MTP inhibition as a treatment for dyslipidaemias: time to deliver or empty promises?

The development of cholesterol-lowering drugs, including a statins, bile acid sequestrants and cholesterol absorption inhibitors has expanded the options for cardiovascular prevention. Recent treatment guidelines emphasise that individuals at substantial risk for atherosclerotic coronary heart disease should meet defined lipid targets. Combination therapy with drugs that have different and complementary mechanisms of action is often needed to achieve these goals. Existing approaches to the treatment of hypercholesterolaemia are still ineffective in halting the progression of coronary artery disease in some patients despite combination therapies. Other patients are resistant to, or intolerant of, conventional pharmacotherapy and remain at high-risk of atherosclerotic cardiovascular disease, so that alternative approaches are needed. New agents, including inhibitors of microsomal triglyceride transfer protein (MTP), may play a future role, either alone or in combination, in the treatment of hyperlipidaemias. This review focuses on novel approaches to treat dyslipidaemias via the inhibition of MTP. Patients most suitable for use of MTP inhibitors include those with hepatic hypersecretion of apoB, including the metabolic syndrome, Type 2 diabetes mellitus and familial combined hyperlipidaemia, as well as homozygous and heterozygous familial hypercholesterolaemia. However, certain safety issues with these agents need resolving, particularly fatty liver disease.     

New therapies for familial hypercholesterolemia

The development of cholesterol-lowering drugs, including a variety of statins, bile acid binding resins and recently discovered inhibitors of cholesterol absorption has expanded the options for cardiovascular disease prevention. However, existing approaches to the treatment of familial hypercholesterolemia (FH) are still ineffective in halting the progression of coronary artery disease (CAD) in some patients despite combination therapies. Homozygous FH (and many heterozygous FH subjects) are resistant to conventional drug treatment and remain at high-risk for development and progression of atherosclerotic cardiovascular disease, therefore alternative approaches are needed. Novel agents that include inhibitors of the apical sodium-dependent bile acid transporter, cholesteryl ester transfer protein, microsomal triglyceride transfer protein and squalene synthase may play a future role in combination with statins. It is possible that with improvements in vector technology, liver-directed somatic gene therapy would be an effective approach for this disorder.     

Cholesterol absorption inhibitors as a therapeutic option for hypercholesterolaemia

The development of cholesterol-lowering drugs (including a variety of statins, bile acid-binding resins and recently discovered inhibitors of cholesterol absorption) has expanded the options for cardiovascular prevention. Recent treatment guidelines emphasise that individuals at substantial risk for atherosclerotic coronary heart disease should meet defined targets for LDL cholesterol concentrations. Combination therapy with drugs that have different or complementary mechanisms of action is often needed to achieve lipid goals. Existing approaches to the treatment of hypercholesterolaemia are still ineffective in halting the progression of coronary artery disease in some patients despite combination therapies. Other patients are resistant to conventional drug treatment and remain at high risk for the development and progression of atherosclerotic cardiovascular disease and alternative approaches are needed. The discovery and development of ezetimibe (a novel, selective and potent cholesterol absorption inhibitor) has advanced the treatment of hypercholesterolaemia. New agents including the phytostanol preparation FM-VP4 and inhibitors of acyl coenzyme A:cholesterol acyltransferase, the apical Na(+)-dependent bile acid transporter and microsomal triglyceride transfer protein may also play a future role in combination therapy. This review focuses on the recent progress in the molecular mechanisms of intestinal cholesterol absorption and transport, and novel therapeutic approaches to inhibit the cholesterol absorption process.     

