Major epidemiological studies have demonstrated the exponential relationship between the level of cholesterol in the blood and the risk of developing coronary heart disease (CHD) (see figure 1). Low-density lipoprotein (LDL) cholesterol has been described as the “final common pathway to develop atherosclerosis”.1
Very high cholesterol levels are seen in inherited disorders, such as familial hypercholesterolaemia (FH) (where levels can often be double those seen ‘normally’), and the likelihood of developing premature and often fatal heart disease is increased greatly. The majority of those who will develop atherosclerosis, however, may have only a moderately elevated LDL cholesterol, which might be ‘normal’ for that particular Westernised society. Many populations in the developing world with negligible CHD mortality rates will have LDL cholesterol levels of 2 mmol/L or less, probably reflecting our hunter-gatherer ancestors.
Several genetic polymorphisms have been identified as being associated with lower serum LDL cholesterol levels and consequently lower lifetime cardiovascular risk. A Mendelian randomisation study of a selection of these polymorphisms has shown that lifelong exposure to lower levels is linked with substantially lower risk of CHD.2 Mutations resulting in the inactivation of the LDL receptor regulatory, proprotein convertase subtilisin/kexin – 9 (PCSK9), have been linked with particularly low LDL levels and cardiovascular risk and have become a pharmaceutical target.3, 4
The evidence base
Many randomised clinical trials over the past 30 years or so have demonstrated that lowering cholesterol reduces cardiovascular events. The Cholesterol Treatment Trialists Collaboration (CTTC) reviewed data from 27 clinical trials of statins (170,000 participants) for both primary and secondary prevention and reported a 20% relative risk reduction per 1 mmol/L reduction in LDL cholesterol concentration for major vascular events. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2−3 mmol/L would reduce risk by about 40−50%. These beneficial effects were seen in both men and women, at ages from <60 to >70 years, in people with and without cardiovascular disease, in those at high and low cardiovascular disease risk, in patients with diabetes, and in those with average levels of blood cholesterol.5 No excess in non-cardiovascular mortality, including cancers, was observed with lipid lowering.
How low to go?
Several treatment strategies have been proposed for the management of dyslipidaemia, including ‘treat to target,’ ‘fire and forget’ and ‘the lower the better’. The latest Joint British Societies’ recommendations for the prevention of cardiovascular disease (JBS3)6 suggest that, in patients with established cardiovascular disease (CVD) and others at high risk, statins are recommended as they are “highly effective at reducing CVD events with evidence of benefit to LDL cholesterol levels <2 mmol/L which, justifies intensive non high-density lipoprotein (HDL) cholesterol lowering”. JBS3 has a suggested target of non-HDL cholesterol <2.5 mmol/L. The National Institute of Health and Care Excellence (NICE) do not recommend specific targets but propose monitoring with achievement of >50% reduction of LDL cholesterol in FH patients being a considered satisfactory response (CG71)7 or >40% reduction of non-HDL cholesterol in non-FH patients (CG181).8
Therapeutic lifestyle intervention underpins the management of dyslipidaemia. Indeed, the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on dyslipidaemia place emphasis on nutritional approaches, either alone or complementary to pharmacotherapy, in managing hypercholesterolaemia to reduce cardiovascular risk.9
Dietary intervention favourably influences lipids and cardiovascular risk and should therefore be a cornerstone of treatment efforts. Observational studies have shown that traditional Mediterranean diets, including vegetables, fruits, fish, whole cereal grains, legumes, unsaturated fats, moderate alcohol intake and limited consumption of red meat, improved lipids and glycaemic control and reduced cardiovascular mortality.
Improving the diet by substitution of saturated fats with unsaturated or monosaturated fats not only lowers LDL cholesterol, but also benefits triglycerides (TGs) and HDL cholesterol. There is growing support for the value of so-called ‘functional foods’ in the diet. Consumption of plant sterols or stanols is consistently associated with lowering of LDL cholesterol levels by up to 10%. Additionally, increasing intake of soluble (viscous) fibre, such as in oats, can produce modest reductions in total and LDL cholesterol (by about 0.13 mmol/L). Advice on incorporating such foods into the diet is included in the recent ESC/EAS guidelines, especially for patients for whom total cardiovascular risk assessment does not justify the use of pharmacotherapy.9 Comparison shows that dietary changes can produce a cumulative 20−30% reduction in LDL cholesterol (table 1).10
A NICE pathway brings together all NICE guidance, quality standards and materials to support implementation of cardiovascular disease prevention, including the ‘cardioprotective diet’ and physical exercise: available at: http://pathways.nice.org.uk/pathways/cardiovascular-disease-prevention
More about the importance of focusing on lifestyle, and the practicalities of sustaining this change is discussed by Professor Naveed Sattar, Institute of Cardiovascular and Medical Sciences, University of Glasgow, in this podcast.
