familial hypercholesterolemia (HeFH) and multiple statin intolerance with muscle aches and creatine kinase elevation, presented at the Outpatient Lipid Clinic of Verona University Hospital in May 2015. Hypercholesterolemia was firstly diagnosed during adolescence, followed in adulthood by a diagnosis of Cogan's syndrome, a rheumatologic disorder characterized by corneal and inner ear inflammation. No xanthomas, corneal arcus, or vascular bruits were detectable at physical examination. Screening for macrovascular complications did not reveal relevant damages. Ongoing medical therapy included salicylic acid, methylprednisolone, methotrexate, and protonic‐pump inhibitor. In the absence of specific lipid‐lowering therapy, plasma lipid levels at first visit were: total‐cholesterol = 522 mg/dL, LDL‐cholesterol = 434 mg/dL, HDL‐cholesterol = 84 mg/dL, triglycerides = 120 mg/dL, Lp(a) = 13 mg/dL. On December 2015, evolocumab 140 mg sc every 2 weeks was initiated. After a 24‐week treatment, the LDL‐cholesterol levels decreased by an average of 21.2% to 342 ± 22 mg/dL (mean ± SD). On May 2016, LDL‐apheresis (H.E.L.P.system) was started as add‐on therapy. Compared to the average levels obtained during the evolocumab monotherapy period, the LDL‐cholesterol was reduced by 49.4%, thus reaching an inter‐apheresis level (mean ± SD) of 173 ± 37 mg/dL. This report suggests that a combination therapy with evolocumab and lipoprotein‐apheresis may have synergic effects on circulating lipid levels. Its relevance as a highly effective treatment option for hyperlipidemia in HeFH patients warrants further investigation in larger datasets.     

Prognostic evaluation of primary non-small cell lung carcinoma patients using biological fluid variables. A systematic review

There is growing experimental evidence to suggest the role of oxidatively modified low‐density lipoprotein (LDL) in the initiation and progression of atherosclerosis. The oxidation of lipoprotein moiety causes modification of positively charged lysine residues and results in negative net charge of lipoprotein particles. Objective: To measure the amount of circulating electronegatively charged LDL particles (LDL–) in plasma of patients with angiographically documented coronary artery disease (CAD). Methods: Thirty patients were assigned to the study group (CAD+) and 10 patients to the control group (Ctrl). LDL– was quantitated in homogeneous LDL fractions obtained by ultracentrifugation, using ion exchange high performance liquid chromatography. Plasma lipids were measured using enzymatic kits. Results: The CAD+ group had significantly higher levels of LDL– in the whole LDL fraction (7.66±1.92 vs. 5.14±0.84%, p=0.0003). Moreover the CAD+ group had significantly higher levels of total cholesterol (255.4±35.1 vs. 210.4±22.4?mg/dL), LDL cholesterol (154.5±26.9 vs. 122.4±21.1?mg/dL) and significantly lower levels of high‐density lipoprotein (HDL) cholesterol (40.4±9.4 vs. 51.0±11.5?mg/dL). LDL– remained significantly higher in the CAD+ group after adjustment for total cholesterol, LDL cholesterol and HDL cholesterol (6.3 vs. 5.14% at p=0.0095). There is a trend towards a positive correlation between LDL– levels and LDL cholesterol in the control group (Spearman R=0.55 at p=0.098). Conclusions: Electronegatively charged LDL appears to be an additional hallmark of coronary artery disease, independently of established lipid risk factors. The trend towards a positive correlation between LDL cholesterol concentration and the level of LDL– in the control group may reflect the susceptibility of LDL cholesterol to autoxidation, Moreover, this may indicate other oxidative mechanisms in coronary artery disease. Nonetheless, further studies assessing the prognostic value of electronegatively charged LDLs are necessary.     

