Raising High-density Lipoprotein Cholesterol Levels Research Articles

Inhibition of cholesteryl ester transfer protein activity: a new therapeutic approach to raising high-density lipoprotein.

High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease (ASCVD), leading to the concept that pharmacologic therapy to raise HDL cholesterol levels may reduce ASCVD risk. There is substantial interest in the concept of inhibition of the cholesteryl ester transfer protein (CETP) as a novel strategy for raising HDL cholesterol levels, as well as reducing levels of atherogenic lipoproteins. This article reviews the physiology of CETP in lipoprotein metabolism and the data in animals and humans that are relevant to the question of whether CETP inhibition may some day be part of the clinical armamentarium for treating dyslipidemia and atherosclerotic vascular disease.

Endothelial lipase promotes the catabolism of ApoB-containing lipoproteins.

Endothelial lipase (EL) has been found to be a key enzyme in high-density lipoprotein (HDL) metabolism in mice, leading to the concept that inhibition of EL could be a novel strategy for raising HDL cholesterol levels. However, mice are "HDL animals" and the effect of EL on atherogenic apoB-containing lipoproteins has not been elucidated. We previously found that EL is capable of hydrolyzing very low-density lipoprotein (VLDL) and LDL lipids ex vivo. To investigate the role of EL in the metabolism of apoB-containing lipoproteins in vivo, we expressed human EL in three mouse models of elevated apoB-containing lipoproteins: apoE-deficient, LDL receptor-deficient, and human apoB transgenic mice. Unexpectedly, hepatic expression of EL resulted in markedly decreased levels of VLDL/LDL cholesterol, phospholipid, and apoB accompanied by significantly increased LDL apolipoprotein and phospholipid catabolism. To determine whether lipolytic activity is required for this effect, we also expressed a catalytically inactive form of human EL (ELS149A); unexpectedly, expression of ELS149A did not lower and in fact increased plasma lipids. Coexpression and coimmunoprecipitation studies suggested that catalytically inactive ELS149A inhibits endogenous mouse EL, accounting for the increased lipid levels. We conclude that (1) in addition to its known effects on HDL metabolism, EL influences the metabolism of apoB-containing particles; (2) catalytic activity of EL is required for its effects on apoB-containing lipoproteins; and (3) overexpressed catalytically inactive EL inhibits endogenous mouse EL, resulting in increased levels of plasma lipids. In light of these results, inhibition of EL has the potential to raise levels of atherogenic lipoproteins in addition to HDL-C levels.

Niacin Might Be More Effective for Women Than for Men

Niacin use improves all components of the lipid profile: It lowers triglyceride, LDL cholesterol, and lipoprotein(a) levels and raises HDL cholesterol levels. Some studies have suggested that women respond more favorably than men to niacin. In this meta-analysis, researchers pooled data from five randomized, placebo-controlled, clinical trials of niacin to further evaluate possible sex differences in treatment response. The analysis involved 155 women and 277 men with dyslipidemia who …

Raising an isolated low HDL-C level: why, how, and when?

Treating patients with isolated low high-density lipoprotein cholesterol (HDL-C) remains daunting. The decision to treat depends on the individual patient's overall risk for coronary heart disease (CHD). Strategies for raising HDL-C levels can include various lifestyle and drug therapies, which should be tailored to individual patients. While no current therapy is optimal, many can yield modest increases that translate into reduced risk for CHD events.

Potential therapeutic agents that raise high-density lipoprotein cholesterol levels

Cardiovascular disease remains one of the leading causes of death in westernised societies. A number of risk factors have been identified that accelerate the risk for cardiovascular disease (CVD), including family history for premature disease (first degree male relative with CVD onset before the age of 55; first degree female relative with CVD onset before the age of 65), hypertension (whether treated or not), age, smoking, diabetes mellitus and low high-density lipoprotein cholesterol (HDL-C) levels. One of the recent changes in the US Adult Treatment Panel guidelines was to increase the lower limit of desirable HDL-C levels (now raised to 40 mg/dL from 35 mg/dL). There have been a few clinical studies demonstrating the benefit of raising HDL-C levels but there are not many therapeutic options that easily accomplish this goal. Research into the understanding of HDL metabolism has yielded a number of potential therapeutic targets. HDL is thought to exert its cardioprotective effects by a number of mechanisms. The predominant one appears to be its participation in the process of reverse cholesterol transport, whereby excess cholesterol from peripheral cells is transported to the liver for disposal via bile acid production. The newer potential targets, among others, include peroxisomal proliferator-activated receptors (PPAR-α, -γ and -δ), ATP-binding cassette (ABC) transporters, cholesterol ester transfer protein (CETP) and scavenger receptor class B Type I (SR-BI). Among this group, agonists for PPAR-α and PPAR-γ have been shown to increase HDL-C levels and are commonly used in the management of patients with Type 2 diabetes mellitus (fibrates and glitazones, respectively). The precise mechanism by which activation of PPAR-γ leads to increased HDL-C is still not clearly defined but these agents have been shown to increase expression of ABC transporters and scavenger receptors both in animals and in vitro. An investigational agent, JTT-705, is a CETP inhibitor that has been shown to raise HDL-C levels 34% and without major side effects. The effect of the CETP inhibitor on clinical outcomes is unknown.

