Emerging targets for the treatment of dyslipidemia

Dyslipidemia is one of the main risk factors leading to atherosclerotic cardiovascular disease (CVD). According to recent treatment guidelines, subjects at substantial risk of CVD should meet more aggressive targets for low-density lipoprotein(LDL)-cholesterol levels. Treatment with statins fails to protect a significant percentage of patients from cardiovascular events despite efficient cholesterol-lowering. Moreover, clinical and epidemiologic data highlight the need of therapies to reduce the residual cardiovascular risk associated with low high-density lipoprotein(HDL)-cholesterol and elevated triglyceride levels. There are several novel agents undergoing preclinical or clinical development for the treatment of dyslipidemia. Squalene synthase inhibitors, antisense oligonucleotides targeting the production of apolipoprotein(apo)B-100, inhibitors of proprotein convertase subtilisin/kexin type 9, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor agonists are some of the alternative approaches for lipid-lowering. Moreover, HDL-targeted therapies such as the cholesteryl ester transfer protein inhibitors, HDLderived proteins, and mimetic peptides/lipids can increase HDL-cholesterol levels or improve the antiatherosclerotic properties of HDL. In conclusion, the emergence of agents that act in monotherapy or in combination with available lipid-modifying drugs may allow more effective management of dyslipidemia and, consequently, reduce the burden of CVD.     

The Effects of Phthalimide and Saccharin Derivatives on Low-Density Lipoprotein (LDL) and High-Density Lipoprotein (HDL) Receptor Activity and Related Enzyme Activities

The hypolipidemic agents, phthalimide, saccharin, o-(N-phthalimido) acetophenone, N-(p-chlorobenzoyl) sulfamate, and o-chlorobenzylsulfonamide affected low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptor activity and lipoprotein degradation. In isolated rat hepatocytes, rat aorta foam cells, and human fibroblasts, LDL receptor activity, which is dependent on apo-B and -E, was inhibited by the drugs in a dose-dependent manner. LDL degradation was accelerated in the hepatocytes, while it was inhibited in aorta cells and fibroblasts. The drugs enhanced HDL receptor activity, dependent on apo-E and -Al, and HDL degradation in the hepatocytes, whereas in fibroblasts and aorta cells HDL receptor binding and degradation were suppressed. In parallel, activities of acyl Co A acyl transferase, sn-glycerol-3-phosphate acyl transferase, and heparin-induced lipoprotein lipase decreased and activities of HMG–CoA reductase and cholesterol oleate-ester hydrolase increased. In fibroblasts the presence of drugs enhanced HDL binding of intracellular cholesterol. In vivo studies demonstrated that phthalimide and saccharin treatment enhanced the clearance of HDL and decreased the clearance of LDL from the serum of rats. The results suggest that the mode of action of the agents is to modulate the lipoprotein receptor and, thereby, the clearance of lipids from peripheral tissue as part of the hypolipidemic activity.     

