The armamentarium for the treatment of dyslipidemia today comprises six different modes of action with overall around 24 different drugs. The treatment of lipid disorders was revolutionized with the introduction of statins which have become the most important therapeutic option available today to reduce and prevent atherosclerosis and its detrimental consequences like cardiovascular diseases and stroke. Consequently, the search for novel lipid-modifying drugs is still one of the most active areas in research and development in the pharmaceutical industry. Major focus lies on approaches to LDL-lowering drugs superior to statins with regard to efficacy, safety, and patient compliance and on approaches modifying plasma levels and functionality of HDL particles based on the clinically validated inverse relationship between high-plasma HDL levels and the risk for CVD. The available drugs today for the treatment of dyslipidemia are small organic molecules or nonabsorbable polymers for binding of bile acids to be applied orally.
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The armamentarium for the treatment of dyslipidemia today comprises six different modes of action with overall around 24 different drugs. The treatment of lipid disorders was revolutionized with the introduction of statins which have become the most important therapeutic option available today to reduce and prevent atherosclerosis and its detrimental consequences like cardiovascular diseases and stroke.
Consequently, the search for novel lipid-modifying drugs is still one of the most active areas in research and development in the pharmaceutical industry. Major focus lies on approaches to LDL-lowering drugs superior to statins with regard to efficacy, safety, and patient compliance and on approaches modifying plasma levels and functionality of HDL particles based on the clinically validated inverse relationship between high-plasma HDL levels and the risk for CVD.
The available drugs today for the treatment of dyslipidemia are small organic molecules or nonabsorbable polymers for binding of bile acids to be applied orally.
Besides small molecules for novel targets, biological drugs such as monoclonal antibodies, antisense or gene-silencing oligonucleotides, peptidomimetics, reconstituted synthetic HDL particles and therapeutic proteins are novel approaches in clinical development are which have to be applied by injection or infusion.
The promising clinical results of several novel drug candidates, particularly for LDL cholesterol lowering with monoclonal antibodies raised against PCSK9, may indicate more than a decade after the statins, the entrance of new breakthrough therapies to treat lipid disorders. Worldwide cardiovascular diseases CVD including coronary heart disease CHD and stroke are the leading causes of mortality with an increasing prevalence National Clinical Guideline ; atherosclerotic cardiovascular disease accounts for The overall risk for CHD is determined by multiple parameters such as dyslipidemia, hypertension, smoking, diabetes mellitus, obesity, coagulopathies, diet, and sedentary lifestyle as well as hereditary genetic variations Roger et al.
Dyslipidemia, mainly hypercholesterolemia, plays a causal role in the pathogenesis of atherosclerosis being responsible for the development and progression of CHD, stroke, and peripheral vascular disease Roger et al. Dyslipidemia is defined as a spectrum of deviations from lipid homeostasis characterized by elevations in plasma concentrations of low-density lipoproteins LDL , lipoprotein a Lp a , apolipoproteins B and triglycerides TG , as well as decreased plasma levels of high-density lipoproteins HDL or apolipoprotein A1 ApoA-I.
Primary dyslipidemias result from mutations in proteins involved in critical pathways involved in lipid and lipoprotein metabolism such as the LDL receptor familial hypercholesterolemia FH , apolipoprotein B familial defective ApoB , or PCSK9 variant FH. Most cases of dyslipidemia are of secondary cause, resulting from other diseases or health conditions such as diabetes, hypothyroidism, or a sedentary lifestyle with overcaloric nutrition, decreased physical exercise, or excessive alcohol consumption.
Aging of the general population also contributes to the growing incidence of hypercholesterolemia because plasma levels of LDL-C exert a natural rise with increasing lifetime Schaefer et al. From pathological examination, we know that the earliest stages of the atherogenic process can be detected in coronary arteries already in adolescence and early adulthood Strong and McGill ; Newman et al. Pathological examination of 2, individuals in the age range of 15—34 years died from noncardiovascular reasons revealed an increase of fatty streaks and lesions with increasing age and a positive correlation of the lesions with plasma cholesterol levels McGill et al.
