Lipid-lowering effects of colesevelam HCl in combination with ezetimibe

ABSTRACT

Objective: The primary aim of this study was to compare the effect of colesevelam HCl in combination with ezetimibe to ezetimibe monotherapy on low-density lipoprotein cholesterol (LDL.C) levels in subjects with primary hypercholesterolemia.

Methods: Subjects with primary hypercholesterolemia (N = 86) were enrolled in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a 4- to 8‐week washout period, subjects received colesevelam HCl 3.8?g/day plus ezetimibe 10?mg/day or colesevelam HCl placebo plus ezetimibe 10?mg/day for 6 weeks. The primary efficacy endpoint was the mean percent change in LDL‐C during randomized treatment. Secondary endpoints included mean absolute change in LDL‐C, mean absolute and mean percent change in levels of high-density lipoprotein cholesterol (HDL‐C), non-HDL‐C, total cholesterol (TC), apolipoprotein (apo) A-I and apo B, and median absolute and percent changes in triglycerides (TG) and high-sensitivity C‐reactive protein from baseline to end of treatment. Of the 86 subjects randomized to treatment, 85 were included in the intent-to-treat analysis.

Results: After 6 weeks of treatment, colesevelam HCl plus ezetimibe produced a mean percent change in LDL‐C of –32.3% versus–21.4% with ezetimibe monotherapy (?p < 0.0001). Colesevelam HCl plus ezetimibe was significantly more effective than ezetimibe alone at producing mean percent reductions in TC, non‐HDL‐C, and apo B and increases in apo A-I (?p < 0.005 for all). Neither treatment regimen resulted in significant changes in median TG levels compared with baseline (?p = NS). Both treatments were safe and generally well tolerated.

Conclusions: Colesevelam HCl plus ezetimibe combination therapy significantly reduced mean LDL‐C, TC, non-HDL‐C, and apo B levels and increased apo A-I levels (?p < 0.005 for all) without significantly increasing median TG levels in hypercholesterolemic subjects compared with ezetimibe alone. Although limited in that atherosclerotic coronary heart disease outcomes were not evaluated, this study demonstrated that combining colesevelam HCl with ezetimibe is a therapeutic option in hypercholesterolemic patients, such as those in whom statins are contraindicated and/or who may have intolerances to statin therapy.     

Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia

OBJECTIVE: High-density lipoprotein (HDL)-associated paraoxonase (PON) activity may play an important role in the inhibition of low-density lipoprotein (LDL) oxidation. Previous studies have demonstrated that serum PON activity is decreased in patients with hyperlipoproteinaemia and coronary heart disease. The study presented here examined the effect of short-term treatment with simvastatin and atorvastatin on lipids and PON activity in patients with hyperlipoproteinaemia. RESEARCH DESIGN AND METHODS: A prospective, non-blinded, single-group, cross-over, comparative trial was performed. Following an 8-week dietary run-in period, 49 patients (23 men and 26 women, mean age: 59.8 +/- 7.9 years) with Fredrickson type IIa. and IIb. hyperlipoproteinaemias were randomized to receive either simvastatin 20 mg/day or atorvastatin 10 mg/day for 3 months. Following an 8-week washout period, patients were crossed-over to receive the other drug for a further 3 months. Serum lipids were measured and serum PON activity was determined spectrophotometrically using paraoxon as a substrate. RESULTS: Simvastatin treatment significantly reduced serum cholesterol, LDL-cholesterol (LDL-C) and apolipoprotein (apo) B levels (p < 0.001). Atorvastatin had a more pronounced cholesterol, LDL-C- and apo B-lowering effect (p < 0.001) compared with simvastatin. Both statins also significantly reduced serum triglyceride levels (p < 0.01). Simvastatin and atorvastatin caused no significant change in the levels of HDL-cholesterol (HDL-C) and apo A1. HDL-associated PON activity did not change significantly after simvastatin therapy, but significantly increased after atorvastatin treatment (p < 0.05). CONCLUSIONS: Short-term administration of simvastatin did not increase PON activity. Atorvastatin treatment had a favourable effect on lipid profile and increased the activity of HDL-associated PON.     