Current, new and future treatments in dyslipidaemia and atherosclerosis

The new therapeutic options available to clinicians treating dyslipidaemia in the last decade have enabled effective treatment for many patients. The development of the HMG-CoA reductase inhibitors (statins) have been a major advance in that they possess multiple pharmacological effects (pleiotropic effects) resulting in potent reductions of low density lipoproteins (LDL) and prevention of the atherosclerotic process. More recently, the newer fibric acid derivatives have also reduced LDL to levels comparable to those achieved with statins, have reduced triglycerides, and gemfibrozil has been shown to increase high density lipoprotein (HDL) levels. Nicotinic acid has been made tolerable with sustained-release formulations, and is still considered an excellent choice in elevating HDL cholesterol and is potentially effective in reducing lipoprotein(a) [Lp(a)] levels, an emerging risk factor for coronary heart disease (CHD). Furthermore, recent studies have reported positive lipid-lowering effects from estrogen and/or progestogen in postmenopausal women but there are still conflicting reports on the use of these agents in dyslipidaemia and in females at risk for CHD. In addition to lowering lipid levels, these antihyperlipidaemic agents may have directly or indirectly targeted thrombogenic, fibrinolytic and atherosclerotic processes which may have been unaccounted for in their overall success in clinical trials. Although LDL cholesterol is still the major target for therapy, it is likely that over the next several years other lipid/lipoprotein and nonlipid parameters will become more generally accepted targets for specific therapeutic interventions. Some important emerging lipid/lipoprotein parameters that have been associated with CHD include elevated triglyceride, oxidised LDL cholesterol and Lp(a) levels, and low HDL levels. The nonlipid parameters include elevated homocysteine and fibrinogen, and decreased endothelial-derived nitric oxide production. Among the new investigational agents are inhibitors of squalene synthetase, acylCoA: cholesterol acyltransferase, cholesteryl ester transfer protein, monocyte-macrophages and LDL cholesterol oxidation. Future applications may include thyromimetic therapy, cholesterol vaccination, somatic gene therapy, and recombinant proteins, in particular, apolipoproteins A-I and E. Non-LDL-related targets such as peroxisome proliferator-activating receptors, matrix metalloproteinases and scavenger receptor class B type I may also have clinical significance in the treatment of atherosclerosis in the near future. Before lipid-lowering therapy, dietary and lifestyle modification is and should be the first therapeutic intervention in the management of dyslipidaemia. Although current recommendations from the US and Europe are slightly different, adherence to these recommendations is essential to lower the risk of atherosclerotic vascular disease, more specifically CHD. New guidelines that are expected in the near future will encompass global opinions from the expert scientific community addressing the issue of target LDL goal (aggressive versus moderate lowering) and the application of therapy for newer emerging CHD risk factors.     

A bright future of researching AMPA receptor agonists for depression treatment

Management of dyslipoproteinaemia is one of the key strategies in the prevention of cardiovascular disease. The major target of hypolipidaemic drugs is the reduction of low density lipoprotein (LDL) cholesterol. Lifibrol, a novel lipid-lowering agent, is highly potent in reducing total cholesterol, LDL cholesterol, and apolipoprotein B. Its efficacy in lowering serum triglycerides, lipoprotein(a) and fibrinogen implies additional benefit in the prophylaxis and treatment of coronary heart disease. Thus, lifibrol appears to be a multivalent anti-atherosclerotic agent. The hypolipidaemic properties of lifibrol have been examined in several clinical trials and in various animal models. The mode of action of lifibrol involves at least three mechanisms: lifibrol enhances LDL catabolism by sterol-independent stimulation of LDL receptor activity, reduces cholesterol absorption from the intestine, and slightly decreases hepatic cholesterol biosynthesis. Lifibrol’s lipid-lowering profile and putative mode of action clearly distinguish it from other classes of hypolipidaemic drugs, such as HMG-CoA reductase inhibitors or fibric acid derivatives. Thus, lifibrol may represent a new class of agents affecting lipid metabolism.     

Lifibrol: first member of a new class of lipid-lowering drugs?

Management of dyslipoproteinaemia is one of the key strategies in the prevention of cardiovascular disease. The major target of hypolipidaemic drugs is the reduction of low density lipoprotein (LDL) cholesterol. Lifibrol, a novel lipid-lowering agent, is highly potent in reducing total cholesterol, LDL cholesterol, and apolipoprotein B. Its efficacy in lowering serum triglycerides, lipoprotein(a) and fibrinogen implies additional benefit in the prophylaxis and treatment of coronary heart disease. Thus, lifibrol appears to be a multivalent anti-atherosclerotic agent. The hypolipidaemic properties of lifibrol have been examined in several clinical trials and in various animal models. The mode of action of lifibrol involves at least three mechanisms: lifibrol enhances LDL catabolism by sterol-independent stimulation of LDL receptor activity, reduces cholesterol absorption from the intestine, and slightly decreases hepatic cholesterol biosynthesis. Lifibrol's lipid-lowering profile and putative mode of action clearly distinguish it from other classes of hypolipidaemic drugs, such as HMG-CoA reductase inhibitors or fibric acid derivatives. Thus, lifibrol may represent a new class of agents affecting lipid metabolism.     