Oat-derived beta-glucan significantly improves HDLC and diminishes LDLC and non-HDL cholesterol in overweight individuals with mild hypercholesterolemia

OBJECTIVE: To investigate the effect of bread formulated with 6 g of beta-glucan (oat soluble fiber) on serum lipids in overweight normotensive subjects with mild to moderate hypercholesterolemia. DESIGN: Thirty-eight male subjects [mean age 59.8 +/- 0.6 yr, mean body mass index (BMI) 28.3 +/- 0.6 kg/m(2)] who were eligible for the study ate an isocaloric diet for a 1-week period. They were then divided into 2 groups: group A (n = 19), who were maintained on American Heart Association (AHA) Step II diet, including whole wheat bread, and group B (n = 19), who were maintained on AHA Step II diet containing high levels of monounsaturated fatty acids plus bread containing 6 g of beta-glucan (Nutrim-OB) for 8 weeks. Plasma lipids and glucose were measured at baseline and after weeks 8 in all subjects. All subjects were advised to walk for 60 minutes every day. RESULTS: There was a significant increase (upward arrow 27.8%) in plasma high density lipoprotein (HDL) cholesterol in the beta-glucan group (group A) from 39.4 +/- 2.0 to 49.5 +/- 2.1 mg/dL (P < 0.001), but there was no change in group B. There was a significant reduction in total cholesterol in the 2 groups to approximately the same extent: group A, from 232.8 +/- 2.7 mg/dL to 202.7 +/- 6.7 mg/dL; P < 0.001; and group B, from 231.8 +/- 4.3 mg/dL to 194.2 +/- 4.3 mg dL; P < 0.001. Plasma low density lipoprotein (LDL) cholesterol also decreased significantly in the two groups: group A, from 160.3 +/- 2.8 mg/dL to 133.2 +/- 5.4 mg/dL; P < 0.001; group B, from 167.9 +/- 4.3 mg/dL to 120.9 +/- 4.3 mg/dL; P < 0.001; however, the beta-glucan fortified diet was significantly more effective (downward arrow 27.3% vs. downward arrow 16.8%; P < 0.04). There was a small and insignificant reduction in plasma very LDL (VLDL) cholesterol and triglycerides in the two groups. Similarly, non-HDL cholesterol levels were also decreased, with beta-glucan diet producing significantly higher effect (downward arrow 24.5% vs. downward arrow 16.1%; P < 0.04). The beta-glucan diet also produced higher reduction in total cholesterol/HDL cholesterol ratio (downward arrow 33.3% vs. downward arrow 8.4%; P < 0.003) and LDL cholesterol/HDL cholesterol ratio (downward arrow 42.1% vs. downward arrow 13.3%; P < 0.001) than the diet without beta-glucan. The beta-glucan diet also decreased fasting plasma glucose (P < 0.4), whereas the other diet had no effect. Interestingly, both diets reduced body weight and BMI significantly, with beta-glucan diet having a greater effect. CONCLUSIONS: Six grams of beta-glucan from oats added to the AHA Step II diet and moderate physical activity improved lipid profile and caused a decrease in weight and, thus, reduced the risk of cardiovascular events in overweight male individuals with mild to moderate hypercholesterolemia. The diet with added beta-glucan was well accepted and tolerated.     

Circulating electronegatively charged low-density lipoprotein in patients with angiographically documented coronary artery disease

