The key role of dyslipidaemia in determining cardiovascular disease (CVD) has been proved beyond reasonable doubt, and therefore several dietary and pharmacological approaches have been developed. The discovery of statins has provided a very effective approach in reducing cardiovascular risk as documented by the results obtained in clinical trials and in clinical practice. The current efficacy of statins or other drugs, however, comes short of providing the benefit that could derive from a further reduction of LDL cholesterol (LDL-C) in high-risk and very high risk patients. Furthermore, experimental data clearly suggest that other lipoprotein classes beyond LDL play important roles in determining cardiovascular risk. For these reasons a number of new potential drugs are under development in this area. Aim of this review is to discuss the available and the future pharmacological strategies for the management of dyslipidemia.
Atherosclerosis is a multifactorial disease in which plaque formation is the final process for several common pathogenetic mechanisms, including the individual susceptibility of genetic origin, hemodynamic stress, and various combinations of risk factors such as hypercholesterolemia, hypertension, diabetes, immune reactions and autoimmune diseases, inflammation, viral infections, and cigarette smoking [
The initiating event in atherosclerosis is the subendothelial retention of apolipoprotein apoB-containing lipoproteins in the arterial wall. This process is strictly related to the plasma levels of apoB-lipoproteins, however other properties can influence it, including lipoprotein size, charge and composition, and endothelial permeability. Very large lipoprotein (nonhydrolyzed chylomicrons) cannot enter the arterial wall, thus they do not directly promote atherosclerosis [
The deposition and modification of LDL in the arterial wall promote a number of key processes including (1) impairment of endothelial function, (2) invasion of the arterial wall by leukocytes, particularly monocytes and T lymphocytes, (3) internalization of lipoproteins in macrophages and smooth muscle cells and accumulation of lipids, and (4) phenotypic modulation and proliferation of smooth muscle cells and synthesis of extracellular matrix.
Atherosclerotic lesions develop primarily in large and medium arteries, and above all in the intima, that is, the innermost layer of the arterial wall, consisting of a monolayer of endothelial cells adherent to a thin layer of connective tissue. The intima is separated from the tunica media, consisting of smooth muscle cells, collagen, and glycosaminoglycans, by the internal elastic lamina.
The evolution of the atherosclerotic lesion is characterized by three stages [ Fatty streak formation [ Fibrous plaque formation: at this stage the lesion is enriched in macrophages and proliferating smooth muscle cells; moreover, the formation of connective tissue and intracellular and extracellular accumulation of lipids are characteristic of this step. Complicated lesions are the most advanced form of fibrous plaques. An important feature of complicated lesions is the formation of a lipid core, whose dimensions are related to the stability of atherosclerotic plaque [
The key role of dyslipidaemias in determining cardiovascular disease (CVD) has been proved beyond reasonable doubt, and therefore several dietary and pharmacological approaches are used in the clinical practice for the management of dyslipidemia (Table
Established pharmacological agents for dyslipidaemia management and their effects on lipid fractions.
Agent | Lipid fraction (%) | ||
---|---|---|---|
LDL-C | HDL-C | TG | |
Bile acid sequestrants | 15–30 |
3–5 |
No change |
Ezetimibe | 18–20 |
1–4 |
8 |
Statins | 18–55 |
5–15 |
7–30 |
Fibrates | 5–20 |
10–20 |
20–50 |
Nicotinic acid | 5–25 |
15–35 |
20–50 |
Ezetimibe + statin | +15–20 |
||
Fibrate + statin | +5 |
+5 |
|
Nicotinic acid + statin | +8–31 |
+17–32 |
+24–27 |
There are many functional foods and dietary supplements that are currently promoted as beneficial for people with dyslipidaemia or for reducing the risk of CVD. Some of these products have been shown to have potentially relevant functional effects but have not been tested in long-term clinical trials and should therefore be utilized only when the available evidence clearly supports their beneficial effects on plasma lipid values and their safety. Based on the available evidence, foods enriched with phytosterols (1-2 g/day) may be considered for individuals with elevated TC and LDL-C values in whom the total CV risk assessment does not justify the use of cholesterol-lowering drugs [
Bile acid sequestrants are anion exchange resins that bind bile acids in the gastrointestinal tract. Bile acids are synthesized in the liver from cholesterol and released into the intestinal lumen; however most of the bile acid is returned to the liver from the terminal ileum via active absorption. The bile acid sequestrants are not systemically absorbed or altered by digestive enzymes. Therefore, the beneficial clinical effects are indirect. By binding the bile acids, the drugs prevent the entry of bile acid into the blood and thereby remove a large portion of the bile acids from the enterohepatic circulation. The decrease in bile acid returned to the liver leads to upregulation of key enzymes responsible for bile acid synthesis from cholesterol. The increase in cholesterol catabolism to bile acids results in a compensatory increase in hepatic LDLR activity, clearing LDL-C from the circulation and thus reducing LDL-C levels [
Compared with the first-generation bile acid sequestrants (cholestyramine and colestipol), the second-generation bile acid sequestrant colesevelam hydrochloride (HCl) exhibit a greater binding capacity for bile acids. Therapy with colesevelam can lower LDL-cholesterol levels by 15–19% [
Ezetimibe is a lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol by binding to the Niemann-Pick C1-like 1 protein, a sterol transporter [
Ezetimibe can be used as second-line therapy in association with statins when the therapeutic target is not achieved at maximal tolerated statin dose or in patients intolerant of statins or with contraindications to these drugs.