Low high-density lipoprotein cholesterol: physiological background, clinical importance and drug treatment.

Low high-density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease (CHD). In vitro, HDL exerts several potentially anti-atherogenic activities. HDLs mediate the reverse cholesterol transport (RCT) from peripheral cells to the liver, inhibit oxidation of low-density lipoprotein (LDL), adhesion of monocytes to the endothelium, apoptosis of vascular endothelial and smooth muscle cells and platelet activation, and stimulate the endothelial secretion of vasoactive substances as well as smooth muscle cell proliferation. Hence, raising HDL-cholesterol levels has become an interesting target for anti-atherosclerotic drug therapy. Levels of HDL cholesterol and the composition of HDL subclasses in plasma are regulated by apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors and cellular transporters. The interplay of these factors leads to RCT and determines the composition and, thereby, the anti-atherogenic properties of HDL. Several inborn errors of metabolism, as well as genetic animal models, are characterised by both elevated HDL cholesterol and increased rather than decreased cardiovascular risk. These findings suggest that the mechanism of HDL modification rather than simply increasing HDL cholesterol determine the efficacy of anti-atherosclerotic drug therapy. In several controlled and prospective intervention studies, patients with low HDL cholesterol and additional risk factors benefited from treatment with fibric acid derivatives (fibrates) or HMG-CoA reductase inhibitors (statins). However, only in some trials was prevention of coronary events in patients with low HDL cholesterol and hypertriglyceridaemia related to an increase in HDL cholesterol. We discuss the clinical and metabolic effects of fibrates, statins, nicotinic acid and sex steroids, and present novel therapeutic strategies that show promise in modifying HDL metabolism. In conclusion, HDL-cholesterol levels increase only moderately after treatment with currently available drugs and do not necessarily correlate with the functionality of HDL. Therefore, the anti-atherosclerotic therapy of high-risk cardiovascular patients should currently be focused on the correction of other risk factors present besides low HDL cholesterol. However, modification of HDL metabolism and improvement of RCT remain an attractive target for the development of new regimens of anti-atherogenic drug therapy.

Antiatherogenic effect of Caps HT2, a herbal Ayurvedic medicine formulation

The antiatherogenic effect of a herbal formulation, Caps HT2, was evaluated as antioxidant, anticoagulant, platelet antiaggregatory, lipoprotein lipase releasing, anti-inflammatory and hypolipidaemic activity in rats. The formulation contained the methanolic extracts of selected parts of plants, Commiphora mukul, Allium sativum, Plumbago indica, Semecarpus anacardium, Hemidesmus indicus, Terminalia arjuna, Tinospora cordifolia, Withania somnifera and Ocimum sanctum. The formulation, Caps HT2 was found to scavenge superoxide and hydroxyl radicals; the IC50 required being 55.0 and 610.0 microg/ml respectively. The lipid peroxidation was found inhibited (50%) by 48.5 microg/ml of Caps HT2. The intravenous administration of the formulation (5 mg/kg) delayed the plasma recalcification time in rabbits and enhanced the release of lipoprotein lipase enzyme significantly (p < 0.001). The formulation also inhibited ADP induced platelet aggregation in vitro, which was comparable to commercial heparin. The anti-inflammatory action of the formulation was significant (p < 0.001) with acute and chronic inflammations induced by carrageenan and formalin respectively in rats. The hypolipidaemic effect of Caps HT2 was significant (p < 0.001) with the administration of the formulation, in diet-induced hyperlipidaemia of rats for a period of 30 days. Oral administration of the formulation, Caps HT2 (100, 200, 300 and 400 mg/kg) significantly raised HDL cholesterol levels. The atherogenic index and the reduction in body weight were significant indicating the effectiveness against hyperlipidaemia and obesity. All these results revealed the therapeutic potential of Caps HT2 against vascular intimal damage and atherogenesis leading to various types of cardiovascular problems.