There is growing experimental evidence to suggest the role of oxidatively modified low-density lipoprotein (LDL) in the initiation and progression of atherosclerosis. The oxidation of lipoprotein moiety causes modification of positively charged lysine residues and results in negative net charge of lipoprotein particles. OBJECTIVE: To measure the amount of circulating electronegatively charged LDL particles (LDL-) in plasma of patients with angiographically documented coronary artery disease (CAD). METHODS: Thirty patients were assigned to the study group (CAD+) and 10 patients to the control group (Ctrl). LDL- was quantitated in homogeneous LDL fractions obtained by ultracentrifugation, using ion exchange high performance liquid chromatography. Plasma lipids were measured using enzymatic kits. RESULTS: The CAD+ group had significantly higher levels of LDL- in the whole LDL fraction (7.66+/-1.92 vs. 5.14+/-0.84%, p=0.0003). Moreover the CAD+ group had significantly higher levels of total cholesterol (255.4+/-35.1 vs. 210.4+/-22.4 mg/dL), LDL cholesterol (154.5+/-26.9 vs. 122.4+/-21.1 mg/dL) and significantly lower levels of high-density lipoprotein (HDL) cholesterol (40.4+/-9.4 vs. 51.0+/-11.5 mg/dL). LDL- remained significantly higher in the CAD+ group after adjustment for total cholesterol, LDL cholesterol and HDL cholesterol (6.3 vs. 5.14% at p=0.0095). There is a trend towards a positive correlation between LDL- levels and LDL cholesterol in the control group (Spearman R=0.55 at p=0.098). CONCLUSIONS: Electronegatively charged LDL appears to be an additional hallmark of coronary artery disease, independently of established lipid risk factors. The trend towards a positive correlation between LDL cholesterol concentration and the level of LDL- in the control group may reflect the susceptibility of LDL cholesterol to autoxidation, Moreover, this may indicate other oxidative mechanisms in coronary artery disease. Nonetheless, further studies assessing the prognostic value of electronegatively charged LDLs are necessary.     

Efficacy and tolerability of lovastatin in elderly hypercholesterolemic patients.

In a previously published multicenter study (Kannel and associates, 1990), the effects of six months' treatment with lovastatin were evaluated in patients with hypercholesterolemia. In the present report the results from the 144 elderly patients (aged 65 to 83 years) are presented and compared with those from the 343 patients aged less than 65 years. The initial dose of lovastatin was 20 mg daily and could be increased to a maximum of 80 mg/day. After one month of treatment, in both the elderly and younger patients, levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein cholesterol, and triglycerides, and the total cholesterol: high-density lipoprotein (HDL) cholesterol and LDL:HDL [corrected] cholesterol ratios were significantly lower and high-density lipoprotein cholesterol levels were significantly higher. These improvements in the lipid profile were maintained for six months in both patient groups. LDL cholesterol goals of less than 130 mg/dl in patients with coronary heart disease (CHD) or two CHD risk factors and less than 160 mg/dl among the other patients were achieved by 53% of the elderly patients and 40% of the younger patients at one month (P less than 0.01) and by 62% and 47% at six months (P less than 0.01). By the end of the study, the mean daily dose of lovastatin was 35.4 mg for the elderly and 38.4 mg for the younger patients. The drug was generally well tolerated by all patients. The results indicate that both elderly and younger hypercholesterolemic patients respond well to treatment with lovastatin.     

A multiple-dose pharmacodynamic, safety, and pharmacokinetic comparison of extended- and immediate-release formulations of lovastatin

