Indications for lipid-lowering drugs

Summary There is overwhelming evidence from prospective studies that plasma cholesterol levels are exponentially related to coronary artery disease (CAD) risk. Inversely, the beneficial effect of lowering plasma cholesterol is convincingly established from major clinical trials. A consensus has been reached in a large number of countries on the need to lower plasma lipid levels, especially LDL-cholesterol, to delay the onset, slow the progression and induce regression of atherosclerotic lesions in the coronary arteries. This remains the major indication of lipid-lowering therapy. In recent years, the emphasis has been put on target plasma lipid concentrations for dietary and drug therapy. In the process of establishing prevention strategies, however, some confusion arose: target values and criteria for assessing CAD risk and initiating therapy have differed from country to country, as well as among various groups within a country. Population strategies and high-risk case-finding strategies have clashed. Treatment algorithms have emphasized lipid levels rather than lipid transport disorders. With time, these algorithms have become more and more complex and the confused physician in practice, sometimes, has started to treat mg/dL (or mmol/L) rather than patients. This confusion has been compounded by debates on the variability of plasma lipid measurements within as well as across laboratories. In the one to one relationship that exists in the physician's office, much of this confusion can be dispelled if, after a thorough clinical evaluation, the patient's situation is taken in context, a diagnosis is made and the indicated therapy is prescribed. A good algorithm is one that focuses first on diagnosis, separates secondary from primary causes of dyslipoproteinemia, starts with diatary therapy, targets drugs to the metabolic disturbance, takes into account the psycho-social environment and the risk factor context and adjusts the treatment according to the observed response. Within this framework, specific target levels may be given due consideration. Treatment should be individualized and the key lipid transport disorders identified. Today, the physician has the advantage of prescribing drugs that have been proven valuable for the ultimate goal of therapy: prevention of atherosclerotic complications.     

New prospects for lipid-lowering drugs

The advent of 3-hydroxy-methylglutaryl Co-enzyme A (HMG-CoA) reductase inhibitors has dramatically improved the treatment of dyslipidaemia and the prevention of atherosclerosis over the past 10 years. Similar but less marked benefit had previously been demonstrated for fibrates and bile acid sequestrants, which were first introduced over 30 years ago and are still in use. The discovery that fibrates are ligands for peroxisome proliferator activated receptors (PPARs) may lead to innovations in the future. However, most of the compounds now undergoing clinical trials are either HMG-CoA reductase inhibitors or bile acid sequestrants, which is indicative of the current emphasis on lowering low density lipoprotein (LDL) cholesterol. Drugs in an earlier stage of development include inhibitors of squalene synthase, which have yet to fulfil their initial promise, and of acylcholesterolacyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). Most of the earlier ACAT inhibitors were poorly absorbed, but compounds with better bioavailability hold considerable promise by virtue of their ability to inhibit ACAT in liver and arterial wall macrophages. MTP inhibitors have the potential to drastically reduce apolipoprotein B (apoB) secretion, but safety issues could negate this advantage. Thus, despite the impact of statins, the development of new lipid-modulating drugs continues to be a dynamic field of research.     

New prospects for lipid-lowering drugs

The advent of 3-hydroxy-methylglutaryl Co-enzyme A (HMG-CoA) reductase inhibitors has dramatically improved the treatment of dyslipidaemia and the prevention of atherosclerosis over the past 10 years. Similar but less marked benefit had previously been demonstrated for fibrates and bile acid sequestrants, which were first introduced over 30 years ago and are still in use. The discovery that fibrates are ligands for peroxisome proliferator activated receptors (PPARs) may lead to innovations in the future. However, most of the compounds now undergoing clinical trials are either HMG-CoA reductase inhibitors or bile acid sequestrants, which is indicative of the current emphasis on lowering low density lipoprotein (LDL) cholesterol. Drugs in an earlier stage of development include inhibitors of squalene synthase, which have yet to fulfil their initial promise, and of acylcholesterolacyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). Most of the earlier ACAT inhibitors were poorly absorbed, but compounds with better bioavailability hold considerable promise by virtue of their ability to inhibit ACAT in liver and arterial wall macrophages. MTP inhibitors have the potential to drastically reduce apolipoprotein B (apoB) secretion, but safety issues could negate this advantage. Thus, despite the impact of statins, the development of new lipid-modulating drugs continues to be a dynamic field of research.     

