Cardiovascular disease (CVD), of which atherosclerotic cardiovascular disease (ASCVD) is the major component, is responsible for more than 4 million deaths in Europe annually (Mach et al, 2020). It is the cause of death for more women than men (2.2 million versus 1.8 million), although CV deaths before the age of 65 years are more common in men than in women (490 000 versus 193 000) (Townsend et al, 2015). The major risk factors for ASCVD, which have been identified over the past few decades, are blood apolipoprotein-B (APO-B) containing lipoproteins (predominately low-density-lipoproteins [LDL]), elevated blood pressure, cigarette smoking and diabetes mellitus (Visseren et al, 2021). Prevention is defined as a co-ordinated set of actions aimed at eliminating or minimising the impact of CVD and related disabilities (Mach et al, 2020). The importance of ASCVD prevention remains undisputed and needs to be delivered at a general population level by promoting healthy lifestyle behaviour (Cooney et al, 2009), and at an individual level by tackling unhealthy lifestyles and by reducing increased levels of causal risk factors such as cholesterol. Practice nurses have a key role to play in this.
The article will focus on why cholesterol is important, how it is measured and the target levels, why it needs to be managed and the treatment strategies available.
What are lipids?
Lipids are basically fats and are a heterogeneous group of substances that have a low solubility in water but are more readily soluble in a mixture of ethanol and chloroform (Durrington, 2007). Lipids are essential to life and in themselves are not bad; however, if levels become elevated, the risk of ASCVD increases. Cholesterol is the predominant sterol in vertebrates and is an essential component of cell membranes. Cholesterol is absorbed from the gut; however, this absorption is not complete, and usually only around 30–60% of the amount ingested is actually absorbed. Cholesterol is absorbed from the gut and excreted back into it as part of bile. The body synthesises at least as much cholesterol as is ingested each day (Pottle, 2019).
Lipoproteins
Lipoproteins are macromolecular complexes of lipids and proteins, the protein components of which include apolipoproteins or enzymes. Lipoproteins transport lipids to the tissues for energy utilisation, lipid deposition, steroid hormone production and bile acid formation. There are six major lipoproteins in the blood: chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, lipoprotein (a) [Lp(a)] and high-density lipoprotein (HDL) (Mach et al, 2020). APO-B is the most abundant protein in LDL and is essential for the assembly and secretion of chylomicrons and VLDL and also for the removal of LDL via the LDL receptor, as APO-B is the part of LDL that is recognised by the LDL receptor (Durrington and Sniderman, 2000). There are two types of APO-B in humans: APO-B100, which is produced by the liver, and APO-B48, which is produced by the gut. APO-B48 has about 48% of the weight of APO-B100, giving it its name, and does not bind to the lipoprotein receptors (Durrington, 2007).
The role of lipids and lipoproteins in the pathology of atherosclerosis
All APO-B containing lipoproteins that are <70 nm in diameter (LDL is approximately 20 nm) can cross the endothelial barrier, especially when endothelial dysfunction occurs, where they can become trapped (Tabas et al, 2007). APO-B containing lipoproteins, which are retained in the arterial wall, lead to a complex process of lipid deposition and the beginning of atherosclerosis (Boren and Williams, 2016). The growth and progression of atherosclerotic plaques is made worse by continued exposure to APO-B containing lipoproteins, which results in additional particles being retained in the artery wall over time. The size of the atherosclerotic plaque burden is therefore likely to be determined by a combination of the concentration of circulating APO-B containing lipoproteins and the total duration of exposure to them (Ference et al, 2018).
The causal role of LDL and other APO-B containing lipoproteins in the development of ASCVD has been demonstrated beyond doubt in genetic, observational and interventional studies (Ference et al, 2017). Meta-analysis of clinical trials has shown that the relative reduction in CVD risk is proportional to the absolute reduction in LDL, irrespective of the medication prescribed. There is also no evidence for a lower level of LDL or ‘J-curve’ effect (Cholesterol Treatment Trialists’ (CCT) Collaboration, 2010). The absolute benefit of lowering LDL depends on the absolute risk of ASCVD and the absolute reduction in LDL. Even a small absolute reduction in LDL may translate into a significant reduction in ASCVD risk in a high- or very high-risk patient (CTT Collaborators, 2012).