BACKGROUND: Because lovastatin is efficiently extracted by the liver and because its administration in divided doses is associated with increased efficacy, an extended-release (ER) formulation may have the potential for a dose-sparing advantage relative to the immediate-release (IR) formulation in the treatment of hypercholesterolemia. OBJECTIVE: This study compared the short-term pharmacodynamics, safety, and pharmacokinetics of multiple doses of lovastatin ER with those of lovastatin IR in patients with fasting low-density lipoprotein cholesterol (LDL-C) levels between 130 and 250 mg/dL and fasting triglyceride levels < 350 mg/dL. METHODS: The study had a randomized, single-blind, positive-controlled, 2-way crossover design, with a 4-week diet/placebo run-in period and two 4-week active-treatment periods. During period 1, patients received either lovastatin ER or lovastatin IR (both 40 mg OD). After 4 weeks of the initial study treatment and a 2-week washout period, patients were switched to the alternate treatment (period 2). Pharmacodynamic parameters (LDL-C, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels) were evaluated by combining data from weeks 3 and 4 of treatment. In a pharmacokinetic substudy, maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve from zero to 24 hours (AUC(024)) were determined for lovastatin, lovastatin acid, and total and active inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on days 1 and 28 of active treatment. The geometric mean ratio of AUC(0-24) (lovastatin ER/lovastatin IR) was also calculated for each of these substances. RESULTS: Of 76 patients who entered the run-in period, 26 (12 men, 14 women; mean age, 56.2 years) were randomized to receive active treatment and 24 were included in the efficacy analysis; 13 patients were included in the pharmacokinetic substudy, 12 of whom had complete pharmacokinetic data. Compared with lovastatin IR, lovastatin ER produced a 3.9% greater reduction in LDL-C (P = 0.044). Changes in other lipid parameters were not statistically significant. In the pharmacokinetic substudy, C(max) values for lovastatin, lovastatin acid, and in hibitors of HMG-CoA reductase were lower at day 28 with lovastatin ER than with lovastatin IR. The AUC(0-24) ratio for lovastatin was 1.91 (90% CI, 1.77 - 3.35), reflecting higher bioavailability of the prodrug with lovastatin ER; in contrast, the ratios for lovastatin acid and active and total inhibitors of HMG-CoA reductase were < 1. CONCLUSIONS: In this short-term study in a small number of patients, lovastatin ER 40 mg produced significantly greater LDL-C lowering than did an equal dose of lovastatin IR, with a relatively low C(max) and comparable systemic exposure to lovastatin acid and active and total inhibitors of HMG-CoA reductase. Lovastatin ER was well tolerated, with no discontinuations due to adverse events.     

A randomized, open-label study to evaluate the efficacy and safety of pitavastatin compared with simvastatin in Korean patients with hypercholesterolemia

BACKGROUND: Pitavastatin is a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor used to treat hypercholesterolemia. OBJECTIVE: The goal of this study was to compare the efficacy and safety of pitavastatin versus those of simvastatin in Korean patients with hypercholesterolemia. METHODS: This was an 8-week, multicenter, prospective, randomized, open-label, Phase III clinical trial. Male and female Korean patients with hypercholesterolemia who were between the ages of 20 and 75 years and who had a fasting triglyceride level <600 mg/dL and a low-density lipoprotein (LDL) cholesterol level >130 mg/dL after a 4-week dietary lead-in period were eligible for entry. Eligible patients were randomized into 2 groups in a 1:1 ratio. Patients received pitavastatin 2 mg once daily or simvastatin 20 mg once daily for 8 weeks. The medication was administered initially for 4 weeks, and an additional 4 weeks of study medication was prescribed at week 4. The final visit was conducted 8 weeks after randomization. RESULTS: Of the 104 patients randomized to treatment, 95 patients (59 women; 36 men) completed the study (49 in the pitavastatin group [mean age, 59.9 years] and 46 in the simvastatin group [mean age, 56.4 years]). No significant difference was found between groups with respect to patient age, sex, or body mass index. There was no significant difference in the percent decrease in LDL cholesterol levels (mean [SD], 38.2% [11.6%] decrease for the pitavastatin group vs 39.4% [12.9%] decrease for the simvastatin group [P = 0.648]). Also, there were no significant differences between the 2 study groups in the percent changes in total cholesterol, triglyceride, or high-density lipoprotein (HDL) cholesterol levels from baseline to study end. No significant difference was observed for the proportion of patients who achieved the LDL cholesterol goal of the National Cholesterol Education Program Adult Treatment Panel III: 93.9% (46/49) of patients in the pitavastatin group and 91.3% (42/46) of patients in the simvastatin group (P = 0.709) met the target level. At least 1 clinical adverse event and at least 1 adverse drug reaction were observed in 25.0% (13/52) and 11.5% (6/52), respectively, of patients in the pitavastatin group, and 37.3% (19/51) and 23.5% (12/51), respectively, in the simvastatin group; this difference was not statistically significant. The most common adverse event was an elevation in creatine kinase levels >2 times the upper limit of normal in 3.8% of pitavastatin-treated patients and 9.8% of simvastatin-treated patients (P = 0.269). There were no serious adverse drug reactions observed in either group. CONCLUSION: The HMG-CoA reductase inhibitor pitavastatin was found to be noninferior to simvastatin in terms of reducing LDL cholesterol, total cholesterol, and triglyceride levels, and increasing HDL cholesterol levels, in Korean patients with hypercholesterolemia after 8 weeks of treatment.     

