Cardiovascular disease is back at the front and centre of the healthcare agenda following the publication of Public Health England’s 10-year ambition for reducing the burden of cardiovascular disease (CVD) (Waterall, 2020), the CVD-Prevent programme (NHS Health Check, 2021) and the recent announcement of the priorities for primary care for 2021/2 and 2022/3 (NHS England and NHS Improvement, 2021).
This refreshed focus on CVD prevention aims to improve the identification and management of three key risk factors: atrial fibrillation, blood pressure and cholesterol (the ABC of CVD) with the addition of heart failure, which is also seen as a priority for intervention (NHS, 2018). With respect to dyslipidaemia, the aim is to identify and manage dyslipidaemia more effectively and to increase awareness and detection of familial hypercholesterolaemia (FH) (Waterall, 2020). The 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice also highlight the importance of effective lipid management (Visseren et al, 2021).
Once a risk factor is diagnosed, it is important to offer evidence-based therapies and interventions in order to reduce risk and improve cardiovascular outcomes. For years, statin therapy has been recognised as the mainstay of treatment for dyslipidaemia, with the addition of ezetimibe where indicated to improve LDL-cholesterol levels and reduce CVD risk (National Institute for Health and Care Excellence [NICE] 2021a). In recent years, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have also been used where appropriate and this class of medication has been in the news recently with the recent and first NHS population agreement relating to the twice yearly PCSK9 inhibitor, inclisiran (NHS England, 2021a). However, inclisiran is not the only recent addition to the lipid lowering armoury. Bempedoic acid already has a licence for use in the United Kingdom and bempedoic acid with ezetimibe has received NICE approval via a technology appraisal for lipid lowering (NICE, 2021b). This article discusses the role of bempedoic acid as a lipid lowering drug and considers the mode of action, licensed indications, adverse drug reactions and the NICE technology appraisal recommendations.
By the end of this article readers should be more confident in:
- Recognising the place for bempedoic acid in lipid management
- Appreciating the mode of action of bempedoic acid
- Evaluating the licence for its use
- Analysing the NICE technology appraisal on bempedoic acid
- Implementing national guidance on the use of bempedoic acid in practice.
A brief history of lipid management
Cholesterol is a molecule which is an essential component in the body’s ability to form healthy cell membranes, but as far back as the 19th century it was recognised that atheromatous plaques identified in the aortas of affected individuals contained 20 times more cholesterol than healthy aortas (Goldstein and Brown, 2015). The familial connection between cholesterol and heart attacks was highlighted by Muller who had linked high blood-cholesterol levels in families with a history of premature cardiovascular events (Kuijpers, 2021). In the 1950s, the fractions of the lipid profile were identified when research by Gofman demonstrated that the incidence of myocardial infarction correlated not just with raised blood cholesterol but also that the atheroma-causing cholesterol was contained in low-density lipoprotein cholesterol (LDL-C) and that cardiac events were less common in those who had higher levels of high-density lipoprotein (HDL) (Goldstein and Brown, 2015). As time went on, more information about the role of cholesterol in vascular events was established in trials such as the Seven Countries Study and the Framingham Heart Study (Cybulska and Kłosiewicz-Latoszek, 2019). These studies, along with many others, contributed to the so-called lipid hypothesis, which took the view that lowering cholesterol, and in particular LDL-C, would lead to a reduction in cardiovascular events (DuBroff, 2018). Research had identified over 30 steps in the cholesterol synthesis pathway, but it was suggested that inhibiting HMG-CoA reductase could be an effective means of lowering plasma cholesterol, which is why statins are recommended first line (NICE, 2021a).
Statins have been tested in many long-term, large-scale clinical trials, although DuBroff (2018) recommends a note of caution when considering these trial results. Nevertheless, the general view is that treatment with statins lowers LDL-C and reduces the frequency of cardiovascular events.
Although lifestyle changes such as addressing dietary intake of cholesterol, carbohydrates and physical activity levels are important when considering the holistic management of lipid levels, most of the cholesterol in the blood is made by the liver (Shih et al, 2019; Trapani et al, 2012). This is why drugs which impact directly on blood lipid levels can be effective at reducing LDL-C (Althanoon et al, 2020)
In the majority of cases, dyslipidaemia is asymptomatic, which can hamper not only the detection of the condition but also the engagement with people diagnosed with lipid abnormalities. It may be harder to make important lifestyle changes and adhere to daily medication if the person in question has no symptoms and perceives no obvious benefit to making these changes. Furthermore, the public’s perception of statins is not always a positive one and a lack of knowledge about cardiovascular disease risk factors along with media-driven concerns about statins may lead to a poor uptake of and adherence to medication (Chisnell et al, 2017). Whether real or perceived, adverse drug reactions may lead to poor adherence and even discontinuation of treatment, leaving people at ongoing risk of CVD (Rodriguez et al, 2019). This is a concern when reducing low density lipoprotein cholesterol (LDL-C) has been associated with improvements in cardiovascular outcomes.
