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.     

HDL-cholesterol and the treatment of coronary heart disease: contrasting effects of atorvastatin and simvastatin

Although the levels of low-density lipoprotein (LDL) cholesterol remain the main therapeutic goal when treating dyslipidaemias, there is a need to consider high-density lipoprotein (HDL) concentrations. This conclusion is based on the findings of epidemiological surveys and appropriately designed trials using statins or fibrates. The importance of HDL, as a 'protective' lipoprotein fraction, has been recognised by major treatment guidelines. This review considers the differences in HDL-raising capacity of two of the most commonly prescribed statins--atorvastatin and simvastatin. When compared with simvastatin, atorvastatin is associated with progressively decreasing rises in the levels of HDL as the dose increases (negative dose response), an effect not reported with other statins. In contrast, simvastatin shows a positive dose response (increasing concentrations of HDL with increasing dose). This effect is paralleled by changes in apolipoprotein A-I levels. Apolipoprotein A-I is the main apolipoprotein associated with HDL. This dissimilarity in HDL response is an example of several differences that have been reported when comparing various statins. If 'all statins are not created equal', we should focus prescribing on those statins that have end point evidence originating from appropriately designed trials.     

Erectile dysfunction and lipid disorders

Epidemiological studies have shown that elevated serum cholesterol and reduced high density lipoprotein (HDL) cholesterol levels are associated with an increased risk of erectile dysfunction (ED). This is another example of the link between ED and atherosclerosis. Whether correcting a dyslipidaemic profile will result in a reduced risk of developing ED has not been established. Similarly, it is not known if such an intervention will improve symptoms in patients with established ED. The situation is further complicated by the likelihood that one of the rarer side-effects of fibrates and statins is ED. There is a need for appropriately designed trials to establish if intervening with statins or fibrates is beneficial on a short- or long-term basis for the treatment or prevention of ED.     

Clinical pharmacokinetics of fenofibrate

Summary

Although the levels of low-density lipoprotein (LDL) cholesterol remain the main therapeutic goal when treating dyslipidaemias, there is a need to consider high-density lipoprotein (HDL) concentrations. This conclusion is based on the findings of epidemiological surveys and appropriately designed trials using statins or fibrates. The importance of HDL, as a ‘protective’ lipoprotein fraction, has been recognised by major treatment guidelines.

This review considers the differences in HDL-raising capacity of two of the most commonly prescribed statins – atorvastatin and simvastatin. When compared with simvastatin, atorvastatin is associated with progressively decreasing rises in the levels of HDL as the dose increases (negative dose response), an effect not reported with other statins. In contrast, simvastatin shows a positive dose response (increasing concentrations of HDL with increasing dose). This effect is paralleled by changes in apolipoprotein A-I levels. Apolipoprotein A-I is the main apolipoprotein associated with HDL.

This dissimilarity in HDL response is an example of several differences that have

been reported when comparing various statins. If ‘all statins are not created equal’, we should focus prescribing on those statins

that have end point evidence originating from appropriately designed trials.     

Treating dyslipidemic patients with lipid-modifying and combination therapies

Updated guidelines from the National Cholesterol Education Program give greater emphasis to lipoproteins other than low-density lipoprotein cholesterol (LDL) than previous guidelines. Although statins remain first-line therapy for most patients to lower LDL, combination therapy is the next logical step in achieving goals in patients with mixed dyslipidemia or elevated LDL despite statin therapy. As the prevalence of diabetes, metabolic syndrome, and atherogenic dyslipidemia rises, the importance of treating the total lipid profile becomes even more crucial. Niacin, fibrates, and bile acid sequestrants are effective in combination with statins in lowering LDL, triglycerides, and total cholesterol levels and increasing high-density lipoprotein cholesterol (HDL). Although combination therapies may increase the risk of myopathy, both fibrate-statin and niacin-statin combinations are considered safe. In addition, niacin-statin therapy reduces atherosclerotic progression and coronary events. New pharmacologic formulations exist that will further affect treatment: a single-tablet combination of lovastatin and extended-release niacin is available, as is ezetimibe, a cholesterol-absorption inhibitor. In all, both HDL and triglyceride levels correlate with cardiovascular risk and should be considered secondary targets of therapy. Combination therapy can be safe and effective and can be constructed to affect all lipoprotein parameters.     