Epidemiological studies have shown a continuous relationship between total plasma cholesterol levels and the risk of coronary heart disease National Heart Foundation of Australia and New Zealand The major causative role of elevated levels of LDL cholesterol in atherosclerotic vascular disease has been unequivocally proven by clinical landmark studies where reduction of plasma LDL cholesterol levels by statins — inhibitors of cholesterol biosynthesis Scandinavian Simvastatin Survival Study Group ; Downs et al.
The mean age of participants in these statin trials was 63 years Wijeysundera et al. Despite the quantum leap in the treatment of dyslipidemias by the introduction of statins into clinical practice, major gaps in the management of lipid disorders persist. Statins are undoubtedly the 1st-line therapy for the prevention of CVD in almost all population groups except those with severe renal or cardiac failure Saydah et al.
Particularly, in patients with complex metabolic diseases like diabetes mellitus, significant improvements in the control of risk factors are necessary; only 7. However, unequivocal evidence from randomized clinical trials that reduction of other risk factors like low HDL or HDL-C, elevated TG, or non-lipid influences like hypertension, inflammation, and diabetes reduces the risk of CHD and therefore the number of patients with CVD is only available for hypertension Sever et al.
HDL is a mediator of cholesterol transport from peripheral tissues to the liver and is considered as an important regulator of CHD risk Parker et al. Paradoxically, despite the unequivocal role of HDL as an independent risk factor for CVD events, the failure of recent clinical trials with drugs aiming to increase HDL-C levels may suggest that the functionality of the HDL particles rather than the height of HDL-C levels is more relevant for the cardio- and atheroprotective efficacy of HDL particles.
Due to the complex metabolism of HDL particles involving many different proteins and interaction with other lipoprotein particles, the impact of mutations in key proteins of the HDL-particle pathways and CV risk is not fully understood today. Consequently, measuring of HDL-C as a metric for monitoring pharmacological efficacy for reduction of CVD events by modulation of HDL particles is not sufficient to evaluate and predict of the efficacy of a drug approach elevating HDL levels Kingwell et al.
Recently, the results of a population study involving 2, adults free of CVD with a mean follow-up of 9. Whereas baseline levels of HDL were not found to be associated with CV events, the cholesterol efflux capacity from macrophages as a key component of the RCT process was identified as a reliable biomarker being strongly and inversely associated with the incidence of CV events in a population cohort.
Little correlation was found between cholesterol efflux capacity and traditional CV risk factors, coronary artery calcium, or markers of inflammation. From these findings, it can be concluded that measurements of macrophage-specific cholesterol efflux using fluorescently labeled cholesterol could be used in the future as a reliable method to assess the severity of atherosclerosis and its clinical consequences and to predict the efficacy of a drug approach affecting HDL metabolism for reduction of CVD risk.
Observational epidemiological studies and clinical trials using drugs targeting elevated TG levels and low HDL-C levels indicate a causative and predictive role of elevated TG plasma levels for the development of primary CHD. A recent systematic review and meta-regression analysis of 40 randomized controlled trials of lipid-modifying drugs with CHD events as outcome revealed that changes in plasma TG levels are predictive of CV events in randomized controlled clinical trials being significantly in primary prevention populations but not in secondary prevention populations Stauffer et al.
As a potential explanation for the difference in the prediction power of changes in TG levels for CV events in primary and secondary prevention trials elevated plasma TG levels could still be a risk factor in secondary populations but of lower importance for the total risk of coronary events. Today the armamentarium introduced in medical practice for the treatment of lipid disorders comprises five different modes of action and respective molecular targets with overall 24 different drug entities on the market, some of them available only in selected countries.