Exercise is also fundamental for improving lipids, and reducing cardiovascular risk. While physical activity improves LDL cholesterol levels, there is even greater benefit in terms of lowering TGs (by up to 20%) and raising HDL cholesterol (by up to 10%). Not all of the cardioprotective effect of exercise is due to exercise-mediated weight loss, as there is evidence that both weight loss and physical exercise act independently and synergistically to improve lipids and cardiovascular risk.
Pharmacological management of dyslipidaemia
Important notice: prescribers should consult the British National Formulary and Summary of Product Characteristics (SPC) for more extensive advice on prescribing and use of all of the lipid modifying agents discussed in this module.
The difficulties associated with maintaining a healthy lifestyle in the long-term often mean that dyslipidaemic patients will require additional therapeutic intervention. HMG-CoA reductase inhibitor (statin) treatment remains the cornerstone of lipid-modifying treatment to prevent cardiovascular disease. Consideration may be given to the need for additional treatment for lowering elevated TGs, in accordance with current guidelines.
NICE estimates that up to 8,000 lives could be saved every three years by offering statins to anyone with a 10% risk of developing CVD within a decade.
In an update to its 2008 guidance on lipid modification, NICE recommends that the threshold for starting preventative treatment for CVD should be halved from a 20% risk of developing CVD over 10 years to a 10% risk. Up to 4.5 million people could be eligible for statins under the lower threshold. Offering statins to all eligible people could prevent up to 28,000 heart attacks and 16,000 strokes each year.
In the latest clinical guideline8 − CG181 Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of CVD, published July 2014 − key recommendations include:
- Identifying and assessing CVD risk using the QRISK2 assessment tool for the primary prevention of CVD in people up to the age of 84 years.
- Prioritising people for a full formal risk assessment if their estimated 10-year risk of CVD is 10% or more.
- Taking a full lipid profile before starting lipid modification therapy for primary prevention. A fasting sample is not needed.
NICE notes that not everyone with a 10% or greater risk of CVD within 10 years will need to take a statin and the guideline advises that preventative lifestyle measures are adopted first.
Statins (HMG-CoA reductase inhibitors)
Six statins are currently available in the UK: simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin. Statins are grouped into three different intensity categories according to the percentage reduction in LDL cholesterol they produce (see table 2):
- low intensity if the reduction is 20% to 40%
- medium intensity if the reduction is 31% to 40%
- high intensity if the reduction is above 40%.
Statins are reported to have have non-lipid, pleiotropic effects.These include anti-inflammatory activity, and improvement of endothelial dysfunction and plaque stability. To what extent these actions contribute to the beneficial effect of statins is not established.
Statins are indicated for the reduction of elevated total cholesterol and LDL cholesterol in adult patients with primary hypercholesterolaemia and combined dyslipidaemia when response to diet and other non-pharmacological measures are inadequate.
Mode of action
Statins work by inhibiting the mevalonate pathway and thus hepatic cholesterol synthesis (figures 2 and 3) and upregulate hepatic LDL receptor activity.
- Up to 55% reduction in LDL cholesterol (see table 2)
- Modest fall in TG (10–30%)
- Potent, mostly well tolerated, single, nightly dose
- Muscle toxicity
- Potential for toxic interactions (rhabdomyolysis)
- Hepatic toxicity
- Precipitate diabetes (small risk outweighed by cardiovascular benefits)
Muscle and liver effects
Statins are generally well tolerated and serious adverse events are rare. The most serious side effect is myopathy which can progress to rhabdomyoloysis, however the incidence of myopathy is low (<1 per 1,000 treated patients).9 Creatine phosphokinase (CK) is the primary marker of damage. Myopathy is more likely to occur in patients with complex medical problems or on multiple medications and in the elderly. Myalgia without CK elevation occurs in 5–10% of patients, many of whom can continue the medication if the symptoms are tolerable. It is suggested that the risk of muscle symptoms is lower with hydrophilic statins such as pravastatin and rousvastatin.