Effects of Fibrates on Serum Metabolic Parameters

Summary

Fibric acid derivatives are a class of hypolipidaemic drugs used in the treatment of patients with hypertriglyceridaemia, mixed hyperlipidaemia and diabetic dyslipidaemia. Fibrate therapy results in a significant decrease in serum triglycerides and an increase in high-density lipoprotein (HDL) cholesterol levels. The latest drugs of this class are also effective in lowering low-density (LDL) cholesterol levels and can change the distribution of LDL towards higher and larger particles. The effects of fibrates on lipid metabolism are mostly mediated through the activation of peroxisome proliferator-activated receptors (PPARα). A number of angiographic and clinical trials have confirmed that fibrates can slow the progression of atherosclerotic disease and decrease cardiovascular morbidity and mortality. Recently published data suggest that the ability of fibrates to prevent atherosclerosis is not related only to their hypolipidaemic effects but also to other 'pleiotropic effects', such as their anti-inflammatory, antioxidant and antithrombotic effects, as well as their ability to improve endothelial function. Interestingly, fibrates may favourably influence the thrombotic/fibrinolytic system. In fact, most of these drugs can significantly decrease plasma fibrinogen levels and inhibit tissue factor expression and activity in human monocytes and macrophages. Some studies have shown that fibrates can improve carbohydrate metabolism in patients with dyslipidaemia, including diabetic patients. Among fibrates only fenofibrate can significantly decrease serum uric acid levels by increasing renal urate excretion. Fibrates, with the possible exception of gemfibrozil, can significantly increase serum creatinine and homocysteine levels. Finally, a reduction in serum alkaline phosphatase and gamma glutamyltranspeptidase (γGT) activity is a well-documented effect of therapy with fibrates.

The fibrates are generally well-tolerated drugs with few side-effects. The most important side-effect is myositis, which is observed in patients with impaired renal function or when statins are given concomitantly.     

Effects of fibrates on serum metabolic parameters

Fibric acid derivatives are a class of hypolipidaemic drugs used in the treatment of patients with hypertriglyceridaemia, mixed hyperlipidaemia and diabetic dyslipidaemia. Fibrate therapy results in a significant decrease in serum triglycerides and an increase in high-density lipoprotein (HDL) cholesterol levels. The latest drugs of this class are also effective in lowering low-density (LDL) cholesterol levels and can change the distribution of LDL towards higher and larger particles. The effects of fibrates on lipid metabolism are mostly mediated through the activation of peroxisome proliferator-activated receptors (PPARalpha). A number of angiographic and clinical trials have confirmed that fibrates can slow the progression of atherosclerotic disease and decrease cardiovascular morbidity and mortality. Recently published data suggest that the ability of fibrates to prevent atherosclerosis is not related only to their hypolipidaemic effects but also to other 'pleiotropic effects', such as their anti-inflammatory, antioxidant and antithrombotic effects, as well as their ability to improve endothelial function. Interestingly, fibrates may favourably influence the thrombotic/fibrinolytic system. In fact, most of these drugs can significantly decrease plasma fibrinogen levels and inhibit tissue factor expression and activity in human monocytes and macrophages. Some studies have shown that fibrates can improve carbohydrate metabolism in patients with dyslipidaemia, including diabetic patients. Among fibrates only fenofibrate can significantly decrease serum uric acid levels by increasing renal urate excretion. Fibrates, with the possible exception of gemfibrozil, can significantly increase serum creatinine and homocysteine levels. Finally, a reduction in serum alkaline phosphatase and gamma glutamyltranspeptidase (gammaGT) activity is a well-documented effect of therapy with fibrates. The fibrates are generally well-tolerated drugs with few side-effects. The most important side-effect is myositis, which is observed in patients with impaired renal function or when statins are given concomitantly.     

调脂药物的联合应用及安全性监测

血脂异常是动脉粥样硬化性心脑血管疾病的重要危险因素。他汀类药物通过降低低密度脂蛋白胆固醇水平,使心血管事件明显减少。但是即使采用大剂量的他汀类药物仍难以达到指南要求的血脂水平标准,因此针对合并糖尿病、代谢综合征等心血管高危人群,他汀类药物联合贝特类、烟酸类、胆固醇吸收抑制药等药物成为临床上的重要选择。     

Increased toxicity when fibrates and statins are administered in combination--a metabolomics approach with rats