The significance of genetic polymorphisms in modulating the response to lipid-lowering drugs

The response to lipid-lowering drugs is modified by a number of factors like age, gender, concomitant disease and genetic determinants. Even within homogenous groups of patients, individual responses vary greatly. Until now, no clinical or biochemical parameter exists which predicts whether a subject will respond well to a particular lipid-lowering drug or, in the extreme case, will develop adverse, life-threatening effects (e.g., myositis or rhabdomyolysis). The recent advances in the human genome project promises to have a great impact on our understanding of lipid and lipoprotein metabolism and of the individual response to lipid-lowering drugs. Monogenetic disorders of the lipid metabolism produce severe clinical phenotypes, such as Tangier disease, but have a minor role in the evaluation of cardiovascular risk in the general population. On the other hand, several polymorphisms in genes involved in lipoprotein metabolism (e.g., apolipoprotein E) are associated with the plasma levels of lipoproteins, explaining a substantial fraction of the variance of LDL or HDL concentrations. In combination, the knowledge of these polymorphisms, further variants yet to be discovered and variants within the genes involved in the metabolism of lipid-lowering drugs will in the future allow these drugs to be selected according to the patients needs and thus increase both efficacy and cost-effectiveness of lipid-lowering regimes.     

Cyclosporine Transfer from Low- and High-Density Lipoproteins Is Partially Influenced by Lipid Transfer Protein I Triglyceride Transfer Activity

Purpose. The purpose of this study was to determine if lipid transfer protein (LTP I) facilitated triglyceride (TG) transfer activity regulates the plasma lipoprotein distribution of cyclosporine (CSA). Methods. To assess the influence of drug concentration and incubation time on the plasma lipoprotein distribution of CSA, ³H-CSA (50 to 1000 ng/ml) was incubated in human plasma for 5 to 120 minutes at 37°C. To determine if LTP I facilitated TG transfer activity regulates the plasma lipoprotein distribution of CSA, ³H-Triolein (TG)- or ³H-CSA-enriched high-density lipoproteins (HDL) or low-density lipoproteins (LDL) were incubated in T150 buffer (50 mM Tris-HCl, 150 mM NaCl, 0.02% Sodium Azide, 0.01% Disodium EDTA), pH 7.4 which contained a ³H-Triolein (TG) or ³H-CSA-free lipoprotein counterpart ± exogenous LTP I (1.0 g protein/ml) or in delipidated human plasma which contained 1.0 g protein/ml of endogenous LTP I for 90 minutes at 37°C. These experiments were repeated in the presence of a monoclonal antibody TP1 (15 g protein/ml) directed against LTP I. Results. No differences in CSA lipoprotein distribution were observed following incubation of the drug at varying concentrations and incubation times in human plasma. The percent transfer of TG from HDL to LDL and LDL to HDL was greater in T150 buffer than in human plasma. However, the percent transfer of CSA from only LDL to HDL was greater in T150 buffer than in human plasma. Furthermore, undetectable ³H-CSA transfer from HDL to LDL in T150 buffer containing purified LTP I was observed. In addition, when the percent transfer of TG and CSA were determined in the presence of TP1, the percent transfer of TG and CSA from only LDL to HDL were significantly decreased in T150 buffer and human plasma compared to controls. Conclusions. These findings suggest that the transfer of CSA between different lipoprotein particles is only partially influenced by LTP I facilitated TG transfer activity.     

Dyslipidemias in Patients With Diabetes Mellitus: Classification and Risks and Benefits of Therapy