Several clinical trials have demonstrated that statins significantly reduce cardiovascular morbidity and mortality in both primary and secondary prevention [
Statins inhibit HMG-CoA reductase activity resulting in the inhibition the conversion of acetyl-coenzyme A and acetoacetyl-coenzyme A to mevalonate, a key step in cholesterol synthesis. This inhibition leads to a reduced synthesis of cholesterol in the liver and in an increased expression of hepatic low-density lipoprotein receptor (LDLR), thus reducing the concentration of circulating LDL-C and other apoB-containing lipoproteins including TG-rich particles. All statins induce modest elevations in HDL-C [
Besides, statins exhibit several pleiotropic beneficial effects that are independent of cholesterol lowering properties [ The inhibition of HMG-CoA reductase lead to the inhibition of isoprenoid intermediates synthesis, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GPP). Isoprenylation of proteins is involved in the activation of inflammatory pathways [ Statins reduce platelet activation and aggregability in both cholesterol-dependent and cholesterol-independent manner [ Statins reduce the proatherogenic effects of OxLDL by several ways, including the downregulation of macrophage and endothelial scavenger receptors, thus reducing the uptake of OxLDL [ Statins promote eNOS production and function in endothelial cells by increasing eNOS expression and activity, and by preventing the downregulation of eNOS expression and activity induced by OxLDL [ Statins promote endothelial progenitor cell proliferation, migration, and cell survival [ Statins reduce vascular smooth muscle cell migration and proliferation, two key steps of atherogenesis process [ Statins reduce the inflammatory response by inhibiting the induction of major histocompatibility complex class II (MHC-II), involved in the activation of T lymphocytes and in the control of immune response [ Statins stabilize atherosclerotic plaque by lipid lowering [ Statins decrease myocardial remodeling, by inhibiting some effects of angiotensin II (a major effector of the renin-angiotensin system), including cardiac fibroblast proliferation, collagen synthesis, and induction of cardiomyocyte proliferation [
Increased triglyceride levels are key features in certain conditions that lead to premature vascular disease, including type 2 diabetes mellitus, familial combined hyperlipidaemia. and familial hypoalphalipoproteinaemia. Elevated levels of TG are closely correlated with low HDL-cholesterol levels.
Fibrates are agonists of peroxisome proliferator-activated receptor-
However, clinical trial data on the role of fibrates in cardiovascular prevention are conflicting. Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events in the FIELD trial [
Omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] are components of fish oil and the Mediterranean diet and their use is beneficial for the cardiovascular system [
Clinical studies have shown the beneficial effect of omega-3 fatty acids. The GISSI Prevenzione trial showed that the use of omega-3 fatty acids was associated to significant reductions in the risk for reinfarction and sudden death among patients who sustained an acute coronary syndrome prior to randomization [
Not all trials have demonstrated a positive effect of omega-3 supplementation on cardiovascular disease [
Clinical and mechanistical studies are required to define the benefits of omega-3 fatty acids in both primary and secondary prevention.