Combination therapies with fibrates and statins are used to treat cardiovascular diseases, because of their synergistic effect on lowering plasma lipids. However, fatal side-effects like rhabdomyolysis followed by acute renal necrosis sometimes occur. To elucidate biochemical changes resulting from the interaction of fibrates and statins, doses of 100 mg/kg fenofibrate, 50mg/kg clofibrate, 70 mg/kg atorvastatin and 200 mg/kg pravastatin as well as combinations thereof were administered to Crl:Wi(Han) rats for 4 weeks. Plasma metabolome profile was measured on study days 7, 14 and 28. Upon study termination, clinical pathology parameters were measured. In a separate experiment plasmakinetic data were measured in male rats after 1 week of drug administration in monotherapy as well as in combinations. Lowering of blood lipid levels as well as toxicological effects, like liver cell degradation (statins) and anemia (fibrates) and distinct blood metabolite level alterations were observed in monotherapy. When fibrates and statins were co-administered metabolite profile interactions were generally underadditive or at the utmost additive according to the linear mixed effect model. However, more metabolite levels were significantly altered during combination therapy. New effects on the antioxidant status and the cardiovascular system were found which may be related to a development of rhabdomyolysis. Accumulation of drugs during the combination therapy was not observed.     

Combination lipid therapy in type 2 diabetes mellitus

INTRODUCTION: A significant drop in cardiovascular risk has been seen in patients with type 2 diabetes treated with statins. However, this cardiovascular risk remains high, compared with nondiabetic individuals. This is partly due to the typical abnormalities of diabetic dyslipidemia - hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) - that are uncontrolled by statins. For this reason, combination lipid therapy may be considered in patients with type 2 diabetes. AREAS COVERED: This review presents the main reasons for a combination lipid therapy in type 2 diabetes and the effects of several drugs, including fibrates, pioglitazone, niacin and omega 3, on diabetic dyslipidemia and the prevention of cardiovascular events. The real cardiovascular benefit of fibrates in patients with type 2 diabetes is not totally clear, but they may produce a significant benefit in patients with type 2 diabetes and diabetic dyslipidemia (hypertriglyceridemia, low HDL-C). Pioglitazone, which reduces triglycerides and increases HDL-C, has been shown to reduce the risk for major cardiovascular events in type 2 diabetes. Niacin and omega 3 fatty acids have a positive effect on diabetic dyslipidemia, but warrants clinical trials to demonstrate a clear cardiovascular benefit in type 2 diabetes. EXPERT OPINION: Although combination lipid therapy seems to be useful to control diabetic dyslipidemia, the efficacy of such combined therapies on significantly reducing cardiovascular risk has still to be confirmed by additional clinical trials.     

New approaches in the diagnosis of atherosclerosis and treatment of cardiovascular disease

Atherosclerosis is the one of the commonest causes of morbidity and mortality in the world. This review examines some of the recent patents taken out on biomarkers of cardiovascular risk, novel dietary supplements and new methods to treat cardiovascular disease. Though current approaches based on risk stratification into primary and secondary prevention and calculation of risk using simple risk factors are well established, there remains a need to develop more specific biomarkers of risk integrating many of the aspects of the atherosclerotic process including oxidized lipoproteins or inflammation-modified proteins. Diet is established as the mainstay of long-term cardiovascular management with great potential benefits but in the modern environment compliance tend to be low. Many approaches investigate the role of dietary supplementation with omega-3 fatty acids and other agents or the use of nutriceutical compounds capable of competing with cholesterol for absorption. A statin-based strategy is the mainstay of cardiovascular lipid -related risk management. However statins are not universally tolerable and are limited in the effects they have on some fractions of the risk profile especially low high density lipoprotein (HDL)-cholesterol. Many new drugs are in development to raise HDL or mimic its effects. These include novel agents to target nuclear factor receptors already familiar from previous successful drugs such as bile acid sequestrants, fibrates and thiazolidinediones as well as novel approaches investigating key regulatory enzymes such as stearoyl-CoA desaturase. Similarly as inflammation is a central part of atherosclerosis other novel approaches are targeting the multiplicity of inflammation-associated pathways including 5-lipoxygenase and purinergic receptors.     

Statins and metabolism of high density lipoprotein

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. Statins are widely and successfully used for lowering plasma cholesterol levels causing up to 45% reduction of plasma cholesterol and considerable reduction in risk of cardiovascular diseases. The main atheroprotective action of statins is reduction of plasma low density lipoprotein levels due to improved clearance of this lipoprotein by the liver. In addition, statins cause mild elevation of high density lipoprotein (HDL) concentration, but the mechanism responsible for this effect of statins on HDL metabolism is not well understood. It has been hypothesized that statins affect the HDL level through inhibition of cholesteryl ester transfer protein activity or by stimulating apolipoprotein A-I synthesis. Increased cholesterol efflux from liver due to raised expression of the ABCA1 transporter may also elevate HDL levels. Whereas raising the plasma HDL-C concentration may contribute to the atheroprotective effect of statins, its magnitude is uncertain and additional mechanisms that improve the functionality of HDL may be equally or more important. In this review we analyze what is currently known about effect of statins on HDL metabolism and on reverse cholesterol transport in particular.     