Alanine aminotransferase (ALT) is a marker of hepatocellular damage and can occur in 0.5–2.0% of statin-treated patients and is dose dependent. Treatment should be discontinued if there is an increase in ALT more than three times the upper limit of normal. Progression to liver failure is exceedingly rare but levels should be monitored and high levels may resolve with dose reduction.
Editors’ note: If you would like to read further around this topic, see: https://www.gov.uk/drug-safety-update/statins-benefits-and-risks
Side effects and interactions
Many statins undergo significant hepatic metabolism via cytochrome P-450 enzymes (CYPs) except pravastatin, rosuvastatin and pitavastatin, which are not metabolised by this pathway. There is therefore the potential for interaction with other drugs such as warfarin, which are metabolised through the same pathway.
Patients prescribed simvastatin or atorvastatin should be advised to avoid consuming grapefruit products whilst on these medications. Although the studies concerning grapefruit interactions with pravastatin, fluvastatin, pitavastatin, or rosuvastatin are not as significant, it is probably advisable not to consume grapefruit juice a few hours before or after taking this medication and to be moderate in consumption of (or avoid) grapefruit products.
Combinations of statins and fibrates may enhance the risk of myopathy; this is highest for gemfibrozil but increased risk of myopathy is small when statins are combined with other fibrates e.g. fenofibrate, bezafibrate. A summary of some of the drugs that statins may interact with is shown below:
- fibrates (especially gemfibrozil)
- ciclosporin, tacrolimus
- macrolide antibiotics (quinolones)
- calcium channel blockers esp. verapamil, possibly diltiazem, dihydropyridines
- azole antifungals
Cholesterol absorption inhibitors (ezetimibe)
There is only one drug currently available in this class, ezetimibe. This has been available for over a decade and is usually combined with a statin to achieve additional reduction in LDL cholesterol.
Ezetimibe is indicated as an add-on to dietary measures to:
- reduce levels of LDL cholesterol in people with primary hyperlipidaemia, alone or with a statin
- reduce LDL cholesterol in people with mixed hyperlipidaemia, in combination with fenofibrate
- reduce levels of LDL cholesterol in people with homozygous familial hypercholesterolemia (HoFH), in combination with specific statins
- reduce levels of circulating phytosterols in people with homozygous sitosterolaemia (a rare inherited disorder).
Mode of action
This acts as a specific inhibitor of cholesterol absorption in the small bowel (figure 4), without affecting the absorption of fat-soluble nutrients. Ezetimibe blocks the enterohepatic recirculation of cholesterol by inhibiting NPC1L1 transporter. This leads indirectly to reduction of hepatic cholesterol and upregulation of LDL receptors, mimicking the action of statins.
- Up to 15–20% reduction in LDL cholesterol
- Modest fall in TG (10–20%)
- Mostly well tolerated, single, nightly dose
- Gastrointestinal upsets
- Muscle toxicity (rare)
Stanol ester and sterol ester margarines (see above) have a weaker inhibitory effect on cholesterol absorption effect through an unrelated mechanism. Typical LDL cholesterol reduction is less than 10%.
Side effects and interactions
There is little evidence of any hepatotoxicity associated with ezetimibe. No major side effects have been reported. The most frequently observed side effects are moderate elevation of liver enzymes and muscle pain. No dosage adjustment is needed in patients with mild hepatic impairment or mild to severe renal insufficiency.
Bile acid sequestrants
Bile acid sequestrants were the mainstay of cholesterol lowering therapy in the pre-statin era. This further therapeutic class includes colesevelam, colestipol and the oldest agent, cholestyramine.
This class of drugs can be used in hypercholesterolaemia as an adjunct to diet, either alone or with a statin, in hyperlipidaemias unresponsive to diet or other measures, and where systemic exposure to statin must be avoided (e.g. pregnancy, early childhood and in patients with a history of serious statin toxicity).