Gemfibrozil treatment potentiates oxidative resistance of high-density lipoprotein in hypertriglyceridemic patients

BACKGROUND: Studies suggest that both oxidized low and high density lipoprotein (LDL and HDL) play a role in the pathogenesis of atherosclerosis. Gemfibrozil is widely used and is reported to increase cholesterol of LDL and HDL in hypertriglyceridemic patients. The aim of this study was to investigate the effect of gemfibrozil treatment on the oxidative status of lipoprotein particles in Fredrickson phenotype IV hypertriglyceridemic patients. METHODS: Twenty-two patients, aged 38-64 years, with fasting plasma triglyceride concentrations between 2.90 and 8.97 mmol L(-1), were recruited and were given gemfibrozil 300 mg three times daily for 12 weeks. Venous blood samples were collected before gemfibrozil treatment, after 4, 8, or 12 weeks of treatment, and 4 weeks after termination of treatment, and used to analyse the plasma lipid profile, isolate lipoproteins, and analyse the chemical composition and in vitro oxidation of lipoprotein particles. RESULTS: Gemfibrozil treatment resulted in a decrease in plasma total triglyceride levels and the triglyceride content of all lipoproteins. Plasma total cholesterol levels were decreased as a result of a decrease in very low density lipoprotein (VLDL) cholesterol levels. A slight increase in LDL cholesterol levels was observed, whereas the thiobarbituric acid-reactive substances (TBARS) of LDL were decreased and the lag and peak time of LDL to oxidation were unchanged and maximal diene production was decreased. Plasma HDL cholesterol levels, the surface-to-core ratio of HDL particles, and the resistance of HDL to oxidation were increased. CONCLUSION: The decreased TBARS and diene production of LDL, increased HDL cholesterol levels, and increased resistance of HDL to oxidation may, in part, explain why gemfibrozil treatment was found to be generally beneficial in terms of protection against coronary heart disease.     

Evaluation of gemfibrozil therapy: predictive response from lipoprotein subfraction analysis.

Subjects with high-density lipoprotein cholesterol (HDL-C) values of less than 47 mg/dL (mean 35.6 +/- 5.5 mg/dL) were selected for this study to examine relationships between plasma lipids, lipoprotein components, and the outcome of gemfibrozil therapy. Changes in plasma lipoprotein subfractions were determined to better understand the previously observed variability of the responses in both HDL-C and triglycerides to gemfibrozil. Based on the data collected, an attempt was made to identify pretreatment lipid parameters that may be predictive regarding the efficacy of gemfibrozil therapy. Serum samples were analyzed at the outset and after the conclusion of 12 weeks of gemfibrozil therapy. Because the HDL-C response to therapy was highly variable, the data from patients were separated into two groups, responders (>20% increase in HDL-C) and nonresponders (<20% increase in HDL-C). The lipid components of lipoprotein subfractions were evaluated using multiple regression analysis yielding predictive models that show the relationship between specific lipoprotein subfractions and the percentage change in HDL-C and posttreatment triglyceride levels. Group classification was then predicted with 78% accuracy using specific lipoprotein subfractions to estimate an individual's percentage change in HDL-C. The major difference between the responder and nonresponder groups was their respective correlations between triglyceride-lowering and changes in HDL-C. In the responder group, there was a significant correlation between the changes in HDL-C and the lowering of triglycerides (r = 0.61, p = 0.03), whereas the nonresponder group showed no such correlation (r = 0.17, p = 0.52). The predictive model also proved to be highly accurate in forecasting the effectiveness of the triglyceride-lowering action of gemfibrozil in this group of patients.     

Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind,placebo-controlled study

OBJECTIVE: The oral antidiabetic agent pioglitazone improves insulin sensitivity and glycemic control and appears to lower atherogenic dense LDL in type 2 diabetes. Insulin resistance may occur frequently in nondiabetic patients with hypertension. This study is the first to report the effect of pioglitazone on LDL subfractions in normolipidemic, nondiabetic patients with arterial hypertension. RESEARCH DESIGN AND METHODS: We performed a monocentric, double-blind, randomized, parallel-group comparison of 45 mg pioglitazone (n = 26) and a placebo (n = 28), each given once daily for 16 weeks. Fifty-four moderately hypertensive patients (LDL cholesterol, 2.8 +/- 0.8 mmol/l; HDL cholesterol, 1.1 +/- 0.3 mmol/l; triglycerides, 1.4 mmol/l (median; range 0.5-7.1) were studied at baseline and on treatment. RESULTS: At baseline, dense LDLs were elevated (apolipoprotein [apo]B in LDL-5 plus LDL-6 >250 mg/l) in 63% of all patients. Sixteen weeks of treatment with pioglitazone did not significantly change triglycerides, total, LDL, and HDL cholesterol. However, pioglitazone reduced dense LDLs by 22% (P = 0.024). The mean diameter of LDL particles increased from 19.83 +/- 0.30 to 20.13 +/- 0.33 nm (P < 0.001 vs. placebo), whereas the mean LDL density decreased from 1.0384 +/- 0.0024 to 1.0371 +/- 0.0024 kg/l (P = 0.005 vs. placebo). The effect of pioglitazone on LDL size and density was independent of fasting triglycerides and HDL cholesterol at baseline and of changes in fasting triglycerides and HDL cholesterol. CONCLUSIONS: The prevalence of atherogenic dense LDL in nondiabetic, hypertensive patients is similar to patients with type 2 diabetes. Pioglitazone significantly reduces dense LDL independent from fasting triglycerides and HDL cholesterol. The antiatherogenic potential of pioglitazone may thus be greater than that expected from its effects on triglycerides, LDL, and HDL cholesterol alone.     

Replacement of carbohydrate by protein in a conventional-fat diet reduces cholesterol and triglyceride concentrations in healthy normolipidemic subjects.

OBJECTIVE: To determine the effect on plasma lipid profiles of replacement of dietary carbohydrate by low-fat, high-protein foods. DESIGN: Cross-over randomized controlled trial. PARTICIPANTS: Ten healthy, normolipidemic subjects (8 women and 2 men). INTERVENTIONS: Subjects were randomly allocated to either a low-protein (12%) or high-protein (22%) weight-maintaining diet for 4 weeks and then switched to the alternate diet for 4 more weeks. The first 2 weeks of each diet served as an adjustment/washout period. Fat was maintained at 35% of energy, mean cholesterol intake at 230 mg per day and mean fibre intake at 24 g per day. Compliance was promoted by the use of written dietary protocols based on the food preferences of the subjects and weekly dietary consultation as required. OUTCOME MEASURES: Mean plasma levels of total, very-low-density-lipoprotein (VLDL), low-density-lipoprotein (LDL), and high-density-lipoprotein (HDL) cholesterol, and of total and very-low-density-lipoprotein (VLDL) triglycerides. Satiety levels were self-rated on a 10-point scale. RESULTS: Consumption of the high- versus the low-protein diet resulted in significant reductions in mean plasma levels of total cholesterol (3.8 v. 4.1 mmol/L, p < 0.05), VLDL cholesterol (0.20 v. 0.26 mmol/L, p < 0.02), LDL cholesterol (2.4 v. 2.6 mmol/L, p < 0.05), total triglycerides (0.69 v. 0.95 mmol/L, p < 0.005) and VLDL triglycerides (0.35 v. 0.57 mmol/L, p < 0.001), as well as in the ratio of total cholesterol to HDL cholesterol (3.1 v. 3.5, p < 0.01). A trend towards an increase in HDL cholesterol (1.26 v. 1.21 mmol/L, p = 0.30) was observed but was not statistically significant. Satiety levels tended to be higher among those eating the high-protein diet (6.1 v. 5.4, p = 0.073). CONCLUSIONS: Moderate replacement of dietary carbohydrate with low-fat, high-protein foods in a diet containing a conventional level of fat significantly improved plasma lipoprotein cardiovascular risk profiles in healthy normolipidemic subjects.     