Evaluation of the synergistic adverse effects of concomitant therapy with statins and fibrates on rhabdomyolysis

Rhabdomyolysis is a severe adverse effect of hypolipidaemic agents such as statins and fibrates. We evaluated this muscular cytotoxicity with an in-vitro culture system. Cellular apoptosis was determined using phase-contrast and fluorescein microscopic observation with Hoechst 33342 staining. L6 rat myoblasts were treated with various statins and bezafibrate under various conditions. With statins only, skeletal cytotoxicity was ranked as cerivastatin > fluvastatin > simvastatin > atorvastatin > pravastatin in order of decreasing potency. Combined application of fibrates enhanced atorvastatin-induced myopathy, which causes little apoptosis alone. These results suggest that statins and fibrates synergistically aggravate rhabdomyolysis.     

Combination lipid therapy in type 2 diabetes mellitus

Introduction: A significant drop in cardiovascular risk has been seen in patients with type 2 diabetes treated with statins. However, this cardiovascular risk remains high, compared with nondiabetic individuals. This is partly due to the typical abnormalities of diabetic dyslipidemia – hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) – that are uncontrolled by statins. For this reason, combination lipid therapy may be considered in patients with type 2 diabetes.

Areas covered: This review presents the main reasons for a combination lipid therapy in type 2 diabetes and the effects of several drugs, including fibrates, pioglitazone, niacin and omega 3, on diabetic dyslipidemia and the prevention of cardiovascular events. The real cardiovascular benefit of fibrates in patients with type 2 diabetes is not totally clear, but they may produce a significant benefit in patients with type 2 diabetes and diabetic dyslipidemia (hypertriglyceridemia, low HDL-C). Pioglitazone, which reduces triglycerides and increases HDL-C, has been shown to reduce the risk for major cardiovascular events in type 2 diabetes. Niacin and omega 3 fatty acids have a positive effect on diabetic dyslipidemia, but warrants clinical trials to demonstrate a clear cardiovascular benefit in type 2 diabetes.

Expert opinion: Although combination lipid therapy seems to be useful to control diabetic dyslipidemia, the efficacy of such combined therapies on significantly reducing cardiovascular risk has still to be confirmed by additional clinical trials.     

降血脂药物临床合理用药研究进展

脂质异常是导致动脉粥样硬化的危险因素之一,对其进行调节和治疗是心血管疾病初级预防和二级预防的基础。除通过饮食调节以外,目前临床常用的治疗策略是服用降血脂药物,如他汀类、贝特类、胆固醇吸收抑制剂、烟酸、胆酸螯合剂和Ω-3脂肪酸等。这些药物作用机制不同但通常互相补充,通过合理搭配使用,可使脂质代谢异常得到纠正。本文对现有调脂药物的调脂效果和临床合理用药的研究进展进行综述。     

冠心病住院患者调脂药物应用情况调查

目的 调查冠心病住院患者中调脂药物的应用情况。方法 对347例确诊的冠心病患者在住院期间应用他汀类及贝特类调脂药物的使用情况进行调查，并对不同水平的LDL—C中他汀类药物的应用进行调查。结果 在347例患者中有221例的LDL—C＞2.6mmol/L，占63．69％，但仅有160例使用他汀类药物，使用率为46．1％；而使用贝特类药物的患者只有22例，使用率为6．3％。结论 在冠心病住院患者中存在着他汀类药物量使用不足的现象。     

The effect of fibrates and other lipid-lowering drugs on plasma homocysteine levels

Hyperlipidaemia is a major risk factor for cardiovascular disease. The drugs of choice for the treatment of hyperlipidaemia are either fibrates, in the case of hypertriglyceridaemia, or statins, in the case of hypercholesterolaemia. Recently, it has been shown that some of the most prescribed fibrates cause hyperhomocysteinemia, which itself has been recognised as a cardiovascular risk factor. In particular, fenofibrate and bezafibrate lead to a 20 - 40% elevation of plasma levels of the atherogenic amino acid homocysteine, thereby possibly counteracting the desired cardiovascular protection. The most likely mechanism for this increase is an alteration of creatine-creatinine metabolism and changes in methyl transfer. Gemfibrozil does not increase homocysteine. Statins have no effect on the plasma homocysteine concentration. The increase of plasma homocysteine after fenofibrate can be lowered by the concurrent administration of folic acid and vitamins B(12) and B(6). Thus, patients with hypertriglyceridaemia can either be concurrently treated with fenofibrate and vitamins or with gemfibrozil.