A Multicenter, Placebo-Controlled, Dose-Ranging Study of Atorvastatin

BACKGROUND: Coronary heart disease (CHD) is the number one cause of death in Western societies. Elevated levels of plasma low-density lipoprotein (LDL) cholesterol and triglycerides (TG) increase the risk for CHD. 3-Hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) reductase inhibitors effectively reduce plasma cholesterol levels in patients with hypercholesterolemia. This study assesses the safety and dose-related effects of atorvastatin calcium on lipoprotein fractions in patients with LDL cholesterol levels between 160 mg/dL (4.1 mM) and 250 mg/dL (6.5 mM) or less and TG levels of 400 mg/dL (4.5 mM) or less. METHODS AND RESULTS: Sixty-five patients were enrolled in a 6-week, randomized, placebo-controlled, parallel-group study. Patients received placebo or atorvastatin 10, 20, 40, 60, or 80 mg once daily. Adjusted mean decreases in LDL cholesterol for patients receiving atorvastatin 10, 20, 40, 60, and 80 mg were 37%, 42%, 50%, 52%, and 59%, respectively, compared with a mean increase of 0.3% for patients receiving placebo; the differences between each of the atorvastatin dose groups and placebo were statistically significant (P =.0001). Total cholesterol, triglycerides, and apolipoprotein B were significantly reduced in atorvastatin groups (P =.0001). Adverse events were similar in the placebo and atorvastatin treatment groups. No patient had a serious adverse event or withdrew because of an adverse event during this study. CONCLUSIONS: Atorvastatin effectively lowered plasma LDL cholesterol, triglycerides, and apoB levels in a dose-related manner. Atorvastatin was well tolerated in hyperlipidemic patients over a 6-week period.     

Effects of ezetimibe/simvastatin on lipoprotein subfractions in patients with primary hypercholesterolemia: an exploratory analysis of archived samples using two commercially available techniques

BACKGROUND: Cholesterol-rich lipoproteins, including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), are known to promote atherosclerosis. Ezetimibe/simvastatin (E/S) is an efficacious lipid-lowering treatment that inhibits both the intestinal absorption and biosynthesis of cholesterol. OBJECTIVE: The aim of the current analysis was to compare the effects of ezetimibe and simvastatin monotherapy and E/S treatment on lipoprotein subfractions and LDL particle size in patients with primary hypercholesterolemia. METHODS: This was an exploratory (hypothesis generating) analysis of archived plasma samples drawn from patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study. After a washout and diet/placebo run-in, patients with hypercholesterolemia (LDL-C, > or =145- < or =250 mg/dL; triglycerides, < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: E/S (10/10, 10/20, 10/40, or 10/80 mg), simvastatin monotherapy (10, 20, 40, or 80 mg), ezetimibe monotherapy (10 mg), or placebo. A subset of patients had lipid subfraction measurements taken at baseline (week 0) and postrandomization (week 12). Plasma samples were used to quantify cholesterol associated with VLDL subfractions (VLDLI+2 and VLDL3), IDL, and 4 LDL subfractions (LDL1-4) via the Vertical Auto Profile II method. LDL-C particle size was determined using segmented gradient gel electrophoresis. The primary end point was median percent change in subfraction cholesterol for E/S versus ezetimibe or simvastatin monotherapy, pooled across doses. RESULTS: Of the 1528 patients randomized in the original study, 1397 (91%) had lipid subfraction measurements taken. E/S was associated with significant reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe, simvastatin, and placebo. E/S resulted in near-additive reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe and simvastatin monotherapy. Of the subfractions examined, with regard to E/S, the greatest reductions were observed in IDL-C and LDL-C1, LDL-C2, and LDL-C3. When compared with placebo, ezetimibe, simvastatin, and E/S did not shift the distribution of LDL particles toward a larger, more buoyant LDL subclass pattern. CONCLUSION: E/S was more effective than ezetimibe and simvastatin monotherapy in reducing atherogenic lipoprotein subfractions in these patients with primary hypercholesterolemia.     