Hypocholesterolemic effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the guinea pig: atorvastatin versus simvastatin.

Male Hartley guinea pigs were fed a hypercholesterolemic diet rich in lauric and myristic acids with 0, 10, or 20 mg/kg of simvastatin or atorvastatin for 21 days. Atorvastatin and simvastatin resulted in a lowering of plasma low-density lipoprotein (LDL) cholesterol in a dose-dependent manner by an average of 48 and 61% with 10 and 20 mg/kg, respectively. Both statins were equally effective in lowering plasma LDL cholesterol and apolipoprotein B (apo-B) levels. Atorvastatin and simvastatin treatments yielded LDL particles that differed in composition from the control. Due to the relevance of LDL oxidation and cholesteryl ester transfer in plasma to the progression of atherosclerosis, these parameters were analyzed after statin treatment. Atorvastatin and simvastatin treatment decreased the susceptibility of LDL particles to oxidation by 95% as determined by the formation of thiobarbituric acid reactive substances. An 80% decrease in the transfer of cholesteryl ester between high-density lipoprotein (HDL) and the apo-B-containing lipoproteins was observed after simvastatin and atorvastatin treatment. In addition, statin effects on plasma LDL transport were studied. Simvastatin- and atorvastatin-treated guinea pigs exhibited 125 and 175% faster LDL fractional catabolic rates, respectively, compared with control animals. No change in LDL apo-B flux was induced by either treatment; however, LDL apo-B pool size was reduced after statin treatment. Hepatic microsomal free cholesterol was lower in the atorvastatin and simvastatin groups. However, only atorvastatin treatment resulted in an 80% decrease of acyl-CoA:cholesterol acyltransferase activity (P < 0.001). In summary, atorvastatin and simvastatin had similar LDL cholesterol lowering properties, but these drugs modified LDL transport and hepatic cholesterol metabolism differently.     

Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients

ABSTRACT

Objective: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses.

Research design and methods: Double-blind, multicenter, 6‐week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10?mg/day), the next highest (10/40 or 20?mg/day), and maximum doses (10/80 or 40?mg/day).

Results: At all doses and across doses, ezetimibe/simvastatin reduced LDL‐C levels significantly more (52–61%) than rosuvastatin (46–57%; p ≤ 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p ≤ 0.005) attained LDL‐C levels < 70?mg/dL (1.8?mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (?p < 0.001), non-high-density lipoprotein cholesterol (?p < 0.001), lipid ratios (?p ≤ 0.003), and apolipoprotein B (?p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting (?p = 0.004) and next highest (?p = 0.006) doses, and across all doses (?p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10?mg versus 10/20?mg/day (?p = 0.004) and 40?mg versus 10/80?mg/day (?p < 0.001).

Conclusion: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL‐C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies.     

Lipid altering-efficacy of ezetimibe co-administered with simvastatin compared with rosuvastatin: a meta-analysis of pooled data from 14 clinical trials