To characterize the lipid and lipoprotein abnormalities in patients with diabetes mellitus and evaluate the risks and benefits of marketed pharmacologic therapies, a MEDLINE search of the National Library of Medicine data base was performed of studies published from January 1966 to March 1994. Clinical trials assessing effects on lipids and lipoproteins, and adverse effects of marketed lipid-lowering agents were extracted. Reviews and other relevant articles were included if they provided information regarding lipid and lipoprotein metabolism or guidelines on the treatment of dyslipidemias in patients with diabetes mellitus. An extensive review of clofibrate was not included. The most common dyslipidemia in patients with poorly controlled insulin-dependent diabetes mellitus (IDDM) is combined elevated triglyceride and cholesterol levels, with reduced high-density lipoprotein (HDL) cholesterol (mixed hyperlipidemia). Hypertriglyceridemia combined with a reduced HDL cholesterol is the most common dyslipidemia in patients with noninsulin-dependent diabetes mellitus, but essentially any pattern of dyslipidemia may be present. Small and dense low-density lipoprotein (LDL), glycosylation of lipoproteins, and increased oxidized lipoproteins may be present in patients with diabetes mellitus; all contribute to accelerated atherosclerotic cardiovascular disease. Insulin therapy generally corrects quantitative lipid abnormalities in patients with IDDM, so drug treatment is seldom indicated. Diet, exercise, and insulin or oral sulfonylureas will improve hypertriglyceridemia and low HDL concentrations, but do not always return them to normal. Drug therapy is indicated when nonpharmacologic measures are inadequate. It is administered based on the effects of each agent on lipids and lipoproteins, patient age, adverse effect profile, patient tolerability, and drug-disease and drug-drug interactions. A fibric acid derivative is the drug of choice for marked hypertriglyceridemia in patients with diabetes mellitus. Niacin can worsen glycemic control, but it may be required in severe hypertriglyceridemia, hypercholesterolemia, or mixed hyperlipidemia. Bile-acid binding resins may accentuate hypertriglyceridemia but may be useful in selected patients with marked hypercholesterolemia and normal triglycerides. Hydroxymethylglutaryl coenzyme A reductase inhibitors are preferred in patients with elevated LDL cholesterol and mild hypertriglyceridemia. Patients with marked lipid abnormalities or mixed hyperlipidemias may require carefully dosed combinations of lipid-lowering drugs.     

Novel lipid-regulating drugs

This review describes the major developments in lipid-regulating drugs during the past two years. Most of the novel compounds that have been launched or were in their final stages of development during this period are aimed primarily at lowering low-density lipoprotein (LDL)-cholesterol. These include bile acid sequestrants, HMG-CoA reductase inhibitors and a cholesterol absorption inhibitor. In addition, there have been preclinical reports suggesting the potential usefulness of orally bioavailable inhibitors of cholesterol ester transfer protein in plasma and of acylcoA:cholesterol acyltransferase in monocyte-macrophages. The recent discovery of the roles of the scavenger receptor class B Type 1 and ATP-binding cassette transporter 1 in high-density lipoprotein (HDL)-cholesterol transport may shift the trend of future developments away from compounds that lower LDL to those aimed at promoting HDL turnover.     

Novel lipid-regulating drugs

This review describes the major developments in lipid-regulating drugs during the past two years. Most of the novel compounds that have been launched or were in their final stages of development during this period are aimed primarily at lowering low-density lipoprotein (LDL)-cholesterol. These include bile acid sequestrants, HMG-CoA reductase inhibitors and a cholesterol absorption inhibitor. In addition, there have been preclinical reports suggesting the potential usefulness of orally bioavailable inhibitors of cholesterol ester transfer protein in plasma and of acylcoA:cholesterol acyltransferase in monocyte-macrophages. The recent discovery of the roles of the scavenger receptor class B Type 1 and ATP-binding cassette transporter 1 in high-density lipoprotein (HDL)-cholesterol transport may shift the trend of future developments away from compounds that lower LDL to those aimed at promoting HDL turnover.     

