Lipids module 4: treatment of dyslipidaemia

Released17 March 2021     Expires: 17 March 2023      Programme:

Sponsorship Statement: Novartis has provided sponsorship to support the latest revision of this e-learning programme. The content has been independently written by leading UK experts. Novartis had no input into the writing of the modules and had no editorial control over the content.

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Background

Major epidemiological studies have shown a direct, consistent relationship between non-high-density lipoprotein (HDL) cholesterol lowering and coronary heart disease (CHD) risk reduction (see figure 1). Non–HDL cholesterol is calculated by subtracting HDL cholesterol from total cholesterol. Retention of cholesterol-rich apolipoprotein-B containing lipoproteins (the non-HDL fraction, including low-density lipoprotein (LDL), lipoprotein(a) and remnants) in the arterial wall has been described as the root cause for the initiation and progression of atherosclerosis.1

Lipids module 4 - Figure 1. Estimated change in the relative risk of a coronary heart disease (CHD) event (nonfatal myocardial infarction or CHD death) associated with non–high-density lipoprotein cholesterol (HDL-C) reduction with statins at a mean follow-up of 4.5 years (dashed line) along with the 95% Bayesian confidence interval (dashed boundary lines). The solid line indicates a 1:1 relationship. The crude risk estimates from the individual studies are plotted along with their associated 95% confidence intervals
Figure 1. Estimated change in the relative risk of a coronary heart disease (CHD) event (nonfatal myocardial infarction or CHD death) associated with non–high-density lipoprotein cholesterol (HDL-C) reduction with statins at a mean follow-up of 4.5 years (dashed line) along with the 95% Bayesian confidence interval (dashed boundary lines). The solid line indicates a 1:1 relationship. The crude risk estimates from the individual studies are plotted along with their associated 95% confidence intervals

Very high cholesterol levels are seen in inherited disorders, such as familial hypercholesterolaemia (FH) (where low-density lipoprotein [LDL] cholesterol is typically double that seen in unaffected family members), and the likelihood of developing premature and often fatal heart disease is greatly increased. The majority of those who will develop atherosclerosis, however, may have only a moderately elevated LDL cholesterol, which may be considered ‘normal’ for a Western industrialised 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 those of our hunter-gatherer ancestors.

Several genetic variants 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 protein, proprotein convertase subtilisin/kexin – 9 (PCSK9), have been linked with particularly low LDL levels and cardiovascular risk and PCSK9 has 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 22% 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 40−60%. These beneficial effects were seen in both men and women, at ages from <60 to >70 years, in people with and without cardiovascular disease (CVD), in those at high and low CVD 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 2014 Joint British Societies’ recommendations for the prevention of cardiovascular disease (JBS3) 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”.6 JBS3 has a suggested target of non-HDL cholesterol <2.5 mmol/L. 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommend even lower LDL targets, as low as <1.0 mmol/L for secondary prevention in very-high-risk patients who experience a second vascular event within two years.7 Evidence from intravascular ultrasound studies of coronary atherosclerosis involving statin-treated patients suggest that disease progression can be substantially arrested – and regression promoted – at achieved LDL cholesterol concentrations of 1.8 mmol/L (70 mg/dL) or below, but at present a cost-effectiveness analysis over a long time period is lacking.7,8

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 (Clinical Guideline [CG]71) or >40% reduction of non-HDL cholesterol in non-FH patients (CG181).9,10

Lifestyle intervention

Therapeutic lifestyle intervention underpins the management of dyslipidaemia. Indeed, the ESC/EAS guidelines on dyslipidaemia place emphasis on nutritional approaches, either alone or complementary to pharmacotherapy, in managing hypercholesterolaemia to reduce cardiovascular risk.7

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.7 Comparison shows that dietary changes can produce a cumulative 20−30% reduction in LDL cholesterol (table 1).11