Nicotinic acid has broad lipid-modulating action, raising HDL-C in a dose-dependent manner by
Nicotinic acid may be used in combination with statins as a therapy for combined hyperlipidemia. Nicotinic acid is currently used mostly as an extended release (ER) form. In patients with established CHD, the addition of extended-release (ER) niacin to statin therapy results in the stabilization of CIMT, in contrast to patients receiving statin monotherapy who experienced significant CIMT progression, despite having a mean baseline LDL-C of 90 mg/dL on statin monotherapy [
Niacin usage is limited by cutaneous flushing, a bothersome adverse effect. Flushing is the leading cause for discontinuation of therapy, estimated at 25–40% or more [
In a recently published trial, the addition of niacin to statin therapy did not induce an incremental benefit in patients with established cardiovascular disease, low levels of HDL-C at baseline and levels of LDL-C at target (<80 mg/dL) [
The key role of dyslipidaemias in determining cardiovascular disease (CVD) has been proved beyond reasonable doubt; and the discovery of statins has provided a very effective approach in reducing cardiovascular risk as documented by the results obtained in clinical trials and in clinical practice. Research however is clearly suggesting that other lipoprotein classes beyond low-density lipoprotein (LDL) play important roles in determining cardiovascular risk and that the current efficacy of statins or other drugs comes short of providing the benefit that could derive from a further reduction of LDL cholesterol (LDL-C) in high-risk and very-high-risk patients. For these reasons a number of new potential drugs are under development in this area.
Hepatic biosynthesis of very-low-density lipoprotein (VLDL) is dependent on two dominant proteins, namely, apolipoprotein B (apoB) and microsomal triglyceride (TG) transfer protein (MTP). ApoB is an obligatory structural component of VLDL and requires progressive lipidation, mediated by the resident endoplasmic reticulum chaperone MTP, to maintain conformational integrity and folding during the process of lipoprotein assembly. Interfering with this process is therefore an attractive approach for reducing lipoprotein synthesis and decreasing plasma LDL-C concentration. The possibility of targeting apoB during the process of gene translation is under extensive investigation. One approach to block mRNA translation of a gene is through the use of a single-strand antisense oligonucleotide (ASO) that is complementary to the mRNA. Following hybridization to the mRNA, the ASO inhibits translation and splicing and leads to degradation of the mRNA by RNase [
Emerging targets for dyslipidemia. The novel drugs that are under development for the treatment of dyslipidemia present several mechanisms of action. Emerging therapeutic agents for LDL lowering will: (a) interfere with lipoprotein synthesis in the liver by silencing apolipoprotein B (apoB) expression (1) or inhibiting microsomal triglyceride transfer protein (MTP) activity (2); (b) promote LDL-receptor activity by silencing (3) or blocking (4) proprotein convertase subtilisin/kexin type 9 (PCSK9). Emerging therapeutic agents affecting HDL will: (c) increase HDL-C plasma levels by blocking cholesteryl ester transfer protein (CETP) (5), or inducing apolipoprotein A-I (apoA-I) expression (6), (d) improve HDL activity by mimicking apoA-I (7) or nascent HDL (8) or increase the expression of receptors favoring cholesterol efflux from cells (9). Emerging therapeutic agents for triglycerides lowering will improve the catabolism of triglycerides and the handling fatty acids by peripheral organs (10), by new formulation of omega 3 fatty acids (11) and by inhibiting the expression of apolipoprotein C-III in the liver (12). Specific silencing of apolipoprotein (a) is also under investigation (13).
Mipomersen is an ASO targeting apoB which leads to a dose-dependent reduction in apoB and total cholesterol [
MTP, found in the endoplasmic reticulum of hepatocytes and enterocytes, mediates the formation of apoB-containing lipoproteins in the liver and in the intestine [
Cholesterol homeostasis is regulated by the LDL receptor (LDL-R) through its binding and uptake of circulating apoB-containing lipoproteins which are then internalized into the liver cell. The key mechanism associated with statins’ action involves the increase of LDL-R expression on the hepatocyte surface, followed by increased LDL turnover and reduction of plasma cholesterol levels. This mechanism is partially dampened by a negative feedback response associated with the induction of the expression and secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) [
Given that PCSK9 acts both intracellularly, as a chaperone directing the LDL-R to the lysosomes, and in the circulation, by promoting LDL-R internalization [