Plasma clearance of lovastatin versus chinese red yeast rice in healthy volunteers

OBJECTIVES: It is now accepted that inhibition of cholesterol biosynthesis is effective in the primary and secondary prevention of heart disease. However, the perceived side-effects on muscle and liver reduce the general acceptance of statin drug therapy as well as compliance over the long term, which is necessary for prevention efforts to be successful. Chinese red yeast rice (CRYR) is a supplement containing lovastatin (monacolin K), eight other monacolins, pigments, tannins, and other phytochemicals. The authors previously reported on a double- blind placebo-controlled trial of CRYR supplement in 80 individuals demonstrating a significant decrease in cholesterol levels from 250 mg/dL to 210 mg/dL over 8 weeks independent of diet. The current study compared the pharmacokinetics of CRYR with lovastatin at the same bioeffective dose for lowering cholesterol. METHODS: Eleven (11) healthy volunteers were randomized to a crossover study taking 2400 mg CRYR or 20 mg of lovastatin. RESULTS: The Cmax and area under the curve (AUC) of lovastatin were 22.42 ng/mL, and 80.47 higher than CRYR (p = 0.001 and 0.002, respectively). The Cmax for lovastatin hydroxy-acid was 36.63 ng/mL higher than the Cmax of CRYR hydroxy-acid (p = 0.001). The AUC of lovastatin hydroxy-acid was 258.5 greater than that of CRYR (p = 0.001). CONCLUSIONS: The results suggested that the effect of CRYR on the cholesterol concentration might be caused by the additive and/or synergistic effects of monacolin K with other monacolins and substances in CRYR. It may lead to the ultimate development of a botanical supplement based on CRYR.     

Family history of early cardiovascular disease in children with moderate to severe hypercholesterolemia: relationship to lipoprotein (a) and low-density lipoprotein cholesterol levels

Lipoprotein (a) (Lp(a)) is an established cardiovascular risk factor in adults. We sought to evaluate whether raised Lp(a) levels were predictive of a family history of early cardiovascular disease (CVD) in children already at increased risk for premature atherosclerosis because of elevated low-density lipoprotein (LDL) cholesterol levels. Lp(a) and serum lipid levels were measured in 69 children and offspring with established moderate to severe hypercholesterolemia (serum cholesterol > 170 mg/dL) who were aged 10.7 +/- 4.3 years (range 1.5 to 21 years) and had been referred to a pediatric lipid center. The children represented families with a positive (n = 27) or negative (n = 42) history for premature CVD (<55 years of age in parent or grandparent). In all children, Lp(a) levels ranged from 1 to 140 mg/dL, with a median of 29 mg/dL. Mean total cholesterol, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol levels were 234 mg/dL, 166 mg/dL, and 45 mg/dL, respectively. There was no difference in median Lp(a) levels between the children with a positive family history and those with a negative family history (29.9 mg/dL vs 29.0 mg/dL, respectively). In contrast, children with a positive family history showed significantly higher LDL cholesterol levels (186 +/- 61 mg/dL vs 153 +/- 52 mg/dL, P = .02). Thus, in this group of hypercholesterolemic children, LDL cholesterol but not Lp(a) levels were associated with a family history of premature CVD. Further studies are needed to identify additional specific risk factors associated with the development of CVD in this population.     

Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome

Background: Raised triglycerides (TG), decreased high‐density lipoprotein cholesterol (HDL‐C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). Objective: To compare the effect of high‐dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω‐3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. Methods: We previously randomised patients with low‐density lipoprotein cholesterol (LDL‐C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω‐3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. Results: The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p < 0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL‐C levels (by 7.7%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. Conclusions: All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.     

Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: a 24-week randomized controlled trial

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of colesevelam hydrochloride, a new nonsystemic lipid-lowering agent. PATIENTS AND METHODS: In this double-blind, placebo-controlled trial performed in 1998, 494 patients with primary hypercholesterolemia (low-density lipoprotein [LDL] cholesterol level > or = 130 mg/dL and < or = 220 mg/dL) were randomized to receive placebo or colesevelam (2.3 g/d, 3.0 g/d, 3.8 g/d, or 4.5 g/d) for 24 weeks. Fasting serum lipid profiles were measured to assess efficacy. Adverse events were monitored, and discontinuation rates and compliance rates were analyzed. The primary outcome measure was the mean absolute change of LDL cholesterol from baseline to the end of the 24-week treatment period. RESULTS: Colesevelam lowered mean LDL cholesterol levels 9% to 18% in a dose-dependent manner (P<.001), with a median LDL cholesterol reduction of 20% at 4.5 g/d. The reduction in LDL cholesterol levels was maximal after 2 weeks and sustained throughout the study. Mean total cholesterol levels decreased 4% to 10% (P<.001), while median high-density lipoprotein cholesterol levels increased 3% to 4% (P<.001). Median triglyceride levels increased by 5% to 10% in placebo and colesevelam treatment groups relative to baseline (P<.05), but none of these differences were significantly different from placebo. Mean apolipoprotein B levels decreased 6% to 12% in an apparent dose-dependent manner (P<.001). No significant differences occurred in adverse events or discontinuation rates between groups, and compliance rates were between 88% and 92% for all groups. CONCLUSIONS: Colesevelam was efficacious, decreasing mean LDL cholesterol levels by up to 18%, and well tolerated without serious adverse events.     

Plasma exchange versus an affinity column for cholesterol reduction

The recent introduction of low-density lipoprotein (LDL)/very low-density lipoprotein (VLDL) selective-removal systems offers an alternative to plasma exchange (PE). For the last 10 years, we have treated a inale homozygous hypercholesterolemia type IIA patient with PE using 5% normal serum albumin (NSA) replacement. PE using 6% hydroxyethyl starch (HES) replacement, single dextran sulfate cellulose bead affinity column (DSAC) (Kaneka LA-40), and double DSAC. This report compares the performance of these systems in cholesterol reduction (total, LDL + VLDL), and high-density lipoprotein [HDL] and their effect on the total protein, albumin, and hematocrit levels. The number of procedures and average volume of plasma treated using PE-NSA, PE-HES, I-DSAC, and 2-DSAC were 113, 64, 15, 90 and 3,939, 3,270, 3,519. and 3,588 ml, respectively. The average pretreatment total cholesterol levels were baseline 864 mg/dL, PE-NSA 606 mg/dL, PE-HES 610 mg/dL, I-DSAC 467 mg/dL, and 2-DSAC 395 mg/dL with plasma reductions of 59%, S7%, 47%, and SS%, respectively. Average LDL + VLDL plasma reductions were PE-NSA 58%, PE-HES 59% (N = I), I-DSAC 4670, and 2-DSAC 56%. Average HDL plasma reductions were PE-NSA 58%, PE-HES 69% (N = I ), I-DSAC 58, and 2-DSAC 17%. The average total cholesterol and LDL + VLDL reductions were comparable for both types of PE and the 2-DSAC system. The average HDL loss was 53% lower for the DSAC systems than for PE systems. Of the four systems compared in this study, the 2-DSAC system offers equivalent efficiency in LDL + VLDL reductions as PE while retaining more of the beneficial HDL than PE without the use of replacement solutions. © 1992 Wiley-Liss, Inc.