Table 1. Effects of dietary changes on low-density lipoprotein (LDL) cholesterol

Dietary component Dietary change Approximate reduction in LDL cholesterol (%)
Reducing saturated fat From 15% to 6% of calories 11%
Reducing dietary cholesterol <300mg/day* 5%
Weight reduction 5% weight loss 10%
Functional foods
Viscous fibre 5–10 g/day 5%
Plant stenols/stanols 2–3 g/day 6–15%
Effect with combined dietary intervention 20–30%
Key: LDL = low-density lipoprotein
* 100 mg/day reduction of cholesterol reduces total cholesterol by 1%
Reproduced with kind permission from Viljoen11

A NICE endorsed lipid management pathway created by the NHS England Accelerated Access Collaborative conveniently brings together all NICE guidance, quality standards and materials to support implementation of cardiovascular disease prevention, including the ‘cardioprotective diet’ and physical exercise. This is 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,9 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 NICE clinical guideline10 − 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.

QRISK3 (https://www.qrisk.org/three/), described in module 2, is an updated version of the QRISK2 calculator, which considers additional risk factors including chronic kidney disease stage 3 or above, migraine, corticosteroid use, systemic lupus erythematosus (SLE), use of atypical antipsychotics, severe mental illness, erectile dysfunction and a variability of systolic blood pressure.

Statins (HMG-CoA reductase inhibitors)

Five statins are currently available in the UK: simvastatin, pravastatin, fluvastatin, atorvastatin and rosuvastatin. 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%.

Table 2. The grouping of statins into intensity category

Reduction in low density lipoprotein cholesterol
Dose (mg/day) 5 10 20 40 80
Fluvastatin 21%1 27%1 33%2
Pravastatin 20%1 24%1 29%1
Simvastatin 27%1 32%2 37%2 42%3,4
Atorvastatin 37%2 43%3 49%3 55%3
Rosuvastatin 38%2 43%3 48%3 53%3
1 20–30%: low intensity
2 31–40%: medium intensity
3 Above 40%: high intensity
4 Advice from the MRHA: there is an increased risk of myopathy associated with high dose (80 mg) simvastatin. The 80 mg dose should be considered only in patients with severe hypercholesterolaemia and high risk cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.
Data from NICE guideline CG18110
The information used to make the table is from Law MR, Wald MJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systemic review and meta analysis. Br Med J 2003;326:1423

Statins were once thought to have non-lipid, pleiotropic effects, including 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, but the benefits of statins are most clearly related to the achieved reduction of LDL-, non-HDL-cholesterol and apolipoprotein B levels.

Indications

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.

Figure 2. The cholesterol synthetic pathway
Figure 2. The cholesterol synthetic pathway (click to enlarge)
Figure 3. Mode of action of statins
Figure 3. Mode of action of statins (click to enlarge)
Efficacy
  • Up to 55% reduction in LDL cholesterol (see table 2)
  • Modest fall in TG (10–30%)
Advantages
  • Potent, mostly well tolerated, single, nightly dose
Disadvantages
  • Muscle toxicity
  • Potential for toxic interactions (rhabdomyolysis)
  • Hepatic toxicity
  • Precipitate diabetes (small risk outweighed by cardiovascular benefits)

Statin intolerance is defined as the presence of clinically significant adverse effects from statin therapy that are considered to represent an unacceptable risk to the patient or that may result in adherence to therapy being compromised.

To guide clinicians, a statin intolerance pathway has been developed by the Accelerated Access Collaborative, which has been endorsed by NICE. It is available on the NHS England AAC page at: Statin intolerance pathway https://www.england.nhs.uk/aac/publication/statin-intolerance-pathway/

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).7 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 rosuvastatin.

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 and rosuvastatin. 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, 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)
  • warfarin
  • digoxin
  • calcium channel blockers esp. verapamil, possibly diltiazem, dihydropyridines
  • azole antifungals
  • antiretrovirals
  • amiodarone.

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. NICE has published technology appraisal guidance [TA385] for ezetimibe in primary hypercholesterolaemia.12

Indications

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.