Effect of lovastatin on serum lipids in patients with nonfamilial primary hypercholesterolemia

The effect of lovastatin on serum lipids and its tolerability in patients with non-familial primary hypercholesterolemia (type II-A and type II-B) during a six-month period were evaluated in this open-label study. Thirty-eight patients were enrolled in the study; tolerability was assessed in all 38 patients. Thirty patients completed the study, and the effect of lovastatin on serum lipids in these patients was assessed. Some patients had been treated for hypercholesterolemia with long-term dietary and other non-pharmacologic means before entry into the study. All patients were unresponsive to a six-week program of intensive dietary therapy and other nonpharmacologic treatment to lower their blood cholesterol levels before receiving lovastatin. While maintaining intensive dietary therapy, administration of lovastatin was instituted at a dosage of 20 mg/day, which was increased by 20-mg increments monthly, as necessary, to a maximum of 80 mg/day. In an effort to achieve goal levels of low-density lipoprotein cholesterol (LDL-C), ten patients received a daily dosage of 20 mg, 12 patients received 40 mg, seven patients 60 mg, and one patient 80 mg. Twenty-nine of the 30 patients achieved significant lowering of serum levels of total cholesterol (TC), LDL-C, and apolipoprotein (apo) B-I; this was demonstrated after the first month of therapy with lovastatin and was maintained throughout the six-month treatment period. One patient failed to demonstrate lowering of these serum lipids, despite receiving the maximum recommended dosage of lovastatin of 80 mg/day. Comparative measurements of serum lipids during dietary therapy alone and after six months of diet plus lovastatin therapy were as follows: TC, 289 +/- 5 versus 216 +/- 9 mg/dl (P less than 0.0005); LDL-C, 206 +/- 4 versus 141 +/- 5 mg/dl (P less than 0.0005); and apo B-I, 112 +/- 3 versus 89 +/- 2 mg/dl (P less than 0.0005). Serum levels of very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides decreased slightly during lovastatin therapy, but the changes were not statistically significant. There were slight but statistically insignificant increases in serum levels of high-density lipoprotein cholesterol (HDL-C), apo A-I, and apo A-II.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Efficacy of atorvastatin therapy in ischaemic heart disease - effects on oxidized low-density lipoprotein and adiponectin

The lipid-lowering and anti-atherosclerotic effects of atorvastatin (10 mg/day) were investigated by measuring changes in the levels of oxidized low-density lipoprotein (LDL), serum lipids (total cholesterol [TC], LDL-cholesterol [LDL-C] and triglycerides [TG]), and in the protein adiponectin. This was undertaken in 22 patients with ischaemic heart disease and serum LDL-C levels > 100 mg/dl. After 3 months of therapy, atorvastatin significantly decreased serum lipids, oxidized LDL was reduced from 457.0 +/- 148.6 to 286.9 +/- 88.5 nmol/l, and adiponectin increased from 9.7 +/- 7.4 to 13.9 +/- 9.98 microg/ml. No significant correlation was observed between adiponectin and LDL-C, TG and high-density lipoprotein cholesterol. Atorvastatin therapy was not associated with side-effects, such as myalgia and gastrointestinal disorders, and did not give abnormal laboratory test results. It is concluded that atorvastatin decreases serum lipid and oxidized LDL levels, and increases adiponectin levels in patients with ischaemic heart disease.     

Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia

The advent of treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors has meant that, with a combination of diet and drug therapy, adequate control of serum cholesterol concentrations can be achieved in most patients with hypercholesterolemia. However, some patients, primarily those with familial hypercholesterolemia (FH), may require additional therapy to lower their cholesterol levels. In recent years, low-density lipoprotein (LDL) apheresis has emerged as an effective method of treatment in these patients. The criteria for commencement of LDL apheresis are LDL cholesterol levels of 500 mg/dL or higher for homozygous FH patients, 300 mg/dL or higher for heterozygous FH patients in whom medical therapy has failed, and 200 mg/dL or higher for heterozygous FH patients with documented coronary disease and in whom medical therapy has failed. In addition to cholesterol lowering in patients with FH, other indications for LDL apheresis are emerging. These include its use in the treatment of graft vascular disease in patients receiving cardiac transplants as well as in the treatment of certain glomerulonephritides. This review examines the role of LDL apheresis in the management of lipid disorders and the evidence available to support its use in clinical practice.     

A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia

OBJECTIVE: Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucose- and lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone. RESEARCH DESIGN AND METHODS: We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n = 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n = 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals. RESULTS: Triglyceride levels were reduced by 51.9 +/- 7.8 mg/dl with pioglitazone, but were increased by 13.1 +/- 7.8 mg/dl with rosiglitazone (P < 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 +/- 0.5 vs. 2.4 +/- 0.5 mg/dl; P < 0.001) and the increase in LDL cholesterol was less (12.3 +/- 1.6 vs. 21.3 +/- 1.6 mg/dl; P < 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P < 0.001). LDL particle size increased more with pioglitazone (P = 0.005). CONCLUSIONS: Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size.     