Measuring cholesterol levels
Measurement of lipids is used to estimate the risk of ASCVD and guide decision making. Non-fasting sampling of lipid levels is recommended for general risk screening, as it has the same prognostic value as fasting samples (Doran et al, 2014; Cartier et al, 2018). The difficulty with this is that many laboratories will not provide an LDL result on non-fasting samples, as LDL levels are usually calculated using the Friedwald formula, rather than measured directly. The formula requires the concentration of triglyceride to be lower than 4.5 mmol/l and there is often a concern that as triglyceride is affected by dietary intake, non-fasting levels will not be accurate. However, in most studies, non-fasting samples display a higher triglyceride level of approximately only 0.3 mmol/l (Cartier et al, 2018). This will be of no clinical significance for most patients. The practical advantage of non-fasting samples, including improved patient acceptability, outweigh the potential imprecision in some patients. Plasma LDL should be measured to estimate the risk of ASCVD that can be reduced with LDL lowering therapies and to identify if markedly elevated levels are present that may suggest inherited disorders of lipid metabolism, such as familial hypercholesterolaemia (FH), which indicate a very high risk of ASCVD due to cumulative exposure to high levels of atherogenic lipoproteins. APO-B can be measured as an alternative to LDL, as the measurement is not dependant on triglyceride levels and is not influenced by whether the blood sample is fasting or non-fasting.
The National Institute for Health and Care Excellence (NICE) currently recommend the measurement of total cholesterol (TC) and HDL to achieve the best estimate of CVD risk (NICE, 2016a); however, this guidance is in the process of being updated. Measurement of TC is also needed to calculate risk using the SCORE risk assessment and the inclusion of HDL can improve risk estimation (Conroy et al, 2003).
Lp(a) and the risk of atherosclerosis
Lp(a) is a lipoprotein consisting of a cholesterol-rich LDL particle with one molecule of APO-B100 and an additional lipoprotein, apolipoprotein (a), attached by a disulphide bond (Nordestgaard and Langsted, 2016). Lp(a) is less than 70 nm in diameter and can therefore move across the endothelial barrier, where it can become retained, like LDL, and may increase the risk of ASCVD. The evidence relating to an increased risk of ASCVD with elevated levels of Lp(a) is slightly conflicting. However, a recent Mendelian randomisation study has shown that the causal effect of Lp(a) on the risk of ASCVD is proportional to the absolute change in plasma Lp(a) levels. Approximately 90% of a person's Lp(a) level is inherited and extremely elevated levels may represent an inherited lipid disorder associated with an extremely high lifetime risk of ASCVD (Burgess et al, 2018). The risk conferred by Lp(a) depends on the serum concentration, with levels between 200–400 nmol/l classified as ‘high risk’ and those >400 nmol/l being ‘very high risk’ (Cegla at al, 2019). The European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidance suggests that Lp(a) measurement should be considered at least once in each adult's lifetime to identify those with very high inherited levels who may have a lifetime risk of ASCVD equivalent to the risk associated with heterozygous FH (Mach et al, 2020).
Treatment targets/goals
Treatment targets in the ESC/EAS guidelines are related to the cardiovascular risk (Mach et al, 2020) (Table 1). The total CVD risk needs to be individualised and the lipid goals are part of a comprehensive CVD risk reduction strategy. The recommendations for treatment goals for LDL cholesterol and other risk factors are shown in Table 2. The targeted approach to lipid management is primarily aimed at reducing ASCVD risk by substantially lowering LDL to levels that have been achieved in recent large-scale trials of some of the newer lipid-lowering therapies. Table 3 shows the correlation between LDL, non-HDL and Apo-B levels for the LDL targets quoted above.
