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Background
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
Figure 1. How much can cholesterol lowering reduce coronary heart disease risk
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 23 mmol/L
would reduce risk by about 4050%. 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
Lifestyle intervention
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
Diet
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 2030% reduction in LDL cholesterol
(table 1).10
Table 1. Effects of dietary changes on low-density lipoprotein (LDL) colesterol
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.
Physical activity
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%.
Efficacy
Fibrates can lower TGs by up to 50%
They lower LDL cholesterol by up to 25%
They raise HDL cholesterol by 1015%
Advantages
Well suited to management of severe hypertriglyceridaemia
Disadvantages
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-, 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.
Figure 6. The action of lipoprotein lipase
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.
Figure 8. The Inuit people have low heart disease rates
Treatment summary
A summary of the drugs used in the pharmacological management of dyslipidaemia is shown in
table 3.
Table 3. Current lipid lowering drug clases
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
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.
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.
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.
Lipoprotein(a)
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.
Investigational treatments
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.
PCSK9 inhibitors
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.
Key messages
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
References
1. Sniderman A, Durrington P (eds). Fast facts: hyperlipidaemia. Oxford: Health Press Ltd, 2009.
ISBN 978-1-905832-39-2.
2. Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein
cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian
randomization analysis. J Am Coll Cardiol 2012;60:26319.
http://dx.doi.org/10.1056/NEJMoa054013
3. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and
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http://dx.doi.org/10.1056/NEJMoa054013
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2015;12:261. http://dx.doi.org/10.1038/nrcardio.2015.51
5. Cholesterol Treatment Trialists (CTT) Collaboration. Efficacy and safety of more intensive
lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised
trials. Lancet 2010;376:167081. http://dx.doi.org/10.1016/S0140-6736(10)61350-5
6. JBS3 Board. Joint British Societies consensus recommendations for the prevention of
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7. National Institute of Health and Care Excellence (NICE). Identification and management of
familial hypercholesterolaemia. Clinical guideline 71. London: NICE, August 2008.
http://nice.org.uk/guidance/CG71/
8. National Institute for Health and Care Excellence (NICE). Lipid modification: cardiovascular risk
assessment and the modification of blood lipids for the primary and secondary prevention of
cardiovascular disease. Clinical guideline 181. London: NICE, July 2014 (last modified: January
2015). http://www.nice.org.uk/guidance/CG181/
9. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of
dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of
Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769818.
http://dx.doi.org/10.1093/eurheartj/ehr158
10. ViljoenA.Improving dyslipidaemia management: focus on lifestyle intervention and
adherence issues. Br J Cardiol 2012;19 (suppl 1);S9S11.
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high-risk patients. N Engl J Med 2014;371: 20312. http://dx.doi.org/10.1056/NEJMoa1300955
12. Genest JJ Jr., Martin-Munley SS, McNamara JR et al. Familial lipoprotein disorders in patients
with premature coronary artery disease. Circulation 1992;85:202533. Circulation
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Recommended reading
Nicholls P, Young I (eds). Lipid disorders. Oxford Cardiology Library. Oxford: Oxford University
Press, 2009. ISBN 978-0-19-956965-6.