High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease

Epidemiologic and clinical trials show that elevated triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C) are independent risk factors for coronary heart disease (CHD). However, adjustment for covariates frequently weakens or abolishes the predictive significance of triglycerides, whereas the evidence for HDL-C is more consistently strong. Data indicate that there is a 2% to 3% decrease in coronary risk for each 1 mg/dL increase in HDL-C, whereas the benefit of triglyceride lowering appears to occur largely in patients with the highest baseline levels. The 2001 National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines for detecting and treating high blood cholesterol reflect our improved understanding of triglycerides and HDL as CHD risk factors. However, the guidelines place more emphasis on lowering triglycerides than on raising HDL-C by identifying non-HDL-C (ie, low-density lipoprotein cholesterol [LDL-C] + very-low-density lipoprotein cholesterol [VLDL-C]) as a secondary target of therapy. In clinical practice, VLDL-C is the most readily available measure of atherogenic triglyceride-rich remnant lipoproteins. On the basis of the available epidemiologic and clinical evidence, refinement of the NCEP guidelines to include more emphasis on raising HDL-C levels should be considered. Novel drugs are being developed that have the potential to increase HDL-C concentrations and/or improve the functionality of HDL. (Am Heart J 2002;144:S33-42.)

New approaches to raising the HDL cholesterol level.

Not only a high level of low-density lipoprotein (LDL) cholesterol, but also a low level of high-density lipoprotein (HDL) cholesterol, is a critical risk factor for atherosclerosis and coronary heart disease. Although fibrates and niacin can be used to improve low HDL cholesterol levels, their effect is not wholly satisfactory, so better drugs for the elevation of HDL cholesterol are desired. Among the many methods that may be used to raise HDL cholesterol levels, this review focuses on inhibitors of cholesteryl ester transfer protein (CETP) and on nuclear orphan receptor agonists that mediate the expression of ATP-binding cassette transporter 1 (ABC1).

Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans

Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity (P<0.0001), a 34% increase in HDL cholesterol (P<0.0001), and a 7% decrease in LDL cholesterol (P=0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL2, HDL3, and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects (P=0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.

Beyond LDL-C – The Importance of Raising HDL-C

SummaryEpidemiological studies have established that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk of coronary heart disease (CHD). Recent studies have demonstrated that low HDL-C levels, and high triglycerides and total cholesterol levels are independent predictors of CHD, and that the combination of these lipid abnormalities increases the risk of coronary events. In lipid-modifying intervention studies, agents that raise HDL-C levels have been shown to reduce the incidence of major coronary events. The VA-HIT study consisted of patients with low-density lipoprotein cholesterol (LDL-C) levels similar to those recommended by several guidelines but with low levels of HDL-C. This trial demonstrated that raising HDL-C levels with gemfibrozil reduced the risk of CHD-related events. While the mechanisms by which HDL-C exerts its anti-atherogenic effects have yet to be fully elucidated, its role in the reverse transport of cholesterol and the beneficial effects on endothelial function are plausible explanations for these actions.Although LDL-C reduction is the primary goal in the treatment of dyslipidaemia, current guidelines recognise low HDL-C levels as a major risk factor for CHD. Indeed, the NCEP ATP III guidelines suggest that the treatment of isolated low HDL-C levels in CHD patients or individuals with CHD risk equivalents should be considered. The differing abilities of statins to raise HDL-C levels may be an important factor when making treatment decisions. New lipid-modifying drugs with beneficial effects on both HDL-C and LDL-C levels would be desirable additions to the currently available therapeutic options.

Management of hypercholesterolaemia in postmenopausal women.