OBJECTIVE: Results of direct comparative studies between ezetimibe/simvastatin and rosuvastatin therapies have not been reported. Both of these treatment options offer significant reductions in LDL-C. To evaluate the lipid efficacy of each of these therapies relative to each other, a meta-analysis of data from 14 randomized, double-blind clinical trials that compared the effectiveness of two new options for cholesterol lowering was performed. DATA SOURCES: PubMed, EMBASE and BIOSIS databases were searched up to March 14, 2004. METHODS OF STUDY SELECTION: Efficacy results from clinical trials with the co-administration of ezetimibe 10 mg with simvastatin or with the ezetimibe/simvastatin combination product (ezetimibe/simvastatin 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg) were compared with efficacy results from clinical trials of rosuvastatin 5 mg, 10 mg, 20 mg, and 40 mg in patients with primary hypercholesterolemia. Trials in healthy patients, heterozygous familial hypercholesterolemia or combined hyperlipidemia, and pharmacokinetic trials were excluded. DATA EXTRACTION AND SYNTHESIS: This analysis used pooled data for LDL-C, HDL-C, non-HDL-C, triglycerides, total cholesterol, apolipoprotein (apo) A-I, and apo B for the two therapies at their lowest doses (ezetimibe/simvastatin 10/10 mg and rosuvastatin 5 mg) through their highest doses (ezetimibe/simvastatin 10/80 mg and rosuvastatin 40 mg), and estimated within-treatment percentage changes in these parameters. Percentage reductions from baseline in LDL-C for the pooled data were 46.2% and 41.8% for ezetimibe/simvastatin 10/10 mg and rosuvastatin 5 mg, respectively; 50.6% and 47.4% for ezetimibe/simvastatin 10/20 mg and rosuvastatin 10 mg, respectively; 55.9% and 52.1% for ezetimibe/simvastatin 10/40 mg and rosuvastatin 20 mg, respectively; and 59.7% and 58.5% for ezetimibe/simvastatin 10/80 mg and rosuvastatin 40 mg, respectively. CONCLUSIONS: The results of this meta-analysis suggest greater LDL-C lowering with ezetimibe/simvastatin compared with rosuvastatin. These results need to be confirmed in a head-to-head comparison of both therapies.     

Impact of short‐term low‐dose atorvastatin on low‐density lipoprotein and high‐density lipoprotein subfraction phenotype

Statins can significantly reduce low‐density lipoprotein–cholesterol (LDL‐C) and modestly raise or not alter high‐density lipoprotein–cholesterol (HDL‐C). However, their impact on high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) subfractions has been less examined. The aim of the present study was to investigate the short‐term impact of low‐dose atorvastatin on HDL and LDL subfractions in humans. In this randomized study, data from 52 subjects were analysed. Thirty‐seven patients with atherosclerosis were randomized to treatment with atorvastatin 10 mg/day (n = 17) or 20 mg/day (n = 20) for 8 weeks, with 15 healthy subjects without therapy used as a control group. The lipid profile and lipoprotein subfractions were determined using the Lipoprint system at baseline and at 8 weeks. The data suggest that atorvastatin treatment (10 and 20 mg/day) for 8 weeks significantly decreases LDL‐C levels and reduces the cholesterol concentration of all LDL subfractions, which is accompanied by an increase of the mean LDL particle size. Although 10 mg/day atorvastatin treatment for 8 weeks had no impact on the HDL subfraction, 20 mg/day atorvastatin for 8 weeks significantly increased the cholesterol concentration of large HDL particles and decreased the cholesterol concentration of small HDL particles without changing serum HDL‐C levels in patients with atherosclerosis. Therefore, the results suggest that 20 mg/day atorvastatin treatment for 8 weeks may result in a favourable modification of the HDL subfraction phenotype in addition to its effects on the cholesterol concentration of all LDL subfractions and mean LDL particle size.     

Effect of Atorvastatin versus Simvastatin on Lipid Profile and Plasma Fibrinogen in Patients with Hypercholesterolaemia: A Pilot, Randomised, Double-Blind, Dose-Titrating Study