Effects of a new alpha 1-blocker, bunazosin hydrochloride, on plasma lipid components in hypertensive patients with hypercholesterolemia

Oral bunazosin hydrochloride, a new alpha 1-blocker, for 12 weeks was given to ten outpatients diagnosed as having essential hypertension associated with hypercholesterolemia. High-density lipoprotein (HDL) triglyceride, HDL3 cholesterol, and apolipoprotein E levels were significantly decreased by bunazosin treatment. The decrease in HDL triglycerides was a result of the decrease in HDL3 triglyceride levels. There were no significant changes in the other components. The ratio of cholesterol to triglycerides in the low-density lipoprotein (LDL) and HDL fractions was increased significantly after bunazosin treatment. Furthermore, the ratio of HDL2 cholesterol to HDL3 cholesterol after bunazosin treatment was significantly higher than before treatment. The results suggest that the catabolism of triglycerides in lipoprotein and the reduction in tissue cholesterol increase, and that bunazosin hydrochloride does not adversely affect the lipid component in hypertensive patients with hypercholesterolemia.     

A Randomized Multicenter Trial Comparing and Efficacy of Simvastatin and Fluvastatin

BACKGROUND: Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used for the treatment of hypercholesterolemia. Physicians and third-party payers need an accurate measure of their relative potency and hypolipidemic efficacy. We have therefore compared simvastatin against fluvastatin, the newest member of this class. METHODS AND RESULTS: One hundred fifty-eight hypercholesterolemic patients in seven United States lipid clinics participated in this balanced double-blind incomplete block study. After a placebo-diet run-in period, patients received treatment with active drug for three consecutive 5-week periods, with measurement of lipids in a NHLBI-CDC standardized central laboratory at the end of each period. Each patient was randomly assigned to three of the following five treatments: simvastatin 5 mg, 10 mg, and 20 mg and fluvastatin 20 mg and 40 mg. The mean percent reductions in low density lipoprotein cholesterol from baseline were 21, 27, 32, 16, and 23 respectively. The simvastatin/fluvastatin milligram potency ratio was 6.8 (95% CI, 5.3-9.3). At the same 20 mg dose, simvastatin produced an effect on LDL cholesterol approximately double that of fluvastatin and resulted in 46% of patients achieving their National Cholesterol Education Program low density lipoprotein cholesterol target levels, compared to 12% for fluvastatin. CONCLUSIONS: Fluvastatin at its maximal dose of 40 mg daily is approximately equivalent to simvastatin 5 mg daily. Higher doses of simvastatin are considerably more effective in the treatment of primary hypercholesterolemia.     

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.     

Removal of intravenous Intralipid in patients with familial hypercholesterolemia during inhibition of cholesterol absorption and synthesis

BACKGROUND: While plant stanols are known to upregulate low density lipoprotein (LDL) receptors, we studied the effects of plant stanol (STA) and sterol (STE) ester spreads on triglyceride-rich lipoprotein (TRL) removal in statin-treated patients with familial hypercholesterolemia (FH) using intravenous Intralipid-squalene fat tolerance test. METHODS: Five patients consumed STA and STE in a randomized, crossover study for 4 weeks. TRL removal was studied at baseline and at the end of both periods. Serum, chylomicron (CM), and very low density lipoprotein lipids, squalene, and plant sterols were measured. RESULTS: LDL cholesterol was decreased by both spreads (15-16%, p<0.05). Plant sterol concentrations were doubled in serum and CM by STE vs. STA. After the injection of Intralipid, CM squalene and sitosterol, but not triglycerides (TG), reached higher peak levels (and area under the incremental curve (AUIC) of squalene) by both spreads than at baseline. Despite different plant sterol concentrations by STE vs. STA, the incremental curves for plant sterols were similar by the spreads. CONCLUSIONS: Despite the retarded removal of TRL lipids by STA and STE in the statin-treated subjects with FH, improvement of the fasting lipid profile was suggested important in consideration of combination of cholesterol absorption inhibitor with statins even in FH.     

Achieving National Cholesterol Education Program goals for low-density lipoprotein cholesterol in cardiac patients: importance of diet, exercise, weight control, and drug therapy.