Increased rates of coronary heart disease (CHD) occur with advancing age in both sexes, although CHD rates in women lag behind those of men by about 10 years. There is a sharp increase in CHD rate among women after approximately 50 years of age. The reasons for this are not completely understood and are undoubtedly multifactorial. Cross-sectional data from large-scale population studies suggest that around the time of the menopause, low-density lipoprotein (LDL)-cholesterol levels increase by approximately 15 to 25%. Because this increase is larger than that observed in men over the same age span and closely approximates that observed in women after oophorectomy, it is likely that reduced circulating estrogen levels associated with menopause play a role in the adverse changes in both blood lipid levels and CHD incidence. There is clear evidence that treating hypercholesterolemia reduces cardiovascular risk in women, as well as in men. In the US National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines, diet and other lifestyle changes are recommended as first-line therapy. If the treatment goals cannot be achieved through non-pharmacological measures, drug therapy should be added. Of the available lipid-lowering agents, HMG CoA reductase inhibitors (statins) are the clear choice to decrease LDL-cholesterol levels. However the favourable effects of statins on high-density lipoprotein (HDL)-cholesterol and triglyceride levels are more modest, and statins are not known to decrease lipoprotein (a) [Lp(a)] levels. Estrogen or hormone replacement therapy (ERT/HRT) and nicotinic acid improve LDL- and HDL-cholesterol levels and also decrease Lp(a) levels. However, ERT/HRT is no longer recommended as first-line therapy for decreasing CHD risk. Nicotinic acid is particularly useful for decreasing triglyceride levels (as are fibrates) and raising HDL-cholesterol levels. Bile-acid sequestrants reduce LDL-cholesterol and slightly increase HDL-cholesterol levels. Both bile acid sequestrants and ERT/HRT tend to raise triglyceride levels, therefore they should be used cautiously in women with hypertriglyceridaemia. Treatment should be individualised for each patient. It is important to evaluate the primary form of dyslipidaemia, other CHD risk factors, comorbidities, and the extent of lipid improvement needed in order to reach treatment goals. The effects of each type of therapy and potential adverse effects should also be considered.

A Bit of Joy to Share About Almonds

Some research shows that eating nuts improves lipid profiles, likely because nuts are high in monounsaturated fat and may raise HDL-cholesterol levels. However, eating high-fat foods also can cause weight gain. In a study funded by the California Almond Board, 27 hyperlipidemic men and women (mean total-cholesterol level, about 251 mg/dL) …

Low high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report.

A working group meeting was convened from January 7 to 8, 2000, in Naples, Florida, to assess low HDL cholesterol (HDL-C) concentration as a risk factor for coronary heart disease (CHD). The 30 speakers and discussants at this 2-day meeting included specialists in epidemiology, endocrinology, molecular biology, public health, lipid metabolism, cardiovascular medicine, and preventive cardiology from the United States, Europe, and Australia (Appendix). The group’s wide-ranging presentations and discussions considered the latest knowledge on HDL metabolism and the effects of interventions for raising HDL-C levels on the development of atherosclerosis. It was generally accepted that low HDL-C may be a marker for the metabolic syndrome, an enhanced atherosclerotic disease state that is also associated with an impaired response to insulin, hypertriglyceridemia, and abdominal obesity. Therefore, beyond risk assessment based on LDL cholesterol (LDL-C) alone, the case has been made for considering HDL-C in tandem with triglycerides (TG) as synergistic coronary risk factors.1 The following article summarizes the participants’ discussion of low HDL-C as an independent CHD risk factor and identifies areas requiring further research. Although population studies indicate that a high level of HDL-C in general protects against CHD,2 3 a high HDL-C concentration in any given individual may not necessarily confer cardioprotection. The atherogenicity of low HDL-C seems to be influenced by an array of genetic and environmental factors. Tangier disease, a disorder caused by mutations in the ATP-binding cassette transporter 1 ( ABC1 ) gene,4 is characterized by the absence of normal HDL, with only a very small quantity of abnormal HDL present. However, early atherosclerosis (before 40 years) is not a consistent feature of this disorder.5 In men of Japanese ancestry in Hawaii, mutations in the gene for plasma cholesteryl ester transfer protein ( CETP ), which transfers cholesteryl ester from HDL to TG-rich lipoproteins, have …

Comparison of two regimens of policosanol administered at 20 mg/d in patients with type II hypercholesterolemia: a randomized, double-blind, placebo-controlled study