Figure 4. Mode of action of cholesterol absorption inhibitors
Figure 4. Mode of action of cholesterol absorption inhibitors (click to enlarge)
Efficacy
  • Up to 15–20% reduction in LDL cholesterol
  • Modest fall in TG (10–20%)
Advantages
  • Mostly well tolerated, single, nightly dose
Disadvantages
  • 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.

PCSK9 inhibitors

Targeting the PCSK9 pathway is a mechanism for lowering LDL cholesterol. Two PCSK9 inhibitors approved for use by NICE in June 2016 are the monoclonal antibodies alirocumab and evolocumab. Monoclonal antibodies are designed to bind to a specific target, while avoiding other targets.

Indications

To optimise lipid management in patients at high risk of CVD who have uncontrolled severe hypercholesterolaemia or mixed dyslipidaemia despite maximum tolerated lipid-lowering therapy. NICE has published technology appraisal guidance for LDL treatment thresholds for both alirocumab (TA393) and evolocumab (TA394).13,14 Separate thresholds are assigned to non-FH patients with high and very high risk of CVD and FH patients with and without CVD.

Mode of action

PCSK9 normally binds to LDL receptors, preventing them from recycling to the surface of hepatocytes and targets them for destruction in the lysosome. By preventing the PCSK9 binding with the LDL receptor, PCSK9 inhibitors increase the recycling of LDL receptors to the cell surface (figure 5). The resulting increase in the number of LDL receptors on hepatocytes facilitates LDL clearance from the blood, ultimately leading to LDL cholesterol reduction.

Lipids module 4 - Figure 5. Mechanism of action of PCSK9 inhibitors in presence of a statin
Figure 5. Mechanism of action of PCSK9 inhibitors in presence of a statin
Efficacy
  • Reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy4
  • Early data suggests a reduction in cardiovascular events
Advantages
  • Additional LDL lowering capacity in patients intolerant of statins
  • Some patients with HoFH may achieve sufficient LDL lowering effect with addition of PCSK9 inhibitor treatment that they may require less frequent lipoprotein apheresis
  • Well tolerated, one subcutaneous injection every two weeks
Disadvantages
  • Lifelong self-administered subcutaneous injections may be unacceptable to some patients
  • The increased risk of progression to diabetes seen with high-intensity statin treatment might also occur with PCSK9 inhibition4
  • Short shelf life
  • High cost
Side effects and interactions
  • Very few side effects in clinical studies
  • Flu-like symptoms such as cold, nausea, back and joint pain
  • Soreness or itchiness at injection site
  • Muscle pain

Inclisiran

Inclisiran is the first drug in its class. It is a small interfering RNA (siRNA) molecule which reduces LDL cholesterol by inhibiting the synthesis of PCSK9.

Indications

It is indicated in adults with atherosclerotic CVD or heterozygous FH who have elevated LDL cholesterol despite maximum tolerated therapy.

Mode of action

PCSK9 is an enzyme predominantly synthesised in the liver, which promotes lysosomal degradation of the LDL receptor. Inhibition of this enzyme reduces this degradation, which promotes recycling of the LDL receptor, increasing hepatic LDL receptor numbers and therefore increased LDL uptake from the circulation. Post-translationally this mechanism is the target for the monoclonal antibody medications evolocumab and alirocumab as discussed above. However inclisiran targets this pathway before translation of PCSK9. Inclisiran is a siRNA which works through ‘gene silencing’ pathways to inhibit translation and hepatic production of the PCSK9 enzyme (figure 6).15

Lipids module 4 - Figure 6. The mode of action of inclisiran
Figure 6. The mode of action of inclisiran
Efficacy

In clinical trials, inclisiran showed a mean decrease in LDL cholesterol in patients on statin therapy of over 50.7%,16 with reductions similar to that observed with the monoclonal antibody PCSK9 inhibitors.17
The effect on cardiovascular morbidity and mortality has yet to be determined.