OBJECTIVE: To determine how frequently the National Cholesterol Education Program (NCEP) goal of a low-density lipoprotein (LDL) cholesterol level of 100 mg/dL or less is achieved in clinical practice in patients with coronary artery disease and what fraction of patients can achieve this goal without drug therapy. DESIGN: We examined the results of lipid management in 152 consecutive patients who had completed cardiac rehabilitation after an acute coronary event. Patients were randomized to follow-up by specially trained nurses or by preventive cardiologists, and they were not receiving lipid-lowering drugs at the start of the study. MATERIAL AND METHODS: Patients were given aggressive diet and exercise recommendations and lipid-lowering drugs in accordance with NCEP guidelines. Follow-up was continued for a mean of 526 days after the first lipid assessment subsequent to the coronary event. Multiple logistic regression analysis was used to identify independent predictors of a final LDL cholesterol level of 100 mg/dL or less. RESULTS: Of the study group, 39% achieved the NCEP goal LDL cholesterol level of 100 mg/dL or less. Characteristics of the patients with LDL cholesterol levels of 100 mg/dL or less in comparison with those with LDL cholesterol levels of more than 100 mg/dL included a greater frequency of drug therapy (65% versus 38%), more rigorous dietary compliance, longer follow-up (586 +/- 317 days versus 493 +/- 264 days), more favorable weight change (-0.3 +/- 4.9 kg versus +1.7 +/- 5.0 kg), and more extensive weekly exercise (183 +/- 118 minutes versus 127 +/- 107 minutes). CONCLUSION: The registered nurses managed the lipids of these patients as effectively as did the preventive cardiologists. Appropriate drug therapy was the most important factor in achieving an LDL cholesterol level of 100 mg/dL or less, but 35% of patients attaining this NCEP goal were not receiving drug therapy. Exercise, dietary compliance, and weight loss were also important factors.     

Treatment of high-risk older persons with lipid-lowering drug therapy

Randomized, double-blind, placebo-controlled studies and observational studies have demonstrated that statins reduce mortality and major cardiovascular events in high-risk persons with hypercholesterolemia. The aim of this study was to review the evidence for treating high-risk older persons with lipid-lowering drugs. A MEDLINE search of the English-language literature published from January 1, 1989, to June 2006 was conducted to review all studies in which lipid-lowering drug therapy was administered to high-risk older persons. The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons, regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program (NCEP) III guidelines state that in very-high-risk patients, a serum low-density lipoprotein (LDL) cholesterol level of <70 mg/dL is a reasonable clinical strategy, regardless of age. When a high-risk person has hypertriglyceridemia or low serum high-density lipoprotein cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL cholesterol-lowering drug. For moderately-high-risk persons, the serum LDL cholesterol should be reduced to <100 mg/dL. When LDL cholesterol-lowering drug therapy is used for high-risk persons or moderately-high-risk persons, the serum LDL cholesterol should be reduced at least 30% to 40%. High-risk older persons should be treated with lipid-lowering drugs according to the NCEP III updated guidelines to reduce cardiovascular morbidity and mortality.     

Gemfibrozil improves insulin sensitivity and flow‐mediated vasodilatation in type 2 diabetic patients

BACKGROUND: Endothelial dysfunction is an early feature of atherosclerosis. The relationship between insulin action and hypertriglyceridaemia on endothelial function is still debated. MATERIALS AND METHODS: This study was designed to determine the effect of a 3 month treatment with Gemfibrozil (GF) on flow-mediated vasodilatation and insulin sensitivity. Ten type 2 diabetic patients were randomised in crossover, double blind fashion, either to GF, 600 mg b.i.d. or placebo, for 12 weeks. Lipid profile, low-density lipoprotein (LDL) distribution and flotation properties, insulin action and flow-mediated vasodilatation (FMD) by brachial artery ultrasound, were assessed. RESULTS: GF decreased serum triglyceride (TG) concentration with an absolute difference of 1.79 +/- 1.28 mmol L-1 (P < 0.0016) between active treatment and placebo, and significantly increased serum high-density lipoprotein (HDL) cholesterol (P = 0.0233). No differences were observed in total, intermediate-density lipoproteins (IDL), LDL cholesterol concentration and LDL peak buoyancy between treatments. GF also improved SI, an index of insulin action (P = 0.005). The FMD was 7 +/- 3% in the baseline condition, 7 +/- 2% during placebo and 14 +/- 3% after GF (P < 0.006). CONCLUSIONS: GF treatment improves both insulin action and flow-mediated vasodilatation in type 2 diabetic patients. The reduction of TG concentration allows the simultaneous correction of two important components of the metabolic syndrome.     