Table 1. ESC/EAS risk categories
| Risk category | People with any of the following |
|---|---|
| Very high risk |
|
| High risk |
|
| Moderate risk |
|
| Low risk |
|
ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; TIA, transient ischaemic attack; PAD, peripheral arterial disease; CAD, coronary artery disease; DM, diabetes mellitus; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FH, familial hypercholesterolaemia; T2DM, type 2 diabetes mellitus. Mach et al, 2020
Table 2. Risk factors and desirable goals
| Risk factor | Target/goal |
|---|---|
| LDL |
|
| Non-HDL | Non-HDL-C secondary goals are <2.2, 2.6 and 3.4 mmol/l for very high-, high-, and moderate-risk people, respectively |
| Triglycerides | No goal, but <1.7 mmol/l indicates lower risk and higher levels indicate a need to look for other risk factors |
| Smoking | No exposure to tobacco in any form |
| Diabetes | HbA1c: <7% (<53 mmol/mol) |
| Blood pressure | Healthy diet low in saturated fat with a focus on wholegrain products, vegetables, fruit and fish |
| Body weight | BMI 20–25 kg/m2, and waist circumference <94 cm (men) and <80 cm (women) |
| Physical activity | 3.5–7.0 hours moderately vigorous physical activity per week or 30–60 minutes most days |
Mach et al, 2020
Table 3. Corresponding non-high-density lipoprotein cholesterol and apolipoprotein B levels for commonly used low-density lipoprotein goals
| LDL | Non-HDL | APO-B |
|---|---|---|
| 2.6 mmol/l (100 mg/dl) | 3.4 mmol/l (131 mg/dl) | 100 mg/dl |
| 1.8 mmol/l (70 mg/dl) | 2.6 mmol/l (100 mg/dl) | 80 mg/dl |
| 1.4 mmol/l (55 mg/dl) | 2.2 mmol/l (85 mg/dl) | 65 mg/dl |
Visseren et al, 2021
NICE guidance emphasises that lipids are part of the overall management of CVD risk and recommends a reduction target rather than a treatment target for lipid levels. Statin therapy is suggested for primary prevention in patients with a 10% or greater 10-year risk of developing CVD and all patients who have documented ASCVD should be given statin treatment as part of secondary prevention management. All patients started on a statin should have their TC, HDL and non-HDL measured after 3 months of treatment. The recommendation is for a greater than 40% reduction in non-HDL (NICE, 2016a). If this has not been achieved, NICE guidance suggests a discussion with the patient about adherence and timing of the dose, optimising diet and lifestyle measures and increasing the dose of atorvastatin to 80 mg if the patient was started on a lower dose. The guidance contains specific actions to be taken for those patients with elevated triglyceride levels with management dependant on the actual level recorded (NICE, 2016a).
Treatment recommendations in the ESC/EAS guidance also depend on whether treatment is part of primary or secondary prevention and the overall risk assessment for the patient (Mach et al, 2020).
Management of raised cholesterol
Secondary causes of raised cholesterol must be excluded prior to beginning treatment, as treating the underlying cause may improve raised levels without the need for lipid-lowering therapy. This is particularly true for hypothyroidism. Other secondary causes of raised lipids include diabetes mellitus, alcohol abuse, Cushing's syndrome, liver and kidney disease and some medication, such as corticosteroids.
Strategies to lower cholesterol levels include a combination of lifestyle changes together with, for many patients, lipid-modifying drug therapy. Lipid-lowering medication is the mainstay of cholesterol reduction, but it is important that individuals adhere to a healthy diet if they are to achieve the desired levels of cholesterol.