Advantages

Inclisiran is a long-acting drug, which enables a convenient twice-yearly dosing schedule – this will increase the likelihood of treatment uptake and adherence over medications that need to be taken daily. It is also a further treatment option for patients who are intolerant of statins or are on maximally tolerated treatment, who are not reaching LDL reduction targets, and who may not be eligible for PCSK9 inhibitors but require further LDL cholesterol lowering.

Disadvantages

Subcutaneous injections may be unacceptable to some patients.

Side effects and interactions

Inclisiran has shown good safety profiles in clinical trials but long-term safety is yet to be confirmed. The most common side effects in clinical trials were were limited adverse events at the injection site such as discomfort and erythema.16

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.

Indications

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 7). 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.

Figure 7. Mode of action of bile acid sequestrants
Figure 7. Mode of action of bile acid sequestrants (click to enlarge)
Efficacy
  • 18–25% LDL lowering
Advantages
  • Can reduce glucose levels in hyperglycaemic patients
Disadvantages
  • 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.

Fibrates

Fibric acid derivatives (fibrates) include bezafibrate, ciprofibrate, fenofibrate and gemfibrozil. They are not recommended 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 familial dysbetalipoproteinaemia or 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.

Indications

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).

Efficacy
  • Fibrates can lower TGs by up to 50%
  • They lower LDL cholesterol by up to 25%
  • They raise HDL cholesterol by 10–15%
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-α, leading to: reduced hepatic TG synthesis; reduction of apolipoprotein CIII, an endogenous inhibitor of lipoprotein lipase; increased lipoprotein lipase activity (figure 8) and hence increased very low density lipoprotein (VLDL) and remnant particle clearance and increased levels of HDL cholesterol.

Figure 8. The action of lipoprotein lipase
Figure 8. The action of lipoprotein lipase (click to enlarge)
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 is no longer used as a prominent side effect is prostaglandin-mediated cutaneous vasodilatation, leading to, often profound, facial flushing. 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) showed a failure to reduce major vascular events and an increase in non-fatal serious events.18

Fish oils (omega-3 fatty acids)

Figure 9. The Inuit people have low heart disease rates
Figure 9. The Inuit people have low heart disease rates

Populations who consume diets high in marine oil (omega 3 fatty acids), such as the Inuit of Greenland (see figure 9), 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 currently recommend these compounds for primary or secondary prevention of cardiovascular disease. Recent results from the REDUCE IT trial, however, have shown that the incidence of ischaemic events, including cardiovascular death, was lower in patients with high triglycerides, despite the use of statins, who also received the fish oil icosapent ethyl.19

Bempedoic acid

A small molecule compound, bempedoic acid is the first drug in its class with a novel mechanism of action. It is administered as a prodrug and is taken orally once-daily to lower LDL cholesterol. This drug works through the same pathway as statins and increases LDL receptor-mediated clearance of LDL but inhibits an enzyme two steps upstream from HMG-CoA reductase, the target of statins.20

Indications

Bempedoic acid is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of heterozygous FH or established atherosclerotic cardiovascular disease in those who require further lowering of LDL cholesterol.

Mode of action

It lowers LDL cholesterol by inhibition of cholesterol synthesis in the liver, which causes subsequent upregulation of the hepatic LDL receptors, so more LDL is removed from the circulation. The primary mode of action is to inhibit ATP citrate lyase (ACL), which is an enzyme in the cholesterol biosynthesis pathway upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, the target of statins (figure 10).

Lipids module 4 - Figure 10. The mode of action of bempedoic acid (ETC-1002)
Figure 10. The mode of action of bempedoic acid (ETC-1002)
Efficacy

Analysis of four randomised controlled trials found that bempedoic acid decreased LDL cholesterol by 18% versus placebo when added to maximally tolerated statins in patients with atherosclerotic CVD, heterozygous FH or both.20

The effect on cardiovascular morbidity and mortality has yet to be determined.