Effect of cyclosporine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions

Long-term administration of cyclosporine (CsA) has been shown to cause hypercholesteremia, hypertriglyceridemia, and elevations of plasma low-density and very low-density lipoprotein (LDL and VLDL) levels in humans. This study was undertaken to explore the effects of CsA on expressions of the key lipid regulatory enzymes and receptors. Thus, hepatic expressions of cholesterol 7alpha-hydroxylase (the rate-limiting step in cholesterol conversion to bile acids), LDL receptor, and high-density lipoprotein (HDL) receptor proteins, as well as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were determined in rats treated with CsA (18 mg/kg/day) or placebo for 3 weeks. In addition, skeletal muscle and adipose tissue expressions of lipoprotein lipase and VLDL receptor were measured. Western blot analysis was used for all protein measurements using appropriate antibodies against the respective proteins. CsA-treated animals showed mild but significant elevations of plasma cholesterol and triglyceride concentrations. This was associated with a marked down-regulation of cholesterol 7alpha-hydroxylase in the liver and a severe reduction of lipoprotein lipase abundance in skeletal muscle and adipose tissue. However, hepatic LDL receptor and HDL receptor expressions and HMG-CoA reductase activity were not altered by CsA therapy. Likewise, skeletal muscle and adipose tissue VLDL receptor protein expressions were unaffected by CsA administration under the given condition. In conclusion, CsA administration for 3 weeks resulted in a significant reduction of hepatic cholesterol 7alpha-hydroxylase and marked down-regulation of skeletal muscle and adipose tissue lipoprotein lipase abundance in rats. The former abnormality can contribute to hypercholesterolemia by limiting cholesterol catabolism, whereas the latter may contribute to hypertriglyceridemia and VLDL accumulation by limiting triglyceride-rich lipoprotein clearance in CsA-treated animals.     

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.     

Short-term and long-term effects of low-density lipoprotein (LDL) apheresis on restenosis after percutaneous transluminal coronary angioplasty (PTCA): is lowering Lp(a) by LDL apheresis effective on restenosis after PTCA?

It has been reported that serum lipoprotein(a) (Lp[a]) levels in patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA) were significantly higher than in patients without restenosis. In this study, we evaluated the preventive effect of LDL apheresis on restenosis after PTCA in patients with hypercholesterolemia. For 10 patients who had shown a serum cholesterol level of more than 220 mg/dl despite treatment with antihypercholesterolemic drugs, LDL apheresis was conducted every 2 weeks after a successful PTCA until restenosis could be checked. In 4 patients, LDL apheresis was conducted for 2 years. LDL apheresis significantly reduced serum cholesterol from 248 +/- 22 mg/dl to 135 +/- 26 mg/dl and Lp(a) from 42 +/- 34 mg/dl to 21 +/- 16 mg/dl. The average degree of stenosis in the 11 lesions undergoing PTCA was 92 +/- 6% before PTCA, 35 +/- 10% immediately after PTCA, and 38 +/- 19% at 3 to 4 months after PTCA. Restenosis was observed in only 1 lesion. In 4 patients who received LDL apheresis for 2 years, restenosis did not occur in any of the 4 lesions treated. We concluded that LDL apheresis was an efficacious therapy to prevent restenosis after PTCA in patients with hypercholesterolemia.     

Cord blood lipids in infants born to HIV-1-infected women treated with combination antiretroviral therapy

BACKGROUND: To investigate the effect of exposure to protease inhibitor (PI) therapy in utero on cord blood lipids in infants born to mothers enrolled in AIDS Clinical Trials Group protocol 5084, a prospective, multicentre, observational study of antiretroviral therapy (ART) during pregnancy. METHODS: Clinical outcome was determined in 80 infants born to women treated with PIs and 73 infants born to women treated with other antiretrovirals during pregnancy. Cord blood serum from 117 of these infants was assayed for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein A1 (apoA1), apolipoprotein B100 (apoB) and lipoprotein (a). Covariates considered in the analysis included race/ethnicity, gestational age, infant gender, infant birth weight, mode of delivery, maternal tobacco and alcohol use, post-partum body mass index, and ART duration. RESULTS: Cord blood total and HDL cholesterol, triglyceride, apoA1, apoB, lipoprotein (a) and apoB/apoA1 ratio were not different between the two groups. Cord blood lipid levels in these HIV-exposed infants were similar to those reported in other neonatal cohorts. Controlling for race/ethnicity, infants born to women treated with PIs had higher LDL cholesterol than those born to women not treated with PIs (29 mg/dl versus 27 mg/dl, P = 0.006). CONCLUSION: Only LDL cholesterol was significantly higher in the cord blood of PI-exposed infants versus those not exposed to PIs in utero. As the difference between the two groups was small, the clinical relevance of the effect of maternal PI treatment on infant LDL cholesterol levels at birth is not clear.     