OBJECTIVE: To investigate the effect of atorvastatin vs simvastatin on lipid profile and plasma fibrinogen in patients with hypercholesterolaemia. PATIENTS: 30 outpatients (25 men), with a median age of 51 years were studied. Eight patients had established coronary artery disease (CAD) and four had diabetes mellitus at baseline. 11 patients presented a Frederickson's IIb phenotype and 19 a IIa phenotype at baseline. STUDY DESIGN: After a 6-week placebo period, patients were randomly assigned to simvastatin (10 mg/day, n = 15) or atorvastatin (10 mg/day, n = 15). Lipid profile, apolipoproteins B and A-I and plasma fibrinogen were measured for a 16-week period, at 4-week intervals. Thereafter, the dose of each drug was doubled only in patients with low density lipoprotein cholesterol (LDL-C) levels above 130 mg/dl for a further 16-week period. RESULTS: Ten of 15 patients on atorvastatin 10mg (66%) and four of 15 on simvastatin 10mg (27%) achieved the LDL-C <130 mg/dl goal. Apolipoprotein B was reduced by both drugs (-33%, p < 0.001 for atorvastatin and -18%, p < 0.05 for simvastatin), but plasma fibrinogen and triglyceride were reduced only by atorvastatin (-20%, p < 0.01; -36%, p < 0.001, respectively). During the second 16-week period seven of 11 patients receiving the simvastatin 20mg dose (64%) achieved the LDL-C <130 mg/dl goal. The comparison of atorvastatin 10mg with simvastatin 20mg showed that the drugs appear to be equipotent in terms of LDL-C lowering. CONCLUSIONS: Atorvastatin in equipotent doses to simvastatin appeared to be more effective than the latter in reducing triglyceride and plasma fibrinogen in patients with hypercholesterolaemia, mainly in those with Frederickson's phenotype Iib.     

Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia

OBJECTIVE: The aim of this study was to evaluate the amount of low-density lipoprotein cholesterol (LDL-C) reduction achieved by adding the specifically engineered bile acid sequestrant (SE-BAS) colesevelam HCl to a stable dose of fenofibrate in patients with mixed hyperlipidemia. RESEARCH DESIGN AND METHODS: Patients with mixed hyperlipidemia (n = 129) were enrolled in a randomized, double-blind, placebo-controlled, parallel-group study investigating the efficacy of fenofibrate plus colesevelam HCl versus fenofibrate monotherapy. After a 4- to 8-week washout period, subjects received fenofibrate 160 mg/day for 8 weeks and were then randomized to receive colesevelam HCl 3.75 g/day or placebo, in addition to fenofibrate 160 mg/day, for 6 weeks. MAIN OUTCOMES MEASURES: The primary efficacy endpoint was mean percent change in LDL-C during randomized treatment. Secondary endpoints included absolute and percent changes in mean levels of LDL-C, triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), and apolipoproteins (apo) A-I and B during randomized treatment and from washout to end of randomized treatment. RESULTS: Of the 129 patients randomized to treatment, 119 completed the study. After 6 weeks of treatment, fenofibrate plus colesevelam HCl produced a mean percent change in LDL-C of -10.4% versus +2.3% with fenofibrate monotherapy (p < 0.0001). Fenofibrate plus colesevelam HCl was significantly more effective than fenofibrate alone at reducing levels of non-HDL-C, TC, and apo B (p < or = 0.0002). Colesevelam HCl did not significantly affect the TG-lowering effects of fenofibrate. Both treatment regimens were safe and well tolerated. CONCLUSIONS: Compared with fenofibrate monotherapy in patients with mixed hyperlipidemia, fenofibrate/colesevelam HCl combination therapy significantly reduced mean LDL-C, non-HDL-C, TC, and apo B levels without significantly affecting the TG-lowering or HDL-C-raising effects of fenofibrate. Fenofibrate/colesevelam HCl combination therapy is a safe, useful alternative for the treatment of mixed hyperlipidemia.     

Lipid altering-efficacy of ezetimibe co-administered with simvastatin compared with rosuvastatin: a meta-analysis of pooled data from 14 clinical trials

ABSTRACT

Objective: Results of direct comparative studies between ezetimibe/simvastatin and rosuvastatin therapies have not been reported. Both of these treatment options offer significant reductions in LDL-C. To evaluate the lipid efficacy of each of these therapies relative to each other, a meta-analysis of data from 14 randomized, double-blind clinical trials that compared the effectiveness of two new options for cholesterol lowering was performed.

Data sources: PubMed, EMBASE and BIOSIS databases were searched up to March 14, 2004.