Mode of action
Bile acid sequestrants are non-absorbable anion-exchange resins that bind to bile salts in the gut, preventing their reabsorption from the terminal ileum (figure 5). The resulting depletion in the bile acid pool leads to diversion of cholesterol to form new bile acids. This, in turn, leads to upregulation of LDL receptors to maintain the cholesterol pool within the liver and lowering LDL levels.
- 18–25% LDL lowering
- Can reduce glucose levels in hyperglycaemic patients
- Can aggravate hypertriglyceridaemia
- May cause deficiency of folic acid with long-term use.
- Older agents less palatable
Side effects and interactions
Gastrointestinal side effects such as constipation or nausea predominate. Colesevelam is generally better tolerated.
Bile acid sequestrants have important interactions with many commonly prescribed drugs and it is recommended that they are taken either four hours before or one hour after other drugs. Colesevalam is less interactive and can be co-administered with a statin.
Fibric acid derivatives (fibrates) include bezafibrate, ciprofibrate, fenofibrate and gemfibrozil. They are not recomended for isolated hypercholesterolaemia but they are the drugs of choice when TGs are severely raised (>10 mmol/L) and the risk of acute pancreatitis is the most immediate concern. They may also be of great value in combination with statins in severe mixed hyperlipidaemias (especially type III). They may improve the lipid profiles of patients who have a pattern of moderately high TG and low HDL cholesterol, the most frequent form of dyslipidaemia seen in metabolic syndrome and type 2 diabetes. In the absence of large scale trials showing improvement in outcomes, the evidence favours statins as first-line therapy for cardiovascular risk reduction.
Fibrates are indicated in the treatment of moderate to severe hypertriglyceridaemia, in mixed hyperlipidaemia (where the predominant component is raised TG) and in type III dyslipidaemia (usually resulting from an inherited defect of apolipoprotein E).
- Fibrates can lower TGs by up to 50%
- They lower LDL cholesterol by up to 25%
- They raise HDL cholesterol by 10–15%
- Well suited to management of severe hypertriglyceridaemia
- Variable effects on LDL cholesterol
- Increased risk of muscle effects if TG are raised and they are combined with statin (see statins, above)
- Increased lithogenicity of bile, and risk of gallstones
Mode of action
The mechanism of action of fibrates involves activation of peroxisome proliferator-activated receptors (PPAR), particularly PPAR-α, leading to: reduced hepatic TG synthesis; reduction of apolipoprotein CIII, an endogenous inhibitor of lipoprotein lipase; increased lipoprotein lipase activity (figure 6) and hence increased very low density lipoprotein (VLDL) and remnant particle clearance and increased levels of HDL cholesterol.
Side effects and interactions
Side effects with fibrates are generally mild. Gastrointestinal problems are reported in about 5% of patients and skin rashes in 2%. The principle problem is dyspepsia. They may also increase gallstone formation and so should not be used in patients known to have gallstones. Statins appear to reduce the risk of gallstones and the combination may be safer in this respect. Used alone, they may cause myositis and liver enzyme elevations. Gemfibrozil and statins should not be used concomitantly due to the increased frequency of severe myopathy.
Nicotinic acid (niacin)
Nicotinic acid is related to nicotinamide, part of the vitamin B group. In the past it has been considered for use as an adjunct to a statin or where a statin was not tolerated. It has always been considered to be problematic as a prominent side effect is prostaglandin-mediated cutaneous vasodilatation, leading to, often profound, facial flushing. It acts to reduce TG and LDL cholesterol, and lipoprotein(a) (Lp[a]) levels are also reduced while there is an increase HDL cholesterol. It was considered that it may reduce long-term cardiovascular events but the most widely prescribed formulation of niacin was withdrawn from the European market for commercial reasons. Similarly, a preparation of niacin combined with an ‘anti-flushing’ (anti-prostaglandin) agent – laropiprant – was withdrawn throughout the European Union in 2013 after a study (HPS2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events)11 showed a failure to reduce major vascular events and an increase in non-fatal serious events.
Fish oils (omega-3 fatty acids)
Populations who consume diets high in marine oil (omega 3 fatty acids), such as the Inuit of Greenland (see figure 8), have low heart disease rates. These compounds may be used to reduce TGs as an alternative to fibrates and in addition to statins in patients with combined (mixed) hyperlipidaemia not controlled by a statin alone. There is little clinical trial evidence that the TG-lowering effects of fish oils decreases cardiovascular risk and NICE does not recommend these compounds for primary or secondary prevention of cardiovascular disease.