Untreated Hypercholesterolemia in an Emergency Department Chest Pain Observation Unit Population

OBJECTIVES: To describe the prevalence of hypercholesterolemia in a predominantly African American, innercity chest pain observation unit (CPOU) patient population, and to estimate the percentage of patients eligible for cholesterol-lowering therapy as indicated by the 2001 National Cholesterol Education Program guidelines. METHODS: A cross-sectional study design utilizing a convenience sample of patients from a high-volume urban hospital CPOU. Patients with chest pain suspicious of cardiac etiology who had negative initial electrocardiograms and cardiac markers were assigned to the chest pain protocol. Consenting subjects were screened for hypercholesterolemia through capillary blood point-of-care testing with a cutoff of 190 mg/dL. Those who tested positive had four-hour fasting complete lipid profiles performed by the central laboratory. RESULTS: There were 112 patients enrolled in this study (mean age = 51 years; 57% male; and 83% African American). Elevated values on the screening test were obtained on 28 [25%; 95% confidence interval (95% CI) = 16.9 to 33.0] of these patients. These patients were found to have a mean four-hour fasting total cholesterol level of 224 mg/dL, a low-density lipoprotein (LDL) level of 138 mg/dL, a high-density lipoprotein (HDL) level of 52 mg/dL, and a triglyceride level of 168 mg/dL. Of the patients identified through the screening test, 54% proved eligible for cholesterol-lowering medications and 91.7% of these patients reported an interest in initiating therapy. CONCLUSIONS: In this study, approximately 25% of inner-city CPOU patients are possible candidates for cholesterol-lowering interventions. Benefits of initiating therapy during this potential "teachable moment" in a CPOU should be investigated in a subsequent multicenter randomized trial.     

Effects of fenofibrate on high-density lipoprotein particle size in patients with hyperlipidemia: a randomized,double-blind,placebo-controlled,multicenter, crossover study

BACKGROUND: Fenofibrate lowers serum total cholesterol and triglyceride levels while it elevates serum high-density lipoprotein cholesterol (HDL-C) level. OBJECTIVE: The aim of this study was to investigate the effects of fenofibrate on the particle size of high-density lipoprotein (HDL). METHODS: Patients with hyperlipidemia (as defined by serum triglyceride level > or = 150 mg/dL in the fasting state) were enrolled in this randomized, double-blind, placebo-controlled, multicenter, crossover study. Fenofibrate 300 mg (corresponding to 200 mg of micronized fenofibrate) or placebo was administered orally once daily after dinner for 8 weeks, followed by crossover of the 2 drugs for an additional 8 weeks. RESULTS: Fifty hyperlipidemic patients (31 men, 19 women; mean [SD] age, 54.6 [12.7] years) were enrolled. Serum total cholesterol and triglyceride levels were significantly reduced with fenofibrate treatment compared with placebo (9.4% [P = 0.007] and 34.4% [P < 0.001], respectively), whereas HDL-C levels were significantly elevated (by 25.8% [P < 0.001]). Lipoprotein lipase (LPL) activity, LPL protein level, and hepatic triglyceride lipase activity increased by 10.5%, 13.4%, and 11.4%, respectively, with fenofibrate compared with placebo. HDL was classified into 3 groups by particle size: HDL3 <88 A; HDL2a > or = 88 A but <98 A; and HDL2b > or = 98 A. The amount of HDL3 increased significantly with fenofibrate compared with placebo (P < 0.001). Fenofibrate was well tolerated during the study. Abnormal clinical laboratory values were noted in 20 of 48 patients (41.7%), but these events were mild and not clinically significant. CONCLUSION: Taken together, these findings indicate that fenofibrate therapy increased the HDL subfraction with the smallest diameter (HDL3), which is largely responsible for withdrawing cholesterol from peripheral cells.