Guinea pigs as models to study the hypocholesterolemic effects of drugs

Guinea pigs are useful models to investigate the mechanisms of the hypocholesterolemic effects of drugs. Like humans, guinea pigs are one of the few species that carry the majority of cholesterol in LDL. This animal model has also been shown to develop atherosclerosis when challenged with hypercholesterolemic diets. In addition, plasma lipid profiles in males, females and ovariectomized guinea pigs, a model for menopause, follow similar patterns to those observed in humans. In this report, drugs aimed at lowering plasma cholesterol and triglycerides in hyperlipidemic individuals are reviewed. Studies analyzing the hypolipidemic effect of HMG-CoA reductase inhibitors, acyl CoA cholesterol acyltransferase inhibitors, fibrates, bile acid resins, apical sodium bile acid transporter inhibitors, and others show that guinea pigs and humans have comparable responses to drug therapy. In addition, results from the limited clinical reports addressing specific effects of drugs on LDL catabolism or VLDL synthesis are in agreement with observations in guinea pigs. From the review of these studies, it is apparent that the guinea pig is a useful animal model to further explore the mechanisms of action of lipid lowering drugs including effects on specific receptors and regulatory enzymes involved in cholesterol metabolism and on early atherosclerosis development. Abbreviations: ACAT, acyl-CoA:cholesterol acyltransferase; ASBT, apical sodium co-dependent bile acid transporter; ApoB, apolipoprotein B; CHD, coronary heart disease; CYP7, cholesterol 7alpha-hydroxylase; HDL, high density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; FCR, free catabolic rate; LDL, low density lipoprotein; PPAR, peroxisome proliferators-activated receptor; TC, total cholesterol; TG, triglycerides; VLDL, very low density lipoprotein.     

Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia

ABSTRACT

Background: Recent studies suggest that the distribution of lipoprotein subfractions is an independent predictor of vascular events. Therefore, we evaluated the effect of ezetimibe (a selective cholesterol transport inhibitor) on the concentrations of lipoprotein subfractions in patients with primary dyslipidaemia.

Materials and methods: Patients (n = 50) with primary dyslipidaemias were recruited. The concentrations of the individual lipoprotein subfractions were measured using the Lipoprint system at baseline and after 16 weeks of treatment.

Results: Ezetimibe reduced total, low-density lipoprotein cholesterol (LDL?C) and non-high-density lipoprotein cholesterol (HDL?C) values as well as apolipoprotein B concentrations. Subfractionation of apolipoprotein B-containing lipoproteins showed that the reduction in LDL?C values was due to a fall in the concentrations of all LDL subfractions. However, a more pronounced trend towards a decrease in the concen­trations of dense LDL subfractions was observed. Patients with triglyceride values >1.7?mmol/L had significantly greater reductions in the concentrations of small, dense LDL particles compared with those with normal triglyceride levels (49 vs. 19%, respectively; p < 0.05). Ezetimibe decreased the concentrations of HDL?C mainly due to a fall in the concentration of dense HDL subfractions.

Conclusion: Ezetimibe can favourably affect the distribution of LDL subfractions, especially in patients with elevated triglyceride values. Further studies are needed to clarify the significance of the ezetimibe-induced reduction in the concentrations of dense HDL particles.     

Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy

ABSTRACT

Objective: To review and analyse the evidence for the cholesterol-lowering effect of ezetimibe in adult patients with hypercholesterolaemia who are not at low-density lipoprotein cholesterol (LDL?C) goal on statin monotherapy.

Research design: Systematic review and meta-analysis.

Methods: MEDLINE and EMBASE were searched to identify ezetimibe randomised controlled trials (RCTs) published between January 1993 and December 2005. The meta-analysis combined data from RCTs, with a minimum treatment duration of 6 weeks, that compared treatment with ezetimibe 10?mg/day or placebo added to current statin therapy.

The difference between treatments was analysed for four co-primary outcomes: mean percentage change from baseline in total cholesterol (TC), LDL?C, and high-density lipoprotein cholesterol (HDL?C), and number of patients achieving LDL?C treatment goal. Meta-analysis results are presented for a modified version of the inverse variance random effects model.

Results: Five RCTs involving a total of 5039 patients were included in the meta-analysis. The weighted mean difference (WMD) between treatments significantly favoured the ezetimibe/statin combination over placebo/statin for TC (–16.1% (–17.3, –14.8); p < 0.0001), LDL?C (–23.6% (–25.6, –21.7); p < 0.0001) and HDL?C (1.7% (0.9, 2.5); p < 0.0001). The relative risk of reaching the LDL?C treatment goal was significantly higher for patients on ezetimibe/statin relative to those on placebo/statin (3.4 (2.0, 5.6); p < 0.0001). In pre-defined sub-group analyses of studies in patients with coronary heart disease, the WMD between treatments remained significantly in favour of ezetimibe/statin (?p < 0.0001) for TC and LDL?C but was no longer significant for HDL?C. Elevations in creatine kinase, alanine aminotransferase or aspartate aminotransferase that were considered as an adverse effect did not differ significantly between treatments.