A summary of the drugs used in the pharmacological management of dyslipidaemia is shown in table 3.
Management of dyslipidaemias in different settings
This current module reviews specific treatments rather than specific lipid disorders. These are dealt with comprehensively in the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines,9 which cover the different clinical settings where dyslipidaemia may be found. These include:
- familial dyslipidaemias e.g. familial hypercholesterolaemia
- metabolic syndrome and diabetes
- acute coronary syndrome/percutaneous coronary revascularisation
- heart failure valvular diseases
- autoimmune diseases
- renal disease
- transplantation patients
- peripheral arterial disease
- human insufficiency virus.
The way dyslipidaemias are treated varies with the clinical presentation. Many of them require referral to secondary care. While the same drugs may be deployed, these may be used in different doses, in different combinations, and for different durations of time according to the clinical setting
An example of one of the clinical presentations of dyslipidaemia requiring specialist care is FH. Plasma lipid levels are largely determined genetically and one of the most extreme forms of inherited hyperlipidaemia is familial hypercholesterolaemia (FH). Table 4 shows the familial lipid disorders associated with CHD. Heterozygous familial hypercholesterolaemia (HeFH) may affect as many as one in 200 of the population (see module 3). Levels of total cholesterol TC and LDL cholesterol are approximately twice normal in these patients, many of whom develop severe premature coronary heart disease. These patients should be referred to a lipid clinic for counselling, education, and family (cascade) testing in addition to optimisation of their treatment. High intensity statins (atorvastatin, rosuvastatin) are the mainstay of treatment but even these may be insufficient to achieve the reduction of over 50% required to normalise LDL cholesterol levels. Patients may require combination treatment with ezetimibe or a bile acid sequestrant or all three agents (with less frequent use of fibrates or niacin). See NICE guidance on FH for more information.7
Response to statins may be disappointingly poor in patients with the most severe forms, compound and heterozygous and homozygous familial hypercholesterolaemia (HoFH) who may require treatment with LDL apheresis.
LDL apheresis resembles dialysis, and is a technique to physically remove LDL cholesterol from the bloodstream, typically requiring fortnightly treatment in a specialist centre lasting several hours per session. An LDL Apheresis Toolkit is available to healthcare professionals.
For a very comprehensive video review on FH, watch our podcast where world experts discuss the condition, its investigation and treatment.
Strategies for optimising treatment
European guidelines suggest that “no smoking, healthy eating and being physically active are the foundations of preventive cardiology”.9 Many patients, particularly those with inherited conditions, will not achieve cholesterol treatment targets with lifestyle interventions alone. Most patients will therefore require lipid modifying drug treatments. Adherence to statin treatment is poor with up to one third or more of patients stopping their medication within a year. This poor adherence and the reality that prescribers do not sufficiently up-titrate the dose of statin are among the reasons why over half of all coronary patients and about four out of five high-risk patients are not achieving treatment goals.9 A number of other reasons why patients fail to reach goal are shown in table 5. Advice on how this may be improved involves developing a good alliance with the patient and other approaches table 6.
HDL cholesterol as a treatment target
There is conclusive evidence that lowering LDL cholesterol levels with statins reduces the risk of cardiovascular disease events. Statins, even when used optimally, do not always afford complete vascular protection and substantial residual cardiovascular risk persists, despite best treatment efforts. Some of this ‘residual risk’ will be determined by modifiable risk factors, such as lipids, hypertension, smoking and diabetes. Further reducing apolipoprotein (apo) B-containing atherogenic lipoproteins or increasing atheroprotective lipoproteins, specifically raising HDL cholesterol, are alternative proposed approaches to reducing this risk.
In contrast to total cholesterol, LDL cholesterol and TGs, HDL cholesterol is inversely related with cardiovascular disease. Low HDL cholesterol (<1 mmol/L in men and <1.2 mmol/L in women) is associated with increased CHD risk, whereas higher HDL cholesterol levels are protective against atherosclerosis. This may be because of reverse cholesterol transport (see module 1) but HDL cholesterol has numerous functions independent of lipid metabolism (figure 9) including anti-inflammatory activity which may be cardioprotective.