Methods of study selection: Efficacy results from clinical trials with the co-administration of ezetimibe 10?mg with simvastatin or with the ezetimibe/simvastatin combination product (ezetimibe/simvastatin 10/10?mg, 10/20?mg, 10/40?mg, and 10/80?mg) were compared with efficacy results from clinical trials of rosuvastatin 5?mg, 10?mg, 20?mg, and 40?mg in patients with primary hypercholesterolemia. Trials in healthy patients, heterozygous familial hypercholesterolemia or combined hyperlipidemia, and pharmacokinetic trials were excluded.

Data extraction and synthesis: This analysis used pooled data for LDL-C, HDL-C, non-HDL-C, triglycerides, total cholesterol, apolipoprotein (apo) A-I, and apo B for the two therapies at their lowest doses (ezetimibe/simvastatin 10/10?mg and rosuvastatin 5?mg) through their highest doses (ezetimibe/simvastatin 10/80?mg and rosuvastatin 40?mg), and estimated within-treatment percentage changes in these parameters. Percentage reductions from baseline in LDL-C for the pooled data were 46.2% and 41.8% for ezetimibe/simvastatin 10/10?mg and rosuvastatin 5?mg, respectively; 50.6% and 47.4% for ezetimibe/simvastatin 10/20?mg and rosuvastatin 10?mg, respectively; 55.9% and 52.1% for ezetimibe/simvastatin 10/40?mg and rosuvastatin 20?mg, respectively; and 59.7% and 58.5% for ezetimibe/simvastatin 10/80?mg and rosuvastatin 40?mg, respectively.

Conclusions: The results of this meta-analysis suggest greater LDL-C lowering with ezetimibe/simvastatin compared with rosuvastatin. These results need to be confirmed in a head-to-head comparison of both therapies.     

Simvastatin and bezafibrate: Effects on serum lipoproteins and lecithin: Cholesterol acyltransferase activity in familial hypercholesterolaemia

Summary Sixteen subjects with familial hypercholesterolaemia were randomly assigned to treatment with simvastatin 20–40 mg/day (an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase) or with bezafibrate 600 mg/day (a clofibrate analogue) for 12 weeks.Both drugs produced significant reductions in serum and LDL cholesterol; mean percentage fall –30.5% and –38.1% (simvastatin) and –17.8% and –20.6% (bezafibrate), respectively. Both drugs also caused a decrease in VLDL cholesterol, while only bezafibrate decreased the serum and VLDL triglyceride levels and increased HDL cholesterol and serum apolipoprotein A-I and A-II levels. Serum apolipoprotein B fell by 33.3% (simvastatin) and 15.7% (bezafibrate). Simvastatin and bezafibrate produced significant increases in the mean fractional esterification rate of LCAT, by +124,1% and +20.6%, respectively.Thus simvastatin was clearly more effective than bezafibrate in lowering LDL by enhancing its turnover, but bezafibrate had specific effects on VLDL and HDL that might be favourable in combined treatment regimens.     

Piperine, an active principle from Piper nigrum, modulates hormonal and apo lipoprotein profiles in hyperlipidemic rats

PURPOSE: To study the effect of piperine, an alkaloid, on thyroid hormones and apolipoproteins in high-fat-diet (HFD) and antithyroid drug-induced hyperlipidemic rats. EXPERIMENTAL: Male Wistar rats were first divided into two groups, control diet and high-fat diet (HFD) and then subdivided into four subgroups of ten animals each. The animals were treated with the following regimens for 10 weeks: 1% carboxymethyl cellulose; 10 mg carbimazole (CM)/kg body weight; 10 mg CM + 40 mg piperine/kg body weight, and 10 mg CM + 2 mg atorvastatin /ATV//kg body weight. Lipid profiles, hormone levels, and apolipoprotein levels were studied in all groups. RESULTS: HFD and/or CM administration significantly elevated the plasma levels of total cholesterol, VLDL, LDL, triglycerides, free fatty acids, and phospholipids, but significantly reduced the HDL levels. Moreover, CM administration significantly reduced apo A-I levels and T3, T4 and testosterone levels while significantly elevating plasma apo B, thyroid stimulating hormone (TSH) and insulin levels. The simultaneous administration of piperine and HFD significantly reduced plasma lipids and lipoproteins levels, except for HDL, which was significantly elevated. Piperine supplementation also improved the plasma levels of apo A-I, T3, T4, testosterone, and I and significantly reduced apo B, TSH, and insulin to near normal levels. CONCLUSIONS: The data presented here provide evidence that piperine possesses thyrogenic activity, thus modulating apolipoprotein levels and insulin resistance in HFD-fed rats, opening a new view in the management of dyslipidemia by dietary supplementation with nutrients.     