Conclusions: The meta-analysis we performed included only five studies and was restricted to analysis of the changes in cholesterol levels relative to baseline. However, the results suggest that ezetimibe co-administered with ongoing statin therapy provides significant additional lipid-lowering in patients not at LDL?C goal on statin therapy alone, allowing more patients to reach their LDL?C goal.     

Lipid-lowering effects of TAK-475, a squalene synthase inhibitor,in animal models of familial hypercholesterolemia

The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.     

Differences in Lipoprotein Concentration and Composition Modify the Plasma Distribution of Free and Liposomal Annamycin

Purpose. The purpose of these studies were to determine the distribution of a lipophilic antineoplastic agent, annamycin (Ann), and its liposomal counterpart (LAnn) in plasma which had been altered in its lipoprotein concentration and lipid composition. Methods. Ann, LAnn, and doxorubicin (a hydrophilic control) were incubated in human plasma for 1 hour at 37°C. Following incubation plasma samples were assayed by fluorimetry for drug in each of the lipoprotein and lipoprotein-deficient plasma (LPDP) fractions. To assess the influence of modified lipoprotein concentrations and lipid composition on plasma distribution of Ann and LAnn, either Ann or LAnn were incubated in human plasma which had been supplemented with very low density lipoproteins (VLDL) or low density lipoproteins (LDL). Results. When unbound Ann or doxorubicin was incubated in plasma for 1 hour at 37°C, the majority of drug was found in the LPDP fraction. However, when Ann was incorporated into liposomes composed of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol (LAnn) the majority of Ann was recovered in the high-density lipoprotein (HDL) fraction. Elevation of plasma LDL-cholesterol or VLDL-triglyceride concentrations increased the amounts of Ann and LAnn associated with these lipoprotein classes. Alterations in HDL composition decreased the amount of Ann, but increased the amount of L-Ann within the HDL fraction. Lipid transfer protein (LTP) activity did not significantly modify the plasma distribution of Ann and LAnn in short-term experiments, but the modified lipoprotein composition that LTP facilitates in long-term incubations reduced the capacity of VLDL and LDL to accept drug. Conclusions. These findings suggest that lipoprotein concentration and composition alter the plasma distribution of Ann and LAnn and may help to explain the discrepancies observed in the pharmacokinetics of Ann and LAnn when they are administered to healthy versus cancer patients.     

Effects of simvastatin and carnitine versus simvastatin on lipoprotein(a) and apoprotein(a) in type 2 diabetes mellitus

Aim: The aim of the present study was to compare the effects of simvastatin and L-carnitine coadministration versus simvastatin monotherapy on lipid profile, lipoprotein(a) (Lp(a)) and apoprotein(a) (Apo(a)) levels in type II diabetic patients. Patients/methods: In this double-blind, randomized clinical trial, 75 patients were assigned to one of two treatment groups for 4 months. Group A received simvastatin monotherapy; group B received L-carnitine and simvastatin. The following variables were assessed at baseline, after washout and at 1, 2, 3 and 4 months of treatment: body mass index, fasting plasma glucose, glycated hemoglobin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, Apolipoprotein A1, Apo B, lipoprotein(a) and apoprotein(a). Results: At the end of treatment in the carnitine and simvastatin combined group compared with the simvastatin alone group, we observed a significant decrease in glycemia (p < 0.001), tryglicerides (p < 0.001), Apo B (p < 0.05), Lp(a) (p < 0.05), apo(a) (p < 0.05), while HDL significantly increased (p < 0.05). Conclusions: The coadministration of carnitine and simvastatin resulted in a significant reduction in Lp(a) and apo(a) and may represent a new therapeutic option in reducing plasma Lp(a) levels, LDL cholesterol and Apo B100.     

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.     

Effects of gemfibrozil and other fibric acid derivatives on blood lipids and lipoproteins

Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low-density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high-density lipoprotein (HDL) cholesterol levels. Their effects on low-density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid, Parke-Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG-CoA reductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhabdomyolysis.     

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.