Evidence that raising HDL cholesterol prevents cardiovascular events is still being tested in clinical trials. There are relatively few options available for raising HDL cholesterol. Lifestyle measures such as weight reduction, vigorous exercise, smoking cessation and moderate alcohol consumption may improve HDL cholesterol levels. Also niacin (with its limitations) increases HDL cholesterol levels (although it has been withdrawn in the UK). A new therapeutic class, cholesteryl ester transfer protein (CETP) inhibitors can raise HDL cholesterol levels substantially by approximately 30%. Investigations with the first CETP inhibitor, torcetrapib, were terminated due to excess mortality and major cardiovascular events, which were associated with increases in blood pressure.Another CETP inhibitor dalcetrapib, was also withdrawn due to lack of effect on clinical outcomes. Investigations with the agent anacetrapib continue.
For more information about the role of HDL cholesterol, watch our podcast featuring lipid expert, Dr Dirk Blom, from the Groote Schuur Hospital, Cape Town, South Africa, who discusses the ‘state of the art’ on HDL cholesterol including new approaches to management.
Lipoprotein(a) (Lp[a]) has been found to be an additional riskmarker.9 Lp(a) is a composite particle which contains apoliprotein B, in common with LDL, but it also contains a unique plasminogen-like protein, apolipoprotein (a) [apo(a)], with a greater number of structural variants (isoforms) than other apolipoproteins. The plasma level of Lp(a) is to a major extent a reflection of the hepatic production rate which is genetically determined and dependent on the isoform size. Crucially, lipoprotein(a) is not removed by the LDL receptor and, unlike LDL, clearance is unaffected by statins. A number of lipid lowering treatments are known reduce Lp(a) levels including estogens, niacin, LDL apheresis and a new class drugs in development, the PCSK9 inhibitors. To date, there has been no clinical trial evidence to show that reduction in Lp(a) leads to improvement in cardiovascular outcomes, although evidence from genetic Mendelian randomisation studies predict it to be a causative risk factor. Plasma Lp(a) is not currently recommended for risk screening in the general population; but Lp(a) measurement should be considered in people with high risk of cardiovascular disease and in patients with FH or a strong family history of premature atherothrombotic disease.
To learn more about the role of Lp(a) as a novel marker of cardiovascular disease, watch our podcast with Professor Borge Nordestgaard, University of Copenhagen & Copenhagen University Hospital, Denmark, who also discusses how to manage Lp(a) in the clinic.
A number of promising new compounds for LDL cholesterol lowering are in development including:
- MTP (microsomal transfer protein inhibitors
- thyroid hormone mimetics with liver selectivity
- antisense oligonucleotides e.g. mipomersen
- PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors e.g. alirocumab, evolocumab, bococizumab.
It is expected that some agents in the PCSK9 class will soon be clinically available. Targeting the PCSK9 pathway is now a novel mechanism under investigation for lowering LDL cholesterol. By inhibiting PCSK9, PCSK9 inhibitors are believed to increase the number of LDL receptors on hepatocytes and facilitate LDL clearance from the blood, ultimately leading to LDL cholesterol reduction. PCSK9 normally binds to LDL receptors, preventing them from recycling to the surface of hepatocytes and targets them for destruction in the lysosome. By blocking this binding, PCSK9 inhibitors help protect the LDL receptors from being destroyed. The PCSK9 inhibitors currently in late-stage development are monoclonal antibodies. Monoclonal antibodies are designed to bind to a specific target, while avoiding other targets.
- Effective treatment is available for most hyperlipidaemias
- Older low-density lipoprotein lowering drugs (such as resin and niacin) have been replaced by better tolerated and more powerful first-line therapies (statins and fibrates)
- Reduction of non-high-density lipoprotein (low-density lipoprotein, intermediate-density lipoprotein, or very low-density lipoprotein) cholesterol by 1 mmol/L reduces coronary heart disease risk by approximately 25% over five years
- Combination treatments may prove to have an additive benefit
- Several classes of lipid lowering drugs are currently in late stage clinical trials and may reduce residual risk
- Treatments which alter lipoprotein composition (e.g. increasing high-density lipoprotein by cholesteryl ester transfer protein (CETP) inhibition pose a challenge for the laboratory
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