Advantages

The NICE eligibility thresholds for treatment with PCSK9 inhibitors mean many patients remain at LDL cholesterol levels much higher than desirable after maximum tolerated lipid-lowering treatment. Bempedoic acid may be an orally active alternative choice for patients not eligible for PCSK9 inhibition and also an additional option for patients with statin intolerance.

Bempedoic acid is administered as a prodrug and is only converted to the active metabolite in the liver and not muscles. This, theoretically, will reduce the myotoxicity associated with statin, which represents one of the largest barriers to statin uptake and adherence. Bempedoic acid has one dosage strength and has a complementary mechanism of action so it can be combined with ezetimibe in a single oral pill without the need for complex titration.

Disadvantages

Bempedoic acid increases plasma concentrations of statins requiring monitoring of patients for statin-related side effects if on both agents. Bempedoic acid may raise serum uric acid and precipitate gout and may cause elevation of liver enzymes.

Side effects and interactions

Bempedoic acid showed good safety profiles in clinical trials but long term safety is yet to be confirmed. In clinical trials, side effects of tendon rupture, tendonitis, muscle spasms, anaemia, elevated liver enzymes and hyperuricaemia were observed.20

Bempedoic acid inhibits renal tubular OAT2 causing a risk of hyperuricaemia and prescribers are advised to monitor for signs of gout and treat with urate-lowering drugs as appropriate.
There is a risk of myopathy with concomitant use of bempedoic acid with simvastatin or pravastatin, which may necessitate dose reduction of these statins. Prescribers are advised to avoid use of a concomitant simvastatin daily dose greater than 20 mg or a pravastatin dose greater than 40 mg.

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 classes

1. HMG CoA reductase inhibitors – statins
Mode of action: inhibit cholesterol synthesis, ↑ LDL receptor
2. Cholesterol absorption inhibitors
Mode of action: reduce enterohepatic cholesterol cycling, ↑ LDL receptor
3. PCSK9 inhibitors
Mode of action: reduce PCSK9 binding to LDL receptors, ↑ LDL receptor
Anti-PCSK9 monoclonal antibodies – alirocumab and evolocumab
Small interfering RNA (siRNA) inhibits translation and hepatic production of PCSK9 – inclisiran
4. Bile acid sequestrants
Mode of action: divert cholesterol into bile acid synthesis, ↑ LDL receptor
5. Fibrates
Mode of action: induce lipoprotein lipase and other genes
6. ATP citrate lyase inhibitors – bempedoic acid
Mode of action: inhibits cholesterol synthesis, ↑ LDL receptor

The NHS England Accelerated Access Collaborative has produced a summary of national guidance for lipid management for primary and secondary prevention of CVD, which has been endorsed by NICE. This is available at https://www.england.nhs.uk/aac/wp-content/uploads/sites/50/2020/04/lipid-management-pathway-guidance.pdf

Management of dyslipidaemias in different settings

This current module reviews specific treatments rather than specific lipid disorders. These are dealt with comprehensively in the ESC/EAS guidelines, which cover the different clinical settings where dyslipidaemia may be found.7 These include:

  • familial dyslipidaemias e.g. FH
  • children
  • elderly
  • metabolic syndrome and diabetes
  • acute coronary syndrome/percutaneous coronary revascularisation
  • heart failure valvular diseases
  • autoimmune diseases
  • renal disease
  • transplantation patients
  • peripheral arterial disease
  • stroke
  • 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.

Familial hypercholesterolaemia (FH)

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 FH. Table 4 shows the familial lipid disorders associated with CHD. Heterozygous familial hypercholesterolaemia (HeFH) may affect as many as one in 250 of the population (see module 3). Levels of total cholesterol 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 PCSK9 inhibitor, or all three agents (with less frequent use of bile acid sequestrants). See NICE guidance on FH for more information.9

Table 4. Family matters: familial lipid disorders associated with CHD

Familial lipid disorders associated with CHD % of CHD
Familial combined hyperlipidaemia (FCH) (including hyperapoB) 19%
Familial Lp(a) excess (no dyslipidaemia) 19% (13)
Familial dyslipidaemia (↑TG, ↓HDL) 15%
Familial hypoalphalipoproteinaemia (FHA) 4%
Familial hypercholesterolaemia (FH) 3%
Familial hypertriglyceridaemia 1%
>50% of premature CHD have identifiable familial disorder21
Key: CHD = coronary heart disease; HDL = high-density lipoprotein; Lp(a) = lipoprotein a; TG= triglyceride
Adapted from: Genest JJ et al.21

Response to statins may be disappointingly poor in patients with the most severe forms of FH – compound HeFH and 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.