Novel microsomal triglyceride transfer protein inhibitors

Microsomal triglyceride transfer protein (MTP) mediates triglyceride absorption and chylomicron secretion from the intestine and very-low-density lipoprotein (VLDL) secretion from the liver, by linking lipid molecules with apolipoprotein B (ApoB). Inhibition of MTP reduces the level of all ApoB-containing lipoproteins, including low-density lipoprotein (LDL). High-throughput screening has produced several families of compounds that are effective in vitro and in vivo as MTP inhibitors and some drugs are currently at clinical trial stage. Drugs that inhibit MTP can potentially be very effective in reducing atherosclerotic vascular disease by lowering levels of all the atherogenic lipoproteins. Partial inhibition of MTP by an inhibitor could be particularly useful when combined with other drugs that alter lipid metabolism but marked inhibition of MTP could cause significant adverse effects.     

New lipid modulating drugs: the role of microsomal transport protein inhibitors

Microsomal triglyceride transfer protein (MTP) is involved in the synthesis of very low density lipoprotein in the liver. Its deficiency results in abetalipoproteinemia. MTP inhibitors target the assembly and secretion of apolipoprotein B-containing lipoproteins. These agents may potentially play a role, alone or in combination, in the treatment of hypercholesterolemia or hypertriglyceridaemia. Clinical applications of MTP inhibitors initially focused primarily on high-dose monotherapy in order to produce substantial reductions in LDL-cholesterol levels but these proved to induce significant hepatic steatosis and transaminase elevations. However, likely orphan indications for MTP inhibitors, where a different risk-benefit profile applies, include patients with homozygous familial hypercholesterolemia where statins often show a low response. Development of MTP inhibitors has continued to enter clinical trials at lower doses or in formulations aimed at utilizing their efficacy while avoiding their side effects. These have shown promising results in reducing cholesterol, triglycerides and apolipoprotein B with a far lower incidence of, often, transient side-effects. The clinical efficacy and safety of MTP inhibition in patients with hyperlipidaemia remains to be fully determined and to be proven in both surrogate and clinical endpoint trials but there may be a role for these agents in orphan indications for rarer severe hyperlipidaemias.     

Emerging targets for the treatment of dyslipidemia

Dyslipidemia is one of the main risk factors leading to atherosclerotic cardiovascular disease (CVD). According to recent treatment guidelines, subjects at substantial risk of CVD should meet more aggressive targets for low-density lipoprotein(LDL)-cholesterol levels. Treatment with statins fails to protect a significant percentage of patients from cardiovascular events despite efficient cholesterol-lowering. Moreover, clinical and epidemiologic data highlight the need of therapies to reduce the residual cardiovascular risk associated with low high-density lipoprotein(HDL)-cholesterol and elevated triglyceride levels. There are several novel agents undergoing preclinical or clinical development for the treatment of dyslipidemia. Squalene synthase inhibitors, antisense oligonucleotides targeting the production of apolipoprotein(apo)B-100, inhibitors of proprotein convertase subtilisin/kexin type 9, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor agonists are some of the alternative approaches for lipid-lowering. Moreover, HDL-targeted therapies such as the cholesteryl ester transfer protein inhibitors, HDLderived proteins, and mimetic peptides/lipids can increase HDL-cholesterol levels or improve the antiatherosclerotic properties of HDL. In conclusion, the emergence of agents that act in monotherapy or in combination with available lipid-modifying drugs may allow more effective management of dyslipidemia and, consequently, reduce the burden of CVD.     

Effects on Coronary Atherosclerosis by Targeting Low-Density Lipoprotein Cholesterol with Statins

A correlation exists between circulating levels of low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular disease (CVD). Evidence from clinical trials indicates that reducing LDL-C levels can result in beneficial clinical outcomes in patients at risk of CVD and in high-risk patients with clinical symptoms of CVD. Lipid-lowering agents, of which HMG-CoA reductase inhibitors (statins) are the most effective, protect against the vascular changes seen in the development of atherosclerotic plaque formation. Clinical trials assessing the effects of statins on coronary atherosclerosis using quantitative coronary angiography or intravascular ultrasound showed that statins can reduce progression or even cause regression of atherosclerotic plaque. This improvement of vascular structure after statin treatment is correlated with reductions in LDL-C levels. This appears to be the principal mechanism by which statin therapy reduces cardiovascular risk, with emerging evidence for statin-mediated changes in high-density lipoprotein and C-reactive protein levels contributing to modification of the atherosclerotic plaque.     