Statin lipid-lowering drugs and bone mineral density

BACKGROUND: HMG Co-A reductase inhibitors (statin lipid-lowering drugs) have been associated with a reduced rate of fractures in some studies, but not in others. We examined the relationship between statin use and bone density among postmenopausal women. METHODS: We conducted a cross-sectional survey at one academic medical center. Postmenopausal women who underwent bone densitometry and agreed to a telephone interview were surveyed about osteoporosis risk factors, use of hormone replacement therapy and osteoporosis medications and statin exposure. We then developed linear regression models adjusting for known counfounders to assess the relationship between statin use and bone mineral density (BMD). RESULTS: Of 339 women studied, 162 were current or past users of statins, and 177 were not. Statin users and non-users were similar with respect to age, race, prior fracture history, the presence of medical conditions associated with osteoporosis, use of medications for osteoporosis, use of tobacco and use of oral glucocorticoids. Statin users had significantly higher body mass index (BMI) and rates of thiazide use, and were more likely to abstain from alcohol. After adjusting for important confounders, we found that statin use was associated with a significantly higher t-score at the total hip (-0.53 +/- 0.17) compared with non-users (-0.83 +/- 0.18; p = 0.02). At the lumbar spine, there was a trend toward higher t-scores in statin users (-0.91 +/- 0.24) compared with non-users (-1.21 +/- 0.23; p = 0.08). CONCLUSIONS: These results support the hypothesis that statin use is associated with higher BMD. While it is unclear whether their relationship is causal, further controlled studies examining bone formation and resorption would help determine the clinical implications of these findings.     

Emerging lipid-lowering drugs: squalene synthase inhibitors

Background: Lapaquistat was the only squalene synthase inhibitor in Phase III clinical trials in Europe and the United States, but was recently discontinued from clinical development. Unlike statins, the inhibition of de novo cholesterol biosynthesis by lapaquistat does not deplete mevalonate, a precursor of isoprenoids. Isoprenoids are critical in cell growth and metabolism. Objective: The present review will focus on the chemistry, pharmacology, and lipid-lowering effects of novel squalene synthase inhibitors. Methods: A search of Pubmed, IPA, and GoogleScholar for studies (animal and human) and review articles published in English between 1990 and April 2008, using the search terms “squalene synthase inhibitors” or “lapaquistat”. All clinical trials identified were then cross-referenced for their citations. All literature identified was then complied for this analysis. Results/conclusion: Lapaquistat mainly targets LDL-C, but may have some effect on HDL-C and TG. Preliminary reports on Phase II and Phase III associated lapaquistat 100 mg with elevated hepatic enzymes. Hepatotoxicity, possible drug–drug interaction with statins, and the investigation of a statin/coenzyme Q10 combination are among the few challenges that impeded lapaquistat's clinical development.     

降脂药物的肝脏毒性及其防治策略研究进展

肝脏毒性是降血脂药物治疗常见的毒副作用之一,其发生机制尚不完全清楚,大多数降血脂药物的毒副作用都是剂量依赖性的,而且在停药后都有明显的缓解与改善。高龄以及慢性疾病等都是诱发降血脂药物肝脏毒性的潜在因素。降血脂药物的肝脏损伤治疗暂无统一规范,临床应对策略以停药、非特异性保肝和对症治疗为主。研发低毒性或具有保肝作用的降血脂药物,尤其是中药及中药制剂是一个具有良好前景的发展方向。     

调脂药物在非酒精性脂肪肝中的作用

非酒精陛脂肪性肝病（nonalcoholic fatty liver disease,NAFLD）是代谢综合征（MS）在肝脏的表现,既是MS的早期表现,也是MS的预测指标。血脂异常参与胰岛素抵抗及MS的发生及发展,促进肝脂肪变,而肝脂增加进一步启动代谢紊乱、肝脏炎症及纤维化改变。调脂药物能够改善血脂紊乱,     

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.     

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 hyperhomocysteinaemia, 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 B₁₂ and B₆. Thus, patients with hypertriglyceridaemia can either be concurrently treated with fenofibrate and vitamins or with gemfibrozil.     

Interactions between cyclosporin and lipid-lowering drugs: implications for organ transplant recipients

Dyslipidaemia is more frequent in solid organ transplant recipients than in the general population, primarily as a result of immunosuppressive drug treatment. Both cyclosporin and corticosteroids are associated with dyslipidaemic adverse effects. In order to reduce the overall cardiovascular risk in these patients, lipid-lowering drugs have become widely used, especially HMG-CoA reductase inhibitors (statins). Cyclosporin, as well as most statins (lovastatin, simvastatin, atorvastatin and pravastatin) are metabolised by cytochrome P450 (CYP)3A4, so a bilateral pharmacokinetic interaction between these drugs is theoretically possible. However, results from several studies show that statins do not induce increased systemic exposure of cyclosporin. A small (but not clinically relevant) reduction in systemic exposure of cyclosporin has actually been shown in many studies. Cyclosporin-treated patients on the other hand show several-fold higher systemic exposure of all statins, both those that are metabolised by CYP3A4 and fluvastatin (metabolised by CYP2C9). Therefore, the mechanism for this interaction does not seem to be solely caused by inhibition of CYP3A4 metabolism, but it is probably also a result of inhibition of statin-transport in the liver, at least in part. Other lipid-lowering drugs, such as fibric acid derivatives, bile acid sequestrants, probucol, fish oils and orlistat are also used in solid organ transplant recipients. Most of them do not interact with cyclosporin, but there are reports indicating that both probucol and orlistat may reduce cyclosporin bioavailablility to a clinically relevant degree. There is no information on possible interaction effects of cyclosporin on the pharmacokinetics of lipid-lowering drugs other than statins, but it is not likely that any clinical relevant interference exists with fish oil, orlistat, probucol or bile acid sequestrants.     