Efficacy of alternate day dosing of atorvastatin

Atorvastatin is a synthetic inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. It has a longer half life and longer duration of action than that of all other available HMG-CoA inhibitors. We evaluated the efficacy of alternate-day dosing of atorvastatin in comparison with the standard one-daily dose on total cholesterol, low and High-density lipoprotein (LDL and HDL) and triglycerides. This study is a randomized, blinded, and controlled clinical trial. Sixty-six patients with LDL cholesterol of more than 100 mg/dl were enrolled. Baseline fasting lipid profile (total cholesterol, LDL, HDL and triglyceride), liver function tests and creatine kinase were drawn. Patients were randomized to three atorvastatin dose groups. Group I received 10 mg of atorvastatin every day, group II received 20 mg of atorvastatin every day, and group III received 20 mg every other day. After 6 weeks of treatment with atorvastatin, fasting lipid profiles, liver function tests and creatine kinase concentrations were re-taken. Compliance to treatment was assessed at each visit. Of the sixty-six patients enrolled, sixty completed the study. All three regimens significantly reduced total cholesterol and LDL compared to baseline. No statistically significant difference existed between the three groups in regards to total or a percentage decrease in total cholesterol and LDL cholesterol at 6 weeks compared to baseline. All regimens were well tolerated and none of the patients showed significant elevation of liver enzyme or creatine kinase during the course of the study. In conclusions the alternate-day dosing of atorvastatin is an efficacious and safe alternate to daily dosing and yet inexpensive.     

Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.

Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs. CONCLUSION: Atorvastatin is an appropriate first-line lipid-lowering therapy in numerous groups of patients at low to high risk of CHD. Additionally it has a definite role in treating patients requiring greater decreases in LDL-cholesterol levels. Long-term studies are under way to determine whether achieving very low LDL-cholesterol levels with atorvastatin is likely to show additional benefits on morbidity and mortality in patients with CHD.     

The effect of simvastatin,ezetimibe and their combination on the lipid profile,arterial stiffness and inflammatory markers

OBJECTIVE: Arterial stiffness and highly sensitive C-reactive protein (hsCRP) serum level predict the risk for cardiovascular events. The most commonly used drugs for lowering cholesterol levels, the statins, also have anti-inflammatory effects and can decrease arterial stiffness. Ezetimibe is the first drug of a new class of cholesterol absorption inhibitors in common use and, to date, its effect on arterial stiffness has not yet been studied. The aim of this study was to compare the effect of simvastatin and ezetimibe, both singly and in combination, on arterial stiffness and hsCRP serum concentration in hypercholesterolemic patients. METHODS: Forty hypercholesterolemic patients were studied. Group1 comprised previously untreated patients, who received simvastatin at doses of 40 mg/day during the study; group 2 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 80 mg/day during the study; group 3 consisted of patients previously untreated, who received ezetimibe at doses of 10 mg/day during the study; group 4 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 40 mg/day and ezetimibe at 10 mg/day during the study. Arterial stiffness expressed as the Augmentation Index (AIx) (assessed by pulse wave analysis), the lipid profile and the hsCRP level were measured at baseline and after 3 months of treatment. RESULTS: The reduction in low-density lipoprotein (LDL) after treatment was significantly greater in groups 1 and 4 (39.9 and 35.7%) than in groups 2 and 3 (17.7 and 16.9%; p = 0.005). The AIx decreased significantly only in group 1 patients, from 30.2 +/- 8.3% before treatment to 21.6 +/- 6.5% after treatment (p < 0.001). Changes in hsCRP paralleled the changes in AIx, with a significant decrease in patients in group 1 only, from 2.8 +/- 2.5 mg/L before treatment to 1.6 +/- 1.5 mg/L after treatment (p = 0.016). CONCLUSION: Ezetimibe as a monotherapy had no effect on arterial stiffness or hsCRP, while the administration of simvastatin at 40 mg per day improved arterial stiffness and CRP. However, increasing the dose of simvastatin or administering ezetimibe in combination with simvastatin had no beneficial effects on arterial stiffness.     