To date the largest body of information is available for REGN727/SAR236553, a fully human monoclonal antibody, which binds to the catalytic domain of PCSK9 that interacts with LDL-R. Overall, results from phase I and II clinical trials suggest that s.c. injections of SAR236553/REGN727 dose dependently reduce PCSK9 activity and produce significant additional reductions in LDL-C as well as in non-HDL-C independently of statin treatment. The antibody was generally well tolerated over the treatment period, with no drug-related adverse effects on liver function tests or other laboratory parameters, and no serious treatment-emergent adverse effects [
AMG145 is another fully human monoclonal antibody which also binds specifically to human PCSK9. Phase I data in subjects on stable statin therapy demonstrated a dose-dependent decrease in LDL-C and unbound PCSK9 with increasing subcutaneous doses of AMG145. LDL-C was lowered by up to 81% at maximal doses, over and above the LDL lowering achieved with statin alone [
PCSK9 can also be suppressed through gene silencing; among the nucleic acid-based therapies, the development of SPC5001, a locked nucleic acid-based inhibitor, and that of BMS-844421, an antisense RNA therapy, were terminated during phase I clinical trials. ALN-PCS02, an RNA interference molecule, is being tested in an ongoing phase I study in healthy volunteers to evaluate the safety and tolerability of various doses. In interim data on 20 subjects, robust target protein knockdown was observed at the highest dose tested, with a mean 60% reduction in plasma PCSK9 levels 3–5 days after administration. In line with PCSK9 genetics, this type of knockdown entailed a mean 39% reduction in LDL-C., with no drug-related discontinuations or liver enzyme elevations (
High-density lipoproteins (HDL) possess several physiological activities that may explain their antiatherosclerotic properties; among them, the most relevant is the ability of HDL to promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion [
In recent years, the metabolic pathways associated with HDL have been extensively investigated and elucidated, allowing the design of drugs able to interfere with HDL catabolism, improve the expression of the main protein constituent, namely, apoA-I, or mimic their activity.
The pharmacological approaches under development can be grouped in two major clusters: molecules increasing plasma HDL levels and molecule improving HDL function. It is expected that an increase in HDL levels can be beneficial when associated with an improvement in HDL function.
Recently, a mendelian randomization analysis revealed that a single nucleotide polymorphism in the endothelial lipase gene (LIPG Asn396Ser) associated with increased HDL-C levels in the population did not decrease the risk of myocardial infarction, despite a 13% reduction expected from the increased HDL-C levels [
Cholesteryl ester transfer protein (CETP) is an enzyme involved in the transfer of cholesteryl esters from HDL to LDL and VLDL; this process results in a reduction and remodeling of HDL particles and in an increase of LDL and VLDL levels. Furthermore, CETP transfers TG from VLDL or LDL to HDL, resulting in the formation of TG-enriched HDL, which is easily hydrolyzed by hepatic lipase leading to TG-rich small HDL that are cleared more rapidly from the circulation [
The first CETP inhibitor developed, torcetrapib, despite a 72% increase in HDL-C levels, was withdrawn because of an increased risk of cardiovascular events and death from any cause in the investigation of lipid levels management to understand its impact in atherosclerotic events (ILLUMINATE) trial [
The decision to stop dalcetrapib was based on the dal-OUTCOMES trial interim analysis which showed that dalcetrapib, in acute coronary syndrome patients, failed to demonstrate a significant reduction in cardiovascular adverse events (
While disappointing, the pursuit of an extensive programme of clinical trials and basic research to develop dalcetrapib has provided new information on the biology of HDL in both man and animal models, and on CETP inhibition as a viable therapeutic target for raising levels of HDL-C. Several other CETP inhibitors that raise HDL-C levels to a greater extent than dalcetrapib and also significantly lower LDLC and other novel HDL-raising agents remain under development. Ultimately, the benefits of each of these novel CETP inhibitors must be determined through prospective, randomized, clinical outcome trials. The possibility that, while CETP inhibitors were developed on the premise that they would increase HDL-C more than any therapy currently available, the benefit may still be largely due to the incremental lowering of LDL-C observed with the more potent inhibitors, should be considered for the transfer of these drugs in the clinical practice.