For a very comprehensive video review on FH, watch our podcast where Dr Dermot Neely discusses the condition, its investigation and treatment.

Strategies for optimising treatment

Table 5. Why do patients fail to reach treatment goals

1. Poor compliance with drug therapy
2. Poor compliance with diet resulting in weight gain
3. Poor response to drug therapy
4. Inadequacy of follow-up and monitoring
5. Intolerance of drug therapy
6. Development of a secondary hyperlipidaemia

European guidelines suggest that “no smoking, healthy eating and being physically active are the foundations of preventive cardiology”.7 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.7 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.

Table 6. How should lipids be treated

1. Baseline tests required before initiating treatment
Fasting lipids (including HDL), TFT, LFT, CK, glucose
2. Low fat diet and exercise regime
Will reduce drug doses required. Monitoring weight is essential
3. Choice of drug should be evidence based
Statins are not of proven benefit where triglycerides are >4.5
4. Dose titration to achieve appropriate targets
Treatment responses vary greatly
5. Monitoring of response and follow-up consultation essential
Adequacy of follow up is the most important factor in success
Key: CK = creatinine kinase; HDL = high density lipoprotein; LFT = liver function tests; TFT = thyroid function tests

Future therapies

HDL cholesterol as a treatment target

There is conclusive evidence that lowering LDL cholesterol levels with statins reduces the risk of CVD 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 11) including anti-inflammatory activity, which may be cardioprotective.

Lipids module 4 - Figure 11. Overview of antiatherogenic effects of high-density lipoprotein (HDL). In addition to mediating reverse cholesterol uptake, HDL cholesterol confers anti-inflammatory, antiapoptotic, antioxidative and antithrombotic effects that act in concert to improve endothelial function and inhibit atherosclerosis progression
Figure 11. Overview of antiatherogenic effects of high-density lipoprotein (HDL). In addition to mediating reverse cholesterol uptake, HDL cholesterol confers anti-inflammatory, antiapoptotic, antioxidative and antithrombotic effects that act in concert to improve endothelial function and inhibit atherosclerosis progression

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). The therapeutic class, cholesteryl ester transfer protein (CETP) inhibitors can raise HDL cholesterol levels substantially by approximately 30% but 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. The CETP inhibitors dalcetrapib and anacetrapib were also withdrawn due to lack of significant beneficial effect on clinical outcomes.

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)

Lipoprotein(a) has been found to be an additional risk marker for atherosclerosis and for calcific aortic valve stenosis.7,23 Lipoprotein(a) is a composite particle which contains apoliprotein B, in common with LDL, but it also contains a unique plasminogen-like protein, apolipoprotein (a) with a greater number of structural variants (isoforms) than other apolipoproteins. The plasma level of lipoprotein(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 including estogens, niacin and PCSK9 inhibitors are known to reduce lipoprotein(a) levels but, currently, LDL apheresis is the only means to achieve substantial reduction of lipoprotein(a). To date, there has been no clinical trial evidence to show that reduction in lipoprotein(a) leads to improvement in cardiovascular outcomes, although evidence from genetic Mendelian randomisation studies predict it to be a causative risk factor. A number of promising new antisense oligonucleotide based therapies for lipoprotein(a) lowering are in currently clinical trials. Plasma lipoprotein(a) is not currently recommended for risk screening in the general population; but lipoprotein(a) measurement should be considered in people with high risk of CVD and in patients with FH or a strong family history of premature atherothrombotic disease.23

To learn more about the role of lipoprotein(a) as a novel marker of CVD, 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.