Background: Policosanol is a mixture of higher primary aliphatic alcohols purified from sugar cane wax that has demonstrated dose-dependent cholesterol-lowering effects in patients with type II hypercholesterolemia and dyslipidemia associated with non-insulin-dependent diabetes mellitus. The 20 mg/d dosage is particularly useful for patients at high coronary risk and to date this dosage has been administered as two 10-mg tablets once daily. Objective: This 8-week study was undertaken to compare the cholesterol-lowering effects and tolerability of 2 dosing regimens of policosanol 20 mg/d: two 10-mg tablets versus one 20-mg tablet taken once daily with the evening meal. Methods: In this randomized, double-blind, placebo-controlled study, after 4 weeks of dietary stabilization, 62 patients with type II hypercholesterolemia were randomly assigned in a 1:1:1 ratio to receive 2 placebo tablets, 2 policosanol 10-mg tablets, or 1 policosanol 20-mg tablet plus 1 matched placebo tablet. Physical examinations were performed and lipid profiles and blood samples were obtained at baseline and after 4 and 8 weeks of therapy. The incidence of adverse events (AEs) and compliance with study medications were also evaluated at week 4 and week 8 of treatment. Results: The 2 policosanol 20 mg/d regimens were similarly effective. Policosanol administered as two 10-mg tablets significantly reduced total cholesterol (TC) (16.0%, P < 0.001 vs baseline), low-density lipoprotein cholesterol (LDL-C) (35.9%, P < 0.001), as well as the TC:high-density lipoprotein cholesterol (HDL-C) ratio (37.3%, P < 0.001) and LDL-C:HDL-C ratio (52.4%, P < 0.001). The regimen significantly increased HDL-C levels (38.0%, P < 0.001 vs baseline). The 20-mg policosanol tablet also significantly decreased TC (20.0%), LDL-C (37.8%), TC:HDL-C ratio (39.9%), and LDL-C:HDL-C ratio (52.4%) (all P < 0.001), whereas it significantly raised HDL-C levels (39.4%, P < 0.001). Triglyceride levels did not change significantly in either group. The differences between treatment groups were not significant. No significant changes in lipid profile variables were observed in the placebo group. Both policosanol 20 mg/d regimens were well tolerated. No drug-related clinical or blood biochemistry abnormalities were observed after 8 weeks of treatment. Five patients (8.1%) withdrew from the study, 2 from the placebo group, 2 from the 10-mg tablet group, and 1 from the 20-mg tablet group. One of these patients (in the placebo group) withdrew from the study because of an AE (duodenal ulcer). The other AEs reported during the study were mild, and the frequency of AE reports was similar in all the groups. Conclusions: These results demonstrate that policosanol 20 mg/d is an effective and well-tolerated cholesterol-lowering regimen whether administered as a 20-mg tablet once daily or two 10-mg tablets once daily with the evening meal.

The emerging role of HDL cholesterol. Is it time to focus more energy on raising high-density lipoprotein levels?

Low HDL cholesterol levels have been found to be a risk factor for CAD. To date, the focus of treating hyperlipidemia has been on lowering LDL cholesterol levels. Now, as more and more compelling data are reported, it is time to begin focusing more energy on how to raise HDL cholesterol levels. If exercise, smoking cessation, and moderate alcohol consumption fail to achieve HDL cholesterol goals, niacin, fibric acid derivatives, or statin drugs may prove helpful in patients at high risk of CAD.

Evidence that triglycerides are an independent coronary heart disease risk factor

In the past, the relation between hypertriglyceridemia and coronary heart disease (CHD) has been uncertain. However, a recent multivariate analysis of 8-year follow-up data from the large-scale Prospective Cardiovascular Münster study found hypertriglyceridemia to be an independent risk factor for major coronary events after controlling for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Hypertriglyceridemia combined with elevated LDL cholesterol and high LDL:HDL cholesterol ratio (>5) increased the CHD event risk by approximately sixfold. Similarly, a large meta-analysis of 17 prospective trials reported hypertriglyceridemia to be an independent risk factor for cardiovascular disease. In this study, an 88 mg/dl (1.0 mmol/L) increase in plasma triglyceride levels significantly increased the relative risk of cardiovascular disease by ≈30% in men and 75% in women; the corresponding rates were somewhat lower (14% and 37%) but still statistically significant after adjustment for HDL cholesterol level. These data and observations from patients in the Helsinki Heart Study and the Stockholm Ischemic Heart study, that the greatest coronary benefit during lipid-lowering drug therapy occurred among hypertriglyceridemic patients, argue strongly for an independent role for hypertriglyceridemia in CHD risk. In the recent Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial, the use of gemfibrozil to raise HDL cholesterol levels and lower levels of triglycerides without lowering LDL cholesterol levels reduced coronary events in men with established CHD, whereas preliminary results from the Bezafibrate Infarction Prevention Trial indicate a reduction in coronary end points in patients with elevated baseline triglyceride levels. To achieve the greatest possible reduction in CHD risk, antihyperlipidemic treatment strategies should also be aimed at reducing elevated triglycerides.