Dietary management of raised cholesterol
Many national and international organisations and professional societies have developed guidelines for weight control, physical activity levels, smoking cessation and diet. There is a need for dietary changes to be realistic and to be able to deliver impactful cholesterol lowering, such as the HEART UK Ultimate Cholesterol Lowering Plan© (UCLP)© (HEART UK, 2019). Reduction of 5–10% in cholesterol levels can be achieved with good adherence to dietary changes (BHF/HEART UK, 2011). The consumption of saturated fats should be <10% of the total caloric intake and should be reduced further to <7% for those with raised cholesterol. The intake of cholesterol in the diet should be reduced to <300 mg/day (Mach et al, 2020).
The available evidence regarding the effect of functional foods on lipid levels and CVD risk is incomplete. Plant stanols and sterols occur naturally in plant-based foods and imitate the way that cholesterol works, therefore reducing the amount of cholesterol absorbed by the body. The principal plant sterols are phytosterols and phytostanols. Daily consumption of 2 g of phytosterols can reduce the TC and LDL levels by 7–10% in humans, with little or no effect on HDL and triglycerides (Musa-Veloso et al, 2011). There are, however, no studies to date to show any effect on CVD.
Lipid-modifying drug therapy
Statins
Stains are the most widely recommended treatment for raised cholesterol. They reduce the synthesis of cholesterol in the liver by competitively inhibiting the HMG-CoA reductase enzyme, which is the rate limiting step in cholesterol biosynthesis. Reducing the intracellular cholesterol promotes an increase in the LDL receptor (LDLR) expression on the surface of the hepatocyte, which subsequently leads to increased uptake of LDL from the blood stream, and therefore a reduction in the plasma concentration of LDL and other APO-B containing lipoproteins. There have been several large-scale randomised controlled studies that have demonstrated a substantial reduction in CVD mortality and morbidity with the use of statin therapy (Scandinavian Simvastatin Survival Study Group, 1994; Downs et al, 1998). The degree of LDL reduction is dose dependant and varies between the different statins. High-intensity statins will reduce the LDL by an average of≥50% and moderate-intensity stains by 30–50% (Table 4).
Table 4. Statin intensity
| Statin | Dose | % reduction in cholesterol levels |
|---|---|---|
| Atorvastatin | 10 mg od | 37% |
| 20 mg od | 43% | |
| 40 mg od | 49% | |
| 80 mg od | 55% | |
| Rosuvastatin | 5 mg od | 38% |
| 10 mg od | 43% | |
| 20 mg od | 48% | |
| 40 mg od | 53% | |
| Simvastatin | 10 mg od | 27% |
| 20 mg od | 32% | |
| 40 mg od | 37% | |
| Pravastatin | 10 mg od | 20% |
| 20 mg od | 24% | |
| 40 mg od | 29% |
Poor response to statin therapy in clinical studies has been linked to some extent with sub-optimal engagement but can also be explained by individual genetic backgrounds (Stroes et al, 2014; Moriarty et al, 2015). The most common cause of discontinuation of statin therapy is statin-associated muscle symptoms (SAMS) (Toth et al, 2018). Other possible statin-related adverse effects include neurocognitive disorders, hepatotoxity, haemorrhagic stroke and renal toxicity (Stroes et al, 2015). Statin intolerance is an important clinical challenge and is associated with an increased risk of CVD; however, the prevalence is low when diagnosed according to international definitions. Studies suggest the prevalence of complete statin intolerance is often overestimated and highlight the need for careful assessment of patients with potential symptoms of statin intolerance (Bytyçi et al, 2022).
Cholesterol absorption inhibitors
Cholesterol absorption inhibitors lower cholesterol by inhibiting intestinal uptake of dietary and biliary cholesterol at the level of the brush border of the intestine, without affecting the absorption of fat-soluble vitamins. Ezetimibe reduces the amount of cholesterol delivered to the liver, which responds by upregulating LDLR expression, leading to increased clearance of LDL from the blood (Mach et al, 2020). Ezetimibe 10 mg daily monotherapy has been shown to reduce LDL levels by 15–22% with relatively high inter-individual variation (Phan et al, 2012). The IMPROVE-IT study examined the addition of ezetimibe to simvastatin 40 mg after acute coronary syndrome (Cannon et al, 2015). The study demonstrated an incremental lowering of LDL and improved CVD risk outcomes in patients treated with both statin therapy and ezetimibe and supported the proposition that LDL lowering by means other than statins is beneficial and safe (Cannon et al, 2015). Ezetimibe is recommended as monotherapy for patients with contraindications to statin therapy, or co-administered with a statin if the LDL is not adequately controlled by dose titration of the statin, or if dose titration is limited by side effects of statins (NICE, 2016b).