Key messages

  • Effective treatment is available for most hyperlipidaemias
  • Well tolerated and powerful low-density lipoprotein lowering drugs therapies (statins, ezetimibe and PCSK9 inhibitors), can be given alone or in combination to upregulate the LDL-receptor pathway, and have replaced older drugs (such as resins and niacin).
  • Upregulate of the LDL-receptor pathway leads to reduction of non-HDL-C (including low-density lipoprotein, intermediate-density lipoprotein, remnant and very low-density lipoprotein) cholesterol by 1 mmol/L reduces coronary heart disease risk by approximately 20% over five years
  • Combination treatments have an additive benefit commensurate with the achieved reduction of non-HDL-cholesterol
  • Fibrates are of particular value in the management of severe hypertriglyceridaemia which persists despite dietary and lifestyle measures and when secondary causes have been addressed.

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References

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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;60:2631–9. http://dx.doi.org/10.1056/NEJMoa054013

3. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–72. http://dx.doi.org/10.1056/NEJMoa054013

4. Latimer J, Batty JA, Neely RD, Kunadian V. PCSK9 inhibitors in the prevention of cardiovascular disease. J Thrombos Thrombolysis 2016;42:405-19. https://doi.org/0.1007/s11239-016-1364-1

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6. JBS3 Board. Joint British Societies’ consensus recommendations for the prevention of cardiovascular diesase (JBS3). Heart 2014;100:ii1–1167. http://dx.doi.org/10.1136/heartjnl-2014-305693

7. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88. https://doi.org/10.1093/eurheartj/ehz455

8. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72. https://doi.org/0.1093/eurheartj/ehx144

9. 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/

10. 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/

11. Viljoen A. Improving dyslipidaemia management: focus on lifestyle intervention and adherence issues. Br J Cardiol 2012;19(suppl 1);S9–S11. https://doi.org/10.5837/bjc.2012.s03

12. National Institute for Health and Care Excellence (NICE). Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. Technology appraisal guidance [TA385]. London: NICE. Published February 2016. https://doi.org/10.1016/S0140-6736(10)61350-5 [last accessed 11th March 2021]

13. National Institute for Health and Care Excellence (NICE). Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. Technology appraisal 393. London: NICE. Published June 2016. https://www.nice.org.uk/guidance/ta393 [last accessed 18th February 2021]

14. National Institute for Health and Care Excellence (NICE). Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. Technology appraisal 394. London: NICE. Published June 2016. https://www.nice.org.uk/guidance/ta394 [last accessed 18th February 2021]

15. Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discovery Today 2107;5:823-33. http://dx.doi.org/10.1016/j.drudis.2017.01.013

16. Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol 2021;77:1182-93. https://doi.org/10.1016/j.jacc.2020.12.058

17. Ray KK, Landmesser U, Leiter L, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430-40. https://doi.org/10.1056/NEJMoa1615758

18. The HPS2-THRIVE Collaborative Group Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12. https://doi.org/10.1056/NEJMoa1300955

19. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertiglycertidemia. N Engl J Med 2019;380:11-22. https://doi.org/10.1056/NEJMoa1812792

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21. Genest JJ Jr., Martin-Munley SS, McNamara JR et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992;85:2025–33. http://dx.doi.org/10.1161/01.CIR.85.6.2025

22. Hausenloy DJ, Yellon DM. Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol. Heart 2008;94:706–714. http://dx.doi.org/10.1136/hrt.2007.125401

23. Cegla J, Neely RDG, France M, et al. HEART UK consensus statement on Lipoprotein(a): A call to action. Atherosclerosis 2019;291:62-70. https://doi.org/10.1016/j.atherosclerosis.2019.10.011

Recommended reading

Nicholls P, Young I (eds). Lipid disorders. Oxford Cardiology Library. Oxford: Oxford University Press, 2009. ISBN 978-0-19-956965-6.

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