The majority of approaches focus on the reduction of LDL-C levels by inhibition of cholesterol biosynthesis HMG-CoA reductase inhibitors — statins , interruption of the enterohepatic circulation of bile acids bile acid sequestrants , or inhibition of intestinal cholesterol absorption ezetimibe. The molecular target of statins is the enzyme 3-hydroxymethylglutaryl-coenzyme A reductase EC 1. For a detailed overview about statins, some of the recent review articles are recommended Sirtori ; Shitara and Sugiyama Statins are competitive enzyme inhibitors competing with 3-hydroxymethylglutaryl-CoA for the catalytic binding site, thereby reducing biosynthesis rate of mevalonate and its downstream products like cholesterol.
The decrease in the intracellular cholesterol regulatory pool leads to an upregulation of LDL receptors in the hepatocyte plasma membrane, leading to an increased clearance rate of LDL particles from the blood and therefore a fall of plasma LDL-C levels. Based on dosage, atorvastatin and rosuvastatin are the most potent statins; the more polar compounds pravastatin and rosuvastatin are not or only metabolized by cytochrome P enzymes, particularly Cyp3A4, and are therefore less prone to drug—drug interactions with other medications due to cytochrome P metabolism.
Since inhibition of the biosynthesis cascade to cholesterol by statins occurs at a very early step, a potential risk was seen in this approach due to the decrease of other lipids like ubiquinone and dolichol and manifestation of these decreases of non-sterol lipids in adverse side effects in different organs including the liver, muscle, eye, or brain. Today, after more than 25 years of broad clinical use with millions of patients treated, statins can be considered as very effective and safe drugs; currently more than 25 million American people with dyslipidemia are taking statins, and according to a recent recommendation for use, another 13 million are expected to benefit from statin treatment; for all patients with known CVD, the new guidelines by the American College of Cardiology and the American Heart Association for the management of cholesterol recommend statin treatment regardless of their LDL-C levels Pencina et al.
If the public health guidelines being currently discussed in the USA and UK would be fully implemented, one third of the middle-aged and adult population in these countries will be recommended for statin therapy Pencina et al.
Safety and tolerance of statin treatment is good with the exception of myalgia as the major adverse side effect. Statins are taken up in the liver into hepatocytes by the organic anion transporting polypeptide OATP1B, and it was found that genetic variants of the SLCO1B1 gene are associated with the risk of myopathy upon statin treatment Carr et al.
Some of these variants exert a diminished affinity and transport activity for statins, leading to a reduced hepatic uptake resulting in higher blood levels and increased muscle exposure with an increased off-target activity at the neuromuscular endplate: statins are powerful inhibitors of chloride channels at muscle cell membranes Pierno et al.
Acute renal failure maybe a dose-related adverse side effect of statins of low incidence Dormuth et al.
During development of statins, cataracts were an issue due to findings from dog studies; a recent retrospective analysis gave evidence for a slightly increased incidence for cataract formation in patients treated with statins Leuschen et al. Today there are no evidences regarding early concerns that statin use may impair cognitive functions Shepherd et al. As well, no evidence for an increased risk for cancer or cancer mortality was found for treatment with statins Ridker The introduction of inhibitors of HMG-CoA reductase, the statins, into clinical practice has dramatically changed the landscape and treatment regimens for the treatment of lipid disorders.
Nevertheless, the overall mortality by CHD will increase in the future due to the increasing incidence of metabolic disorders like obesity, diabetes, and the metabolic syndrome. Despite optimized drug therapy with statins, a significant proportion of patients fail to achieve the recommended levels of LDL cholesterol Schectman and Hiatt ; Hsu et al.
The reasons for these treatment failures are manifold including the following factors:. Inefficiency of a drug class or statin intolerance Hsu et al. Bile acid sequestrants are polymeric anion-binding resins that strongly bind the negatively charged bile acids in the lumen of the small intestine, thereby interrupting the enterohepatic circulation of bile acids Out et al. Currently there are three bile acid sequestrants on the market — cholestyramine, colestipol, and colesevelam.
Whereas cholestyramine and colestipol show a preference for dihydroxy bile acids, colesevelam binds bile acids by both ionic and hydrophobic interactions, thereby increasing binding affinity and specificity resulting in significantly lower necessary dose. The treatment with sequestrants is safe, and due to their nonsystemic mode of action within the lumen of the intestine, sequestrants do not show systemic toxic effects; because of their non-absorbability, they can also be used in pregnancy.