Proprotein convertase subtilisin/kexin type 9 inhibitors
Monoclonal antibodies to PCSK9 reduce circulating LDL levels by preventing the degradation of LDL receptors when bound to PCSK9. In clinical trials, alirocumab and evolocumab, either alone or in combination with statins or other lipid-lowering therapy, have been shown to significantly reduce LDL levels by an average of 60%, depending on the dose given (Sabatine et al, 2017; Schwartz et al, 2018). Statin treatment increases circulating PCSK9 serum levels, and therefore the best effect of these drugs occurs in combination with statins (Nozue, 2017).
A systematic review and meta-analysis from 2019 reported that the use of evolocumab and alirocumab resulted in a significantly lower risk of myocardial infarction, ischaemic stroke and coronary revascularisation, but not all-cause death or CV death after a mean follow-up of 2.3 years (Guedeney et al, 2019). The absence of significant impact on CV death or mortality shown is likely to be related to the short period of follow-up and the time-lag in the effect of LDL lowering on these parameters (Sabatine, 2019).
Bempedoic acid
Bempedoic acid is a prodrug that acts on the cholesterol biosynthetic pathway. It has been shown in a double-blind placebo-controlled study to reduce LDL levels by a median of 21.4% in patients with hypercholesterolaemia and a history of intolerance to at least two statins (Laufs et al, 2019). The drug had a favourable safety profile with no increase in reported muscle symptoms. Bempedoic acid is available as a single drug or in a fixed dose combination with ezetimibe and has been authorised by NICE for use in patients where statins are contraindicated or not tolerated, or where ezetimibe alone does not adequately control the LDL level (NICE, 2021a).
A recent phase 2, double blind, placebo-controlled study randomised patients to triple therapy with bempedoic acid 180 mg, ezetimibe 10 mg and atorvastatin 20 mg or placebo, and demonstrated a 63.6% reduction in LDL after 6 weeks (Rubino et al, 2021).
Inclisiran
Inclisiran is a small interfering RNA which targets PSCK9 and was approved for use by NICE in 2021 (NICE, 2021b). The ORION-9 trial evaluated the effect of a 300 mg subcutaneous (SC) dose or matching placebo in patients with heterozygous FH and showed a 47.9% reduction in LDL levels (Raal et al, 2020). In the ORION-10 and ORION-11 trials, inclisiran 284 mg or placebo were administered by SC injection on day 1, day 90 and then every 6 months for a period of 540 days in patients with ASCVD (ORION-10) or ASCVD risk equivalent (ORION-11) and elevated LDL levels despite maximum tolerated dose of statin therapy. LDL levels were reduced by approximately 50% compared with placebo, with the adverse event rate being similar in both groups (Ray et al, 2020). Inclisiran is recommended by NICE for use in patients with ASCVD and LDL levels persistently >2.6 mmol/l despite maximum tolerated lipid-lowering therapy (NICE, 2021b). The injection has to be given by a health professional, which may limit its roll out to all eligible patients.
Omega-3 fatty acids
The REDUCE-IT trial involved the administration of 4 g/day of icosapent-ethyl (IPE) and reported a 25% reduction in the risk of major cardiovascular events (Bhatt et al, 2019). IPE has recently been granted NICE guidance for use in patients with established ASCVD and a raised fasting triglyceride level of≥1.7 mmol/l (NICE, 2022).