The life cycle of HDL starts from lipid-poor apoA-I, termed nascent, or pre
The rationale behind the development of HDL mimetics is the possibility of mimicking the first phase of the HDL life cycle and promoting cholesterol efflux, mainly from cholesterol-loaded cells in the vascular wall such as macrophages and foam cells (Figure
To this aim, lipid-poor apoA-I-phospholipid complexes have been extensively studied in preclinical models and preliminary studies in humans. So far, different approaches are under investigation. CSL-111 is a complex of native apoA-I and phosphatidylcholine isolated from soybeans which induced a significant reduction in atheroma volume compared with baseline [
A similar approach was tested also by incorporating recombinant apoA-I Milano, which differs from normal apoA-I by a cysteine-to-arginine substitution at amino acid 173. ETC-216 is a complex of apoA-I Milano with phospholipid and in a small clinical study significantly reduced total atheroma volume, measured by IVUS, in patients with acute coronary syndrome [
CER-001, a synthetic recombinant human apoA-I HDL mimetic, is in phase II testing in approximately 500 patients with acute coronary syndrome, to determine the effect on atherosclerotic plaque progression/regression as assessed by IVUS (CHI SQUARE;
A second approach to improve HDL function is represented by small peptides design to mimic apoA-I function. The most well-studied of these peptides is 4F, consisting of 18 amino acids, which was designed to have the lipid-binding properties of apoA-I through a common secondary structure, the class A amphipathic helix. The use of D-amino acids (D-4F) enables oral delivery of this compound by conferring resistance to gastrointestinal proteolytic enzymes. Several preclinical studies showed that 4F promotes cholesterol efflux via ABCA1 and SR-BI, and possesses anti-inflammatory, antithrombotic and antioxidant properties. The only available human study of D-4F showed that HDL isolated from subjects treated with a single 300 mg or 500 mg dose of unformulated D-4F had increased inhibition of LDL-induced monocyte chemotaxis compared to HDL isolated from control subjects. Data on the safety profile of D-4F in humans are not available yet. Overall at least 22 apoA-I mimetics are under development [
PPAR-
Several attempts to develop a dual PPAR agonist for diabetes have so far failed because of various safety concerns: ragaglitazar, MK-0767, and naveglitazar were found to be associated with an increased incidence of bladder cancer and hyperplasia in rodent studies and tesaglitazar development was discontinued because of indications that it may cause kidney dysfunction.
The dual agonist muraglitazar, a strong PPAR-
The latest dual PPAR-
This broad range of lipid improvements with aleglitazar addresses the pattern of dyslipidaemia often found in patients with type 2 diabetes. This agent may therefore have beneficial cardiovascular as well as anti-inflammatory effects, and long-term use may delay the progression of CVD. Adverse events with aleglitazar were mild (increases in body weight, the number of patients with oedema) and no indications of CVD or hepatotoxicity with this dual agonist was observed.
Whether these benefits will result in a reduction of cardiovascular events is under evaluation in the large phase III study ALECARDIO. This study will also address the safety and tolerability of aleglitazar with a special focus on common PPAR-
Two new formulations of omega-3 fatty acids may provide additional TG-lowering effects by reducing VLDL production and increasing their catabolism. AMR101, which contains ≥96% eicosapentaenoic acid (EPA), ethyl ester, and no docosahexaenoic acid (DHA), reduced TG (relative to placebo, at 4-g/day dose) by 33% in patients with hypertriglyceridaemia [
Lp(a) has been considered a cardiovascular risk factor for a long time and during the last few years, major advances have been achieved in understanding the causal role of elevated Lp(a) in premature CVD [
More recently early preclinical studies suggest that targeting liver expression of apo(a) with ASOs directed to KIV-2 repeats—which are expressed in multiple copies in the human apo(a) gene—may provide a highly effective approach to lower elevated Lp(a) levels in humans. The development of such ASOs to lower Lp(a) levels might then allow clinical tests of the importance of lowering Lp(a) levels for the therapy and prevention of CVD.
It is clear that more detailed studies of the metabolism of Lp(a) are required to aid in the design and development of selective and potent therapies for lowering Lp(a) [
Although statins provide effective and substantial reductions in LDL-C, non-HDL-C, and apoB, as well as other drugs provide beneficial effects on other lipids and lipoproteins, many patients do not achieve the recommended goals despite maximal therapy, and some patients cannot tolerate high-dose statin therapy. Available agents combined with statins can provide additional benefit on LDL-C reduction, and agents in development may increase therapeutic options. Genetic insights into mechanisms underlying regulation of LDL-C levels have expanded potential targets of drug therapy and led to the development of novel agents that are still undergoing testing to determine efficacy and safety. Alternative targets such as triglycerides, HDL, and Lp(a) also require attention; however, the available data are still not conclusive. Drugs increasing HDL may not be all alike and require adequate scrutiny of the mechanisms involved. Drugs increasing apoA-I availability may represent the best approach. Lp(a) also represents an attractive target; however, it will be difficult to address, with currently available intervention, whether decreasing Lp(a) provides a reduction in cardiovascular risk. The most promising approaches such as apoB synthesis inhibitors or PCSK9 inhibitors all decrease LDL as well. Until we have a better understanding of these issues, further LDL lowering in high-risk and very-high-risk individuals is the most sound clinical approach.