Under treatment with lipid-lowering drugs of high-risk coronary heart disease patients of the GENICA study

OBJECTIVES: To assess the proportion of high-risk coronary artery disease (CAD) patients who received lipid lowering drug treatment (LLDT) and met the LDL-Cholesterol (LDL-C) goal of 100 mg/dl defined by the third report of the U.S. National Cholesterol Education Program (NCEP). METHODS: In 86% (n = 1095) of the 1268 consecutive Italian patients, who were enrolled in the GENICA study after undergoing quantitative coronary angiography for suspected coronary artery disease between 1999 and 2001, the levels of total serum cholesterol, HDL-cholesterol, triglycerides, and LDL-C were measured and accurate information on current LLDT were available. All patients were classified according to the NCEP. RESULTS: Seventy-four percent of the patients (n = 805) had established CAD and cardiovascular events and therefore were candidates for secondary prevention with LLDT; 69% of them had concomitant hyperlipidemia. Only 57% of the patients with CAD and hyperlipidemia were on LLDT. Of the 1052 patients who were at the highest risk class according to NCEP, only 34.2% and 16.7% were on LLDT and reached the LDL-C goal, respectively. CONCLUSIONS: Only 1 patient of 6 in the highest-risk class according to the NCEP accomplished the LDL-C goal. Accordingly, in the field of secondary prevention of coronary artery disease, the implementation of guidelines that emerged from scientific evidence into clinical practice with LLDT still requires major efforts.     

Underuse of lipid-lowering drugs and factors associated with poor adherence: a real practice analysis in Italy

Background Many studies have indicated the adequate use of lipid-lowering drugs (LLDs) as a factor in reducing the risk of cardiovascular disease. However, in clinical practice, a very high percentage of patients are not adequately treated.Objective To analyze the management of hypercholesterolemia in a non-experimental setting and to estimate the factors associated with poor adherence to treatment.Methods A longitudinal study was performed using clinical and demographic data recorded in the General Practitioners database. The sample included all patients, aged 30 years or over, with total blood cholesterol measured between 1 January and 31 December 2000. Utilization of LLDs was defined as the standardized daily dose of the drugs purchased during the 12 months preceding the cholesterol measurement.Results The study included 4764 patients (mean age 59.4±14.1 years, 40.7% males). Of the subjects with a total cholesterol higher than a 6.5 mmol/l, approximately 17% were treated with LLDs. About 39% of the patients with previous atherosclerotic diseases were taking statins. Analysis of patients taking LLDs showed that 40.6% of subjects took less than half of the defined daily dose. Factors associated with poor adherence to treatment were: absence of previous atherosclerotic diseases, absence of concomitant diseases, and smoking. A total cholesterol of less than 5 mmol/l was achieved in 19.9% of patients.Conclusions Analyzing the data contained in the general medicine database made it possible to evaluate the use of LLDs in clinical practice and to establish the need to pay greater attention to achieving the objective set by the treatment.     

Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data

Introduction: Cardiovascular (CV) diseases are the leading cause of death and disability in the developed countries. Lipid-lowering therapy is a cornerstone of the CV risk modification strategy. The first line treatment for hyperlipidemia is statins, which decrease low-density lipoprotein cholesterol (LDL-C) by 30–50% and proportionally reduce the CV events. However, they are not always enough to achieve LDL-C goals in many patients, and some patients are statin intolerant. For this reason, new powerful injectable lipid-lowering drugs have been developed.

Areas covered: The aim of this narrative review was to summarize the more recent clinical data on safety and tolerability of injectable lipid-lowering drugs. After an attentive literature search, the authors resumed here information on proprotein convertase subtilisin/kexin 9 inhibitors (evolocumab and alirocumab), small interfering RNA molecule inclisiran, antisense oligonucleotides (mipomersen, volanesorsen, ISIS 681257), and drugs targeting angiopoietin-like protein 3 (evinacumab, IONIS-ANGPTL3_Rx).

Expert opinion: Injectable lipid-lowering therapy for patients at high risk for CV disease complications or with severe inherited hypercholesterolemias can be an important element of the available therapeutic armamentarium. Clinical data prove the favorable risk-benefit profile of evolocumab, alirocumab, and inclisiran. Mipomersen, volanesorsen, ISIS 681257, evinacumab, and IONIS-ANGPTL3_Rx safety is currently less extensively studied, especially in patients with comorbidities and polypharmacotherapy.