In these cases, a time lack between intake of the respective drug and the sequestrant is recommended. First-generation sequestrants may lead to an undesired increase of plasma triglyceride levels which is not or significantly less the case with colesevelam.
By the change in the composition of the bile acid pool with an enrichment of trihydoxy bile acids due to a higher binding affinity of dihydroxy bile acids to cholestyramine and colestipol, the less potent trihydroxy bile acids as FXR agonists lead to a decreased FXR activity such as a decrease in the expression of ApoC-II as an activator of lipoprotein lipase or reduction of the FXR-mediated inhibition of hepatic TG synthesis via Shp and Srebp1c Kast et al.
As a result, the increased TG synthesis and the decreased TG clearance in the vasculature induces an overall increase of circulating TG. Colesevelam is able to reduce as well serum levels of CRP Bays et al.
Recent studies have strengthened early observations that bile acid sequestrants in addition to their cholesterol-lowering activities can improve glycemic control in patients with type 2 diabetes Handelsman et al. The mechanisms whereby bile acid sequestrants improve glycemic control are not yet fully understood but may involve the following contributions:. Increased secretion of incretins like GLP-1 due to spillover of bile acids into the colon Suzuki et al.
Changes in the composition of the bile acid pool with activation of FXR downstream activities like repression of hepatic gluconeogenesis and increasing of insulin sensitivity Zhang et al. Activation of TGR5 receptor in the colon by bile acid spillover with stimulation of energy expenditure Thomas et al. The proven efficacy of bile acid sequestrants on improvement of atherogenic lipid profiles and reduction of CHD events, their safety profile and nonsystemic mode of action, and their beneficial effects on glucose homeostasis strengthens the role and value of bile acid sequestrants particularly for the treatment of patients with statin intolerance, type 2 diabetes, or the metabolic syndrome.
Ezetimibe exerts its hypolipidemic action by inhibiting intestinal cholesterol absorption. Ezetimibe targets the NPC1L1 pathway which is a key regulator of cholesterol uptake from enterocyte brush border membranes and reuptake of cholesterol from bile into hepatocytes.
Cholesterol solubilized in mixed micelles is transferred to the enterocyte brush border membrane via a protein-mediated process Cai et al. NPC1L1 is a cholesterol-sensing protein cycling between this compartment and the brush border membrane dependent on the cholesterol levels sensed in the brush border membrane; when intracellular cholesterol levels are low, NPC1L1 is with the aid of microfilaments recycled to the brush border membrane, thereby initiating and stimulating the microdomain endocytotic process.
Ezetimibe specifically inhibits this NPC1L1 pathway. There is a controversy with regard to the primary molecular target of ezetimibe. However, a direct binding of ezetimibe to NPC1L1 by labeling techniques was never really demonstrated.
In contrast, a direct and specific binding of ezetimibe to aminopeptidase N CD13 was demonstrated by extensive photoaffinity labeling studies with various photoreactive ezetimibe analogues as well as by isolation of the ezetimibe-binding protein by affinity chromatography with an ezetimibe affinity matrix.
Sequence analysis of the purified radiolabeled ezetimibe-binding protein or the affinity-purified ezetimibe-binding protein unequivocally demonstrated its identity with aminopeptidase N CD13 , whereas no amino acid sequences of NPC1L1 were found in the isolated ezetimibe-binding proteins Kramer et al.
Membrane impermeable ezetimibe analogues are able to inhibit cholesterol uptake into CaCo 2 cells as well in vivo, indicating that the binding to the outside of the enterocyte brush border membrane is sufficient for inhibition of cholesterol internalization Kramer et al.