Novel agents to manage dyslipidemias and impact atherosclerosis

Strong epidemiological evidence linked elevated levels of low-density lipoprotein cholesterol (LDL-C) to risk of atherosclerotic heart disease. As a consequence, LDL-C lowering has been the main goal of therapy to reduce cardiovascular risk for the past few decades and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become some of the most commonly prescribed drugs. In spite of the proven efficacy of these drugs, statins reduce cardiovascular events by only 30-40%. Epidemiological analyses clearly indicate that a significant portion of risk is linked to other particles such as low high-density lipoprotein cholesterol (HDL-C), high triglycerides and others. Furthermore, several quantitative coronary angiography studies showing regression of atherosclerosis and reduction in subsequent events utilized a combination of drugs effective on LDL-C as well as other lipoproteins. Hence, several new drugs are being investigated that affect more than the traditional LDL-C pathways. In this article, we review lipoprotein-modifying agents that have either been recently released, or are still in various phases of development. They include agents that reduce LDL-C levels by mechanisms other than HMG-CoA inhibition (such as cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, sterol-regulating binding protein cleavage activating protein ligands, microsomal triglyceride transfer protein inhibitors, LDL-C receptor activators and farnesoid X receptor antagonists) and agents that raise HDL-C cholesterol or improve cholesterol efflux (such as cholesterol ester transfer protein inhibitors, retinoid X receptor selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and estrogen like compounds).     

Emerging drugs for prostate cancer

Prostate cancer mortality usually occurs as a result of castrate resistant disease. Many approaches are currently being evaluated to improve the treatment of this condition. These include drugs that induce androgen deprivation, that is, LHRH antagonists; more active or less toxic chemotherapy agents; immunologic approaches, including passive and active immunization; drugs that target the androgen receptor and/or androgen synthesis; drugs that target specific pathways, including tyrosine kinase inhibitors, angiogenesis inhibitors, endothelin antagonists and matrix metalloproteinase inhibitors; and antioxidants and cell cycle inhibitors. Many of these agents seem promising. The rationale, biologic activity and therapeutic results of these emerging drugs are reviewed.     

Lipid and non-lipid effects of statins

Long- and short-term trials with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated significant reductions in cardiovascular events in patients with and without history of coronary heart disease. Statins are well-established low-density lipoprotein (LDL)-lowering agents, but their clinical benefit is believed to result from a number of lipid and non-lipid effects beyond LDL lowering, including a rise in plasma high-density lipoprotein levels. Beyond improving the lipid profile, statins have additional non-lipid effects including benefit on endothelial function, inflammatory mediators, intima-media thickening, prothombotic factors that ultimately result in plaque stabilization. These effects arise through the inhibition of several mevalonate-derived metabolites other than cholesterol itself, which are involved in the control of different cellular functions. Although statins represent the gold standard in the prevention and treatment of coronary heart disease, combination therapy with other lipid-lowering drugs, as well as novel therapeutic indications, may increase their therapeutic potential.     

Role of lipid-lowering pharmacotherapy in children

For patients with coronary artery disease and healthy middle-aged or older individuals with elevated cholesterol levels, treatment with cholesterol-lowering drugs reduces morbidity and sometimes mortality. Treatment reverses established atherosclerotic lesions within a relatively short period of time, suggesting that starting cholesterol-lowering drugs in adulthood is adequate for most people at risk. Children with genetic lipid disorders, including familial hypercholesterolaemia and familial combined hyperlipidaemia, may be candidates for earlier therapy. A complete assessment of risk factors should be undertaken to determine which children are at highest risk. Treatment should start with diet, because diet is an important independent protective factor for disease. The bile acid sequestrants (resins) are the only drugs approved for children and may reduce low density lipoprotein (LDL)-cholesterol levels by 15 to 20% at best. Long term tolerability is good, but many children will not take the resins because they find them unpalatable. Tablet formulations have higher acceptability. Some children require supplementation with fat soluble vitamins or folate. Although hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have not been tested in long term studies in children, safety records are excellent in adults. Short term studies show that HMG-CoA reductase inhibitors reduce LDL-cholesterol levels similarly in children and in adults. Thus, the drugs may be used in low dosages to treat some adolescents with exceptional risk of disease.     