Other lipid-lowering therapy
Lomitapide is an inhibitor of the microsomal triglyceride transport protein (MTP), which is a key protein in the assembly and secretion of APO-B containing lipoproteins in the liver and intestine. An open-label, single arm titration study evaluated lomitapide as an adjunct therapy to statins and a low-fat diet in patients with homozygous FH and demonstrated reductions in LDL of approximately 50% from baseline at 26 weeks and 44% at 56 weeks (Cuchel et al, 2013). The most frequently observed adverse effects were gastrointestinal (GI) and increased aminotransferase levels, due to the mechanism of action of the drug (Cuchel et al, 2013). The intensity of GI side effects generally reduce with time and therefore careful patient education and liver function monitoring are required.
Fibrates or peroxisome proliferator-activated receptor α (PPAR-α) agonists regulate, amongst other things, various steps in lipid and lipoprotein metabolism. Fibrates have a weaker effect on LDL than statins and act mainly by reducing serum triglycerides and inhibiting lipoprotein lipase. Fibrate trials have reported variable effects on CVD outcomes and results from meta-analysis have not shown any decrease in CVD or total mortality (Lee et al, 2011; Jun et al, 2012). The overall efficacy of fibrates on CVD outcomes seems much less robust than that of statins.
Pelacarsan is an antisense oligonucleotide that reduces Lp(a) levels by up to 80%. Evidence suggests it is well tolerated and that 98% of subjects reach on-treatment target levels of <125 nmol/l (Tsimikas et al, 2020). Whether the reduction in Lp(a) levels is translated into clinical benefit is being examined in the on-going HORIZON outcomes trial.
Lipoprotein apheresis
Lipoprotein apheresis is a selective, extra-corporeal treatment, similar to renal dialysis, which removes atherogenic APO-B containing lipoproteins from the blood. It is indicated in patients with homozygous FH and those with heterozygous FH and non-familial hypercholesterolaemia who have failed to reach target levels with diet and maximally tolerated lipid-lowering therapy (Thompson, 2008). The need for lipoprotein apheresis has reduced to some extent with the development of some of the newer lipid-lowering therapies; however, it is widely underused in the UK and the frequency varies considerably across the world.
Discussion
Lipid control is one of the most important cardiovascular prevention targets. There are now a wealth of evidence-based studies spanning over 30 years which have proved the importance of aggressive lipid control, particularly for patients with established ASCVD, together with clear targets to be achieved. However, despite this, the real-world experience often shows that guideline recommended LDL targets are not being achieved in many high-risk patients (Tokgozoglu and Canpolat, 2019). The reasons for this are likely to be multifactorial including therapeutic passivity by clinicians, cost of prescriptions, the common assumption that statin therapy is associated with side effects, the failure of health professionals to adequately explain the benefit of therapy and a lack of shared decision-making between patients and clinicians. Combination therapy with multiple lipid-lowering treatments may be required to reach the recommended targets, but there is now ample evidence to support this strategy and the benefits that can be achieved.
Conclusion
There has been a significant expansion in information about lipid-lowering therapies and options for treatment in the last few years. We are now in a new era of lipid-lowering with powerful tools and the option of more personalised lipid management, which should enable achievement of lipid targets for the majority of patients. Practice nurses can have a key role in monitoring these patients, providing lifestyle advice and, in some cases, ensuring they are on optimal therapy.
Key points
- Raised cholesterol levels are an identified risk factor for atherosclerotic cardiovascular disease (ASCVD)
- Achievement of current lipid guidelines is poor, putting patients at increased risk of ASCVD
- The options for lipid-lowering therapy have expanded considerably in the past few years
- Healthcare professionals need to work with patients to optimise their risk factors and reduce their risk of ASCVD
CPD REFLECTIVE PRACTICE
- Are you confident in giving lifestyle advice to patients around cardiovascular disease risk?
- Have you experienced patients worrying about side effects of statins? How could you reassure these patients?
- How could you ensure you stay up to date with the latest evidence on lipid-lowering therapies?