The cellular localization of APN between the brush border membrane and an intracellular storage compartment — the so-called deep apical tubules — is cholesterol-dependent as is the case for NPC1L1. Besides its enzymatic activity, APN can act as a receptor involved in endocytotic processes Hansen et al. These findings indicate that specific binding of ezetimibe to APN blocks the internalization of the cholesterol-rich microdomains, thereby preventing cholesterol absorption by interruption of the NPC1L1-cholesterol sensing pathway Skov et al.
Ezetimibe is the only drug available inhibiting intestinal cholesterol absorption. Ezetimibe does not influence intestinal absorption of bile acids, fat-soluble vitamins, or carotenes. Ezetimibe does not show any significant adverse side effects and has no influence on the activities of cytochrome P enzymes, therefore being devoid of significant pharmacokinetic interactions with other drugs.
The additive effect to statins and the lack of necessary titration of the statin dose makes combinations of ezetimibe with statins an important options of patients resistant or intolerant to statins. Large clinical trials, however, like ENHANCE in patients with heterozygous FH did not reveal a statistically significant effect on carotid intima media thickness compared to simvastatin alone despite a higher LDL-C lowering efficacy of the combination Kastelein et al. A conclusive answer regarding a clinically relevant beneficial effect of ezetimibe on cardiovascular morbidity and mortality is awaited by the ongoing IMPROVE-IT study covering 18, patients with acute coronary syndrome, comparing treatment regimens of simvastatin vs a combination with ezetimibe.
Endogenous ligands comprise fatty acids and eicosanoids including leukotriene B4. Overall, reverse cholesterol transport is stimulated by these processes. Currently three fibrates are in clinical use — fenofibrate, gemfibrozil, and bezafibrate: fenofibrate is the preferred drug owing to its lack of PK interaction with statins. Due to their lipid-modifying profile, fibrates can be particularly useful in monotherapy or in combination with statins for the treatment of patients with diabetic dyslipidemia or the metabolic syndrome Fievet and Staels However, microvascular events including retinopathy, nephropathy, and neuropathy were significantly reduced.
The tolerability and safety of fibrates are acceptable: Adverse side effects include myopathy, upper GI-symptoms, mild elevation of serum transaminase and homocysteine levels, and an increased incidence for cholesterol gallstones Prueksaritanont et al.
The most severe adverse side effect is muscle toxicity with rhabdomyolysis Davidson et al. Particularly gemfibrozil treatment in combination with statins is associated with an increased risk for myopathy and hepatotoxicity caused by its competition with statins for the glucuronidation elimination pathway, thereby decreasing the elimination of statins Prueksaritanont et al.
The lipid profile-modifying effects of vitamin B3 — nicotinic acid or niacin — are since nearly 60 years introduced into clinical practice Carlson
Antilipidemic Drug Therapy Today and in the Future
If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus. Atherosclerosis is the abnormal accumulation of lipids and products resulting from an inflammatory response in the walls of arteries, and is the leading cause of death in the Western world. Heart attacks, angina pectoris, peripheral arterial disease, and strokes are common sequelae of atherosclerosis. In some cases, lowering serum lipid concentrations has been shown to prevent the sequelae of atherosclerosis and decrease mortality in patients with a history of cardiovascular disease and hyperlipidemia.
Hypolipidemic agents , cholesterol-lowering drugs or antihyperlipidemic agents , are a diverse group of pharmaceuticals that are used in the treatment of high levels of fats lipids , such as cholesterol, in the blood hyperlipidemia. They are called lipid-lowering drugs. These are drugs which lower the level of lipids and lipoproteins in blood. The several classes of hypolipidemic drugs may differ in both their impact on the cholesterol profile and adverse effects.
Antihyperlipidemic agents promote reduction of lipid levels in the blood. Some antihyperlipidemic agents aim to lower the levels of low-density lipoprotein LDL cholesterol, some reduce triglyceride levels, and some help raise the high-density lipoprotein HDL cholesterol. By reducing the LDL cholesterol, they can prevent both the primary and secondary symptoms of coronary heart disease. Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances. The easiest way to lookup drug information, identify pills, check interactions and set up your own personal medication records. Available for Android and iOS devices.