Cardiovascular effects of phosphodiesterase 5 inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil, vardenafil and tadalafil, are now approved for the treatment of erectile dysfunction. They inhibit the cGMP-specific isoform 5 of phosphodiesterase, resulting in cGMP accumulation, which, for example in smooth muscle cells, reduces muscular tone. In the cardiovascular system, they slightly reduce arterial systemic blood pressure. This moderate effect was also shown in combination with many antihypertensive drugs. But the important contraindication is the concomitant use of PDE 5 inhibitors with any drug serving as a nitric oxide donor, as this combination can lead to significant arterial hypotension. Caution is needed in patients on alpha-blocking agents. In general, this class of drugs was not shown to exhibit direct deleterious effects on the myocardium or promote arrhythmias. Furthermore, statistical evaluations did not demonstrate an increased risk for patients taking PDE 5 inhibitors in comparison with an adequate control population. Many patients suffering from erectile dysfunction may be characterized by multiple cardiovascular risk factors or even ischemic heart disease, suggesting an increased baseline risk. While in many forms of erectile dysfunction, these agents seem to be very effective, it becomes clear that endothelial dysfunction is an attractive target of PDE 5 inhibitors and may also be the underlying cause in many types of erectile dysfunction. In addition, these agents seem to be very effective in lowering pulmonary arterial pressure, which might provide the opportunity to treat primary and some forms of secondary pulmonary hypertension, perhaps in combination with inhaled nitric oxide or other pulmonary arterial vasodilators. Sildenafil was approved for treatment of primary arterial hypertension in the U.S. in June 2005. Recently, direct cardioprotective effects were described in animal research, resembling preconditioning-like effects, which may, under certain conditions, also be applicable in clinical research.     

Cardiovascular risk profile of antirheumatic agents in patients with osteoarthritis and rheumatoid arthritis

Several new drugs have become available for the treatment of patients with osteoarthritis and rheumatoid arthritis (RA). These agents include selective cyclooxygenase (COX)-2 inhibitors, leflunomide and anti-tumour necrosis factor (TNF)-alpha antagonists. COX-2 inhibitors have a more favourable gastrointestinal adverse effect profile than conventional non-steroidal anti-inflammatory drugs (NSAIDs). However, the COX-2 inhibitors are also associated with hypertension, oedema and congestive heart failure, the well-known adverse effects of conventional NSAIDs. Patients with treated hypertension should be monitored regularly when conventional NSAIDs or COX-2 inhibitors are administered. At present, there is a considerable debate regarding the risk of cardiovascular events with the COX-2 inhibitors. The available literature gives no unequivocal answers. This matter can only be solved by an appropriate trial assessing the cardiovascular risk of these agents. Patients with RA appear to have an enhanced cardiovascular risk which might be related to an unfavourable lipid profile. Corticosteroids induce hypercholesterolaemia in patients other than those with RA. It was recently shown that total and high-density lipoprotein (HDL) cholesterol were low in patients with RA who had a high disease activity. Contrary to the expectation, combination therapy with prednisolone rapidly improved the atherogenic index (total/HDL cholesterol). Ongoing studies investigating this topic are underway. It is not known to what extent corticosteroids induce hypertension in patients with RA. Hence, we advocate blood pressure control for these patients. A small percentage of patients with RA develop hypertension when taking leflunomide, and no other serious cardiovascular adverse effects have been reported in the literature. Blood pressure monitoring is recommended especially in the first months of treatment. TNFalpha antagonists are contraindicated in patients with RA who have congestive heart failure. No specific cardiovascular adverse effects have been reported with the use of these agents in the non-cardiovascular compromised patient. TNFalpha antagonists are the most powerful anti-inflammatory drugs presently available. As inflammation plays an important role in RA as well as in cardiovascular disease and, in view of the increased cardiovascular risk in RA, it is tempting to expect that suppression of inflammation ultimately will lower the cardiovascular morbidity and mortality in patients with RA.     