Efficacy of combination of atorvastatin and micronised fenofibrate in the treatment of severe mixed hyperlipidemia

OBJECTIVES: In patients with mixed lipid disorders, monotherapy may not effectively control all lipid abnormalities. We undertook this study to assess the efficacy of fenofibrate in combination with atorvastatin in patients with severe mixed dyslipidemia. METHODS: This was an 18-week, open-label study conducted in our lipid clinic. After a 6-week dietary baseline phase, patients received 200 mg/day micronised fenofibrate for 6 weeks. At the end of this period the subjects discontinued this treatment and received 40 mg/day atorvastatin for 6 weeks. Finally 200 mg/day of micronised fenofibrate was added to the statin therapy. RESULTS: Administration of micronised fenofibrate reduced serum triglycerides (P < 0.01) and total cholesterol and low-density lipoprotein (LDL) cholesterol (P < 0.05 for both parameters), while it evoked a significant increase in serum high-density lipoprotein (HDL) cholesterol levels (P < 0.05). Atorvastatin monotherapy induced a more pronounced decrease of total and LDL cholesterol. However, plasma triglycerides, although significantly lower than baseline values (P < 0.05), were higher than the values observed during treatment with fenofibrate. Moreover, serum HDL cholesterol concentrations were higher during fibrate therapy than during the statin one. During the combination therapy, the decrease in triglycerides was greater than that observed with fenofibrate alone, while the decrease in LDL cholesterol was more pronounced than that observed with atorvastatin alone. CONCLUSION: The combination of atorvastatin with micronised fenofibrate in patients with severe mixed dyslipidemia may have a favourable effect on some major coronary artery disease risk factors.     

Differential effects of beclobrate on lipid/lipoprotein distribution in normal and hypercholesterolemic rats

Beclobrate, a new fibric acid derivative, displays remarkable lipid lowering activity in rodents. In order to evaluate changes in the distribution and liver handling of lipoproteins, beclobrate was tested in rats fed on a normal or hypercholesterolemic diet. On the normal diet, beclobrate lowered total plasma cholesterol by 22-33.4% (10-50 mg/kg); the cholesterol reduction occurred mainly in high density lipoproteins (HDL) (by 24-45% with the three tested doses). The metabolic clearance of 125I-labelled beta-very low density lipoproteins (beta-VLDL) injected into these animals almost doubled (0.20 1/h vs. 0.13 1/h in controls) after treatment with 20 mg/kg of beclobrate. In addition, beclobrate administration dramatically increased the activity of the high-affinity receptors for beta-VLDL in isolated liver membranes (Bmax: 208 +/- 17.6 vs. 146 +/- 2.6 ng/mg of protein for controls). On the hypercholesterolemic diet, beclobrate treatment (50 mg/kg) was associated with a 25% reduction in total cholesterol accompanied, however, by a 166% rise in HDL cholesterol. In these animals, the composition of VLDL, typically cholesterol-enriched, became close to normal. The increased HDL was characterized by a remarkable enrichment with particles containing apolipoprotein E (apo E), which is compatible with either an improved peripheral cholesterol removal or an enhanced direct secretion of apo E. The two models offer different opportunities for evaluating the mechanism of action of this new lipid lowering agent. Lipoprotein catabolism and receptor-mediated clearance were characteristically improved in normolipidemic rats whereas major effects on HDL metabolism could be demonstrated in hypercholesterolemic rats.     