Management of Dyslipidaemias

Dyslipidaemias are major modifiable risk factors for the development of atherosclerosis and its sequelae, namely coronary heart disease (CHD) and peripheral vascular disease. CHD is the leading cause of morbidity and mortality in men and women in Western countries; the costs associated with this disease are substantial and place a large burden on society. The goal of therapy in patients with dyslipidaemia is to achieve target serum lipid levels (established by treatment guidelines) in an effort to reduce the risk of asymptomatic individuals developing CHD (primary prevention) or to slow or retard the progression of atherosclerosis in patients with established CHD (secondary prevention). A multifactorial approach including lifestyle modifications and, if necessary, pharmacological intervention is recommended. Simvastatin is a competitive and reversible inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase. It causes marked reductions in serum low density lipoprotein cholesterol (LDL-C) levels and reductions in serum triglyceride levels in patients with hypertriglyceridaemia. Simvastatin also increases serum high density lipoprotein cholesterol (HDL-C) levels and is the first HMG-CoA reductase inhibitor indicated for this use. The Scandinavian Simvastatin Survival Study (4S) established that simvastatin 20 to 40 mg/day reduces total mortality (by 30% at 5 years compared with placebo) in patients with CHD, mostly because of a reduction in cardiovascular mortality (42% reduction at 5 years). This reduction in mortality was maintained for at least 8 years in simvastatin-treated patients in 4S. As secondary prevention simvastatin is cost effective in men, women and diabetic patients with CHD as shown by data from 4S. Available evidence also indicates that simvastatin slows the progression of coronary atherosclerosis. In patients with diabetes and CHD, 5-years’ treatment with simvastatin during 4S reduced the risk of coronary death and nonfatal myocardial infarction by 55% compared with a 32% reduction in nondiabetic patients with CHD. In high risk patients with CHD, other cardiovascular risk factors and dyslipidaemia, simvastatin 40 to 80 mg/day effectively reduced serum LDL-C and triglyceride levels and raised HDL-C levels. The most common adverse events associated with simvastatin in clinical trials of 5 to 10 years’ duration were gastrointestinal upset and headache. These events were similar in incidence to that with placebo and did not necessitate a discontinuation of therapy. Asymptomatic elevations in hepatic transaminase levels and, rarely, myopathy have been described during simvastatin treatment. Conclusions: The efficacy and tolerability of simvastatin at doses of up 80 mg/day are well established. Together with favourable effects on serum lipoprotein levels compared with related compounds and, more importantly, beneficial long term effects on morbidity and mortality in patients with CHD, simvastatin is firmly established as a first-line agent when cholesterol-altering pharmacotherapy is indicated for treatment of dyslipidaemia.

Effects of 4-methylsterols from algae and of β sitosterol on cholesterol metabolism in rats

Male Sprague Dawley rats (8/gp) were fed one of the following diets: AIN-76A (C), C plus 0.5% 4-methylsterols (CM), C plus 0.5% β sitosterol (CS), C plus 0.5% cholesterol (CC), CC plus 0.15% sodium deoxycholate (CB), CB plus 1% 4-methylsterols (CBM) or CB plus 1% β sitosterol (CBS). The 4-methylsterols had no adverse effect on weight gain or organ weight. The 4-methylsterols did not affect serum or liver lipids when added to the control diet or to the cholesterol-bile salt diet. When added to the control diet β sitosterol increased the percentage of serum HDL cholesterol and lowered levels of liver esterified cholesterol. When added to the cholesterol-bile salt diet β sitosterol significantly lowered serum cholesterol and raised HDL-cholesterol levels; β sitosterol also reduced liver total cholesterol.

Gene therapy for dyslipidemia: clinical prospects.

Current approaches to the treatment of lipid disorders are inadequate for a substantial number of patients with severe hyperlipoproteinemia, isolated low high-density lipoprotein (HDL) cholesterol levels, or other molecular disorders of lipoprotein metabolism. Therefore, dyslipidemias remain important targets for the development of novel therapies. Gene therapy is a logical therapeutic approach to monogenic lipoprotein disorders, such as homozygous familial hypercholesterolemia, familial lipoprotein lipase deficiency, familial lecithin-cholesterol acyltransferase deficiency, and abetalipoproteinemia, for which current therapies are inadequate. Gene therapy could also be used to increase expression of certain proteins, such as apolipoprotein A-I as a strategy to raise HDL cholesterol levels or apoE as a strategy for severe combined hyperlipidemia. With further progress in the development of vectors, gene therapy for severe dyslipidemia is likely to become a clinical reality.