Emerging therapies for dyslipidemia: known knowns and known unknowns of MTP inhibitors

Last decade had witnessed enormous efforts to develop therapies to treat one or more components of metabolic syndrome, a cluster of diseases including diabetes, obesity and dyslipidemia. Several newer targets are identified and evaluated to treat these metabolic disorders. Microsomal triglyceride transfer protein (MTP) has been identified as one of the promising target for the treatment of dyslipidemia. MTP plays crucial role in the assembly of triglyceride rich chylomicrones in enterocytes and VLDL in hepatocytes and several lines of evidence suggested that MTP inhibitors can be instrumental in combating familial hypercholesterolemia. Several first generation compounds are currently being evaluated in clinic and fatty liver is found to be the main adverse effect of these agents. Recently development of enterocyte specific inhibitor of MTP is emphasized in order to deal with fatty liver issue. In this review, we have dealt with important mechanistic aspects of MTP inhibition, patent scenario and clinical trial outcomes and some of the recent patents related to newly discover chemical scaffolds.     

Overcoming 'ageism' bias in the treatment of hypercholesterolaemia : a review of safety issues with statins in the elderly.

Atherosclerosis is a progressive, lifelong condition that is the leading cause of death among middle-aged and elderly individuals aged > or =65 years. Up to 80% of elderly patients are found to have evidence of obstructive coronary heart disease at autopsy. Demographic trends, including the advancing median age and life expectancy of Western societies, suggest that a large share of the burden of atherosclerotic plaque is likely to be borne by elderly individuals. These trends are in part due to increases in a number of chronic diseases associated with adverse cardiovascular outcomes, including metabolic syndrome, diabetes mellitus and chronic kidney disease. Because the elderly have a higher attributable risk of coronary heart disease as a result of hypercholesterolaemia, more coronary deaths and overall events can be prevented via treatment in this age group compared with younger persons with hypercholesterolaemia. The efficacy, safety and tolerability of HMG-CoA reductase inhibitors (statins) have been confirmed in randomised, controlled, multicentre trials involving large numbers of patients aged > or =65 years. Although muscle symptoms such as myalgia are relatively common adverse events, more severe signs of myolysis such as myopathy and rhabdomyolysis are rare, but their risk is elevated by conditions (e.g. concomitant medications) that increase the systemic exposure of these agents. Statins differ in their susceptibility to increases in systemic exposure, but most statins have been demonstrated to be well tolerated and safe when administered to elderly patients. These favourable clinical findings should help clinicians counter highly prevalent 'ageism' bias in statin prescribing, whereby elderly patients, particularly those at highest cardiovascular risk, are often denied the benefits of statins without any meaningful foundation.     

Novel approaches to treating cardiovascular disease: lessons from Tangier disease

Atherosclerotic cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in Western societies. Although cholesterol is a major CVD risk factor, therapeutic interventions to lower plasma cholesterol levels have had limited success in reducing coronary events. Thus, novel approaches are needed to reduce or eliminate CVD. A potential therapeutic target is a newly discovered ATP binding cassette transporter called ABCA1, a cell membrane protein that is the gateway for secretion of excess cholesterol from macrophages into the high density lipoprotein (HDL) metabolic pathway. Mutations in ABCA1 cause Tangier disease, a severe HDL deficiency syndrome characterised by accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis. Studies of Tangier disease heterozygotes revealed that the relative activity of ABCA1 determines plasma HDL levels and susceptibility to CVD. Drugs that induce ABCA1 in mice increase clearance of cholesterol from tissues and inhibit intestinal absorption of dietary cholesterol. Thus, ABCA1-stimulating drugs have the potential to both mobilise cholesterol from atherosclerotic lesions and eliminate cholesterol from the body. By reducing plaque formation and rupture independently of the atherogenic factors involved, these drugs would be powerful agents for treating CVD.     