LDL‐C/HDL‐C ratio in subjects with cardiovascular disease and a low HDL‐C: results of the RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study

ABSTRACT

Background: The ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (LDL‐C/HDL‐C) is a reliable predictor of cardiovascular risk. Low HDL‐C levels in patients with coronary artery disease are associated with a high risk for cardiovascular events.

Objectives: This study compared the effects of rosuvastatin and atorvastatin on the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C.

Methods: Patients aged 40–80 years with established cardiovascular disease and HDL‐C < 1.0?mmol/L (< 40?mg/dL) entered a 6‐week dietary run-in period, before randomisation to open-label treatment with rosuvastatin 10?mg (n = 230) or atorvastatin 20?mg (n = 231) for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20?mg or atorvastatin 40?mg, and after 12 weeks to rosuvastatin 40?mg or atorvastatin 80?mg. Serum lipid parameters were measured at baseline and 6, 12 and 18 weeks.

Results: After 6 weeks of treatment, mean percentage change from baseline in LDL‐C/HDL‐C ratio was –47.0% in the rosuvastatin group and –41.9% in the atorvastatin group (?p < 0.05 for between-group comparison). After 12 and 18 weeks of treatment, change from baseline was –53.0% and –57.3%, respectively, for rosuvastatin, compared with –47.9% and –49.6%, respectively, for atorvastatin (?p < 0.01 and p < 0.001, respectively, for between-group comparison). Rosuvastatin also reduced LDL‐C, total cholesterol and non-HDL‐C significantly more than atorvastatin at all three time points, and significantly improved total cholesterol/HDL‐C and apolipoprotein B/A‐I ratios.

Conclusions: Rosuvastatin 10, 20 and 40?mg is significantly more effective than atorvastatin 20, 40 and 80?mg, respectively, in improving the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C. Further studies are required to clarify the benefits of rosuvastatin for reduction of cardiovascular risk.     

The Effect of Nutritional Supplements on Serum High-Density Lipoprotein Cholesterol and Apolipoprotein A-I

One of the factors contributing to the increased risk of developing premature atherosclerosis is low plasma concentrations of high-density lipoprotein (HDL) cholesterol. Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein A-I (apo A-I). Diet has an important role in modulating HDL cholesterol level. The widespread use of nutritional supplements may also alter the biology of HDL. In this review, we discuss the effect of select nutritional supplements on serum HDL cholesterol and apo A-I levels. Some nutritional supplements, such as phytosterols, soy proteins, and black seed extracts, may increase HDL cholesterol levels, while others such as cholic acid and high doses of commonly used antioxidant vitamins may downregulate HDL cholesterol levels and reduce its cardioprotection. Multiple mechanisms are involved in the regulation of HDL levels, so changes in production and clearance of HDL may have different clinical implications. The clinical relevance of the changes in HDL and apo A-I caused by nutrient supplementation needs to be tested in controlled clinical trials.     

Pharmacoeconomic assessment of HMG-CoA reductase inhibitor therapy: an analysis based on the CURVES study

We conducted a post hoc pharmacoeconomic analysis of a multicenter, open-label, randomized, parallel-group, 8-week efficacy-safety comparison of five HMG-CoA reductase inhibitors-atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The 534 patients requiring cholesterol-lowering therapy took the drugs for 8 weeks with 15 different regimens. Low-density lipoprotein (LDL) was measured after 6 weeks of diet (baseline) and after 8 weeks of treatment with a study drug. At dosages of 10, 20, and 40 mg/day, atorvastatin was associated with significantly greater reductions in LDL than equivalent dosages of the other agents. Cost-effectiveness calculated as the annual acquisition cost/percentage LDL reduction was greatest with atorvastatin 10 mg ($17.96), fluvastatin 40 mg ($19.83), atorvastatin 20 mg ($22.85), and atorvastatin 40 mg ($24.96). All other dosages were above $25.00/year/percentage LDL reduction. Atorvastatin was the most cost-effective HMG-CoA reductase inhibitor. Fluvastatin 40 mg/day also had a favorable cost:effectiveness ratio but lowered LDL only by 23%.