HMG-CoA reductase inhibitors in the prevention of stroke

Stroke is a heterogeneous disorder, with the definition including both haemorrhagic and ischaemic stroke. Although these subtypes of stroke have different underlying pathophysiological mechanisms, atherosclerosis plays a pivotal role in both. Most risk factors for cardiovascular disease are also risk factors for stroke. Patients with a history of cardiovascular events are at an increased risk of stroke. Although hypercholesterolaemia is the most characteristic risk factor for atherosclerotic diseases, recent data suggest that the correlation between cholesterol levels and either ischaemic or haemorrhagic stroke is weak. However, the interpretation of these results is hampered by the inconsistent use of classifications of the various subtypes of stroke in studies. Pooled data on the effect of HMG-CoA reductase inhibitors show a 30% risk reduction in strokes. These beneficial effects are obtained from studies in middle aged patients with ischaemic heart disease, the interpretation being that the effects of HMG-CoA reductase inhibitors on stroke are mediated via (i) cholesterol-lowering effects on the coronary vasculature or (ii) cholesterol-independent effects of these agents. The results cannot be extrapolated to the elderly, among whom stroke most frequently occurs.     

Combination therapy in Alzheimer's disease: a review of current evidence

Treating dementia has become a major challenge in clinical practice. Presently, acetylcholinesterase inhibitors are the first-line drugs in the treatment of Alzheimer's disease (AD). These options are now complemented by memantine, which is approved for the treatment of moderate-to-severe AD. Altogether, a minimum of six agent classes already exist, all of which are approved for clinical use and are either already being tested or ready for phase III clinical trials for the treatment of AD. These include cholinesterase inhibitors, blockers of the NMDA receptor, antioxidants or blockers of oxidative deamination (including Gingko biloba), anti-inflammatory agents, neurotrophic factors (including hormone replacement therapy and drugs acting on insulin signal transduction) and antiamyloid agents (including cholesterol-lowering therapy). These approaches hold promise for disease modification and have a potential to be used as combination therapy for cognitive enhancement. Presently, only nine clinical studies have been published that have investigated the effects of a combination regimen on cognitive performance or AD. Among those, one study was conducted in elderly cognitively intact persons; the others involved patients with AD. Only five of the treatment studies followed a randomised, controlled design. Not all studies favoured the superior efficacy of combination therapy over monotherapy. Some studies, however, showed some evidence for synergistic combination effects of symptomatic therapy, including delay or prevention of disease progression in AD patients. In addition, six studies investigated the effects of AChE inhibitor in combination with antipsychotic or antidepressant therapy on behavioural aspects of AD symptomatology. In four of those studies there were indications that combination therapy had greater efficacy over monotherapy. The treatment of AD patients requires optimised options for all stages of illness based on the available drugs. There is a great need for further well designed studies on combination therapy in AD.     

Diabetes mellitus and vascular endothelial dysfunction: current perspectives

Patients with diabetes mellitus (DM) have a high prevalence of coronary artery disease (CAD), as diabetes is implicated in the formation of atherosclerotic plaque. Endothelial dysfunction is one of the precursor key steps in the development of atherosclerosis in diabetic subjects. Decreased nitric oxide (NO) production, increased oxidative stress and impaired function of endothelial progenitor cells are the main mechanisms involved in the accelerated atherosclerotic process observed in type 2 DM patients. Therapeutic approaches including classic agents such as statins, angiotensinconverting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), antioxidants and novel agents such as tetrahydrobiopterin (BH4), asymmetric dimethylarginine (ADMA) and homocysteine (tHcy), have been implicated in order to ameliorate endothelial function of diabetic patients.