Lipid lowering therapies to date
As described above, statin therapy is the mainstay of lipid lowering therapy for reducing LDL-C, although statins and ezetimibe are also known to have an anti-inflammatory effect (Oh et al, 2019). In England, atorvastatin 20 mg is the recommended starting dose for primary prevention, with the dose uptitrated in order to reach a target of a non-HDL cholesterol reduction of 40% or more or to reach an absolute value of 2.5 mmol/L or less (NICE, 2021a; Mach et al, 2019). In secondary prevention, a dose of 80 mg atorvastatin is recommended (NICE, 2021a).
If an add-on therapy is needed, ezetimibe is recommended as a non-statin lipid lowering drug (NICE 2021a). Although ezetimibe can be used for people who are statin intolerant, it is most effective when used with a statin. In the IMPROVE-IT trial, which focused on people who had recently had a myocardial infarction, demonstrated that ezetimibe reduced LDL-C and was linked to improved CVD outcomes when added to statin therapy, even when target LDL levels had been significantly reduced on a statin alone (Cannon et al, 2015)
PCSK9 inhibitors have also been shown to significantly reduce LDL-C levels and improve outcomes in people who are at high CVD risk and have been unable to reach the recommended target with statin therapies and other treatments, or in those who cannot tolerate those treatments (NICE, 2016). These drugs are recommended for primary prevention in people with heterozygous FH (HeFH) if LDL-C remains persistently above 5 mmol/L. NICE also recommends these PCSK9 inhibitors as secondary prevention in high-risk patients if the LDL-C remains above 4 mmol/L or in very high risk patients with an LDL-C above 3.5 mmol/L. However, the uptake of these drugs has been significantly lower than expected, possibly because clinicians are unaware of where they fit in the lipid management pathway. It is therefore essential that clinicians familiarise themselves with national and local pathways, especially when new therapies such as inclisiran, a twice yearly PCSK9 inhibitor, and bempedoic acid, have recently come onto the market. The guidance from the Accelerated Access Collaborative (AAC) can be useful to access in order to understand the place of all of these lipid lowering therapies, including when patients are unable to tolerate statins, which is where bempedoic acid plays a key role (NHS England, 2020; NHS England, 2021b).
Bempedoic acid – mode of action
Bempedoic acid is an adenosine triphosphate citrate lyase (ACL) inhibitor, which impacts on the liver’s ability to synthesise cholesterol. It is a prodrug, which is converted to its active form in the liver, inhibiting cholesterol synthesis leading to upregulation of LDL-receptors and a reduction in the level of LDL-C in the blood (Ballantyne et al, 2021). Bempedoic acid is cleared and eliminated renally. Trial data from people with or at risk for atherosclerotic cardiovascular disease or who have been diagnosed with heterozygous FH, identified that giving bempedoic acid in combination with statins and/or ezetimibe led to significant reductions in LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein (a marker of inflammation which reflects CV risk) compared with placebo (Ballantyne et al, 2021). The possibility that bempedoic acid could have anti-inflammatory effects is important as this has already been noted with statins (Oh et al, 2019).
Much of the data informing the use of bempedoic acid comes from the CLEAR studies (Jia et al, 2019). These studies have included people with or at high risk of CVD, people with hypertension or diabetes, people with HeFH, people already on a high intensity statin and people who could not tolerate a statin. All trials showed a reduction in LDL-C. Further trials are underway to identify the CV outcomes of lowering LDL-C in these groups.
Licensed indications and dosing
The summary of medical product characteristics (SmPC) for bempedoic acid gives detailed information about the licence, dosing and adverse drug reactions (Electronic Medicines Compendium [EMC], 2020a). Bempedoic acid is licensed for use in adults age 18 years and over in combination with a statin and/or other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin. It can also be used alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated. The recommended dose is one tablet of 180 mg taken once daily, swallowed whole with or without food. Treatment is also available as a combination therapy made up of 180mg of bempedoic acid with 10 mg ezetimibe.
Contraindications and cautions
Bempedoic acid is generally well tolerated, but there are some key interactions, cautions and contraindications of which to be aware. In clinical trials, blood levels of both pravastatin and simvastatin were noted to increase. If prescribing bempedoic acid with pravastatin or simvastatin, the pravastatin dose should be limited to 40mg and the simvastatin dose should be limited to 20 mg daily. The SmPC includes a contraindication to using it with higher doses of simvastatin (40 mg and beyond). However, the SmPC also states that 40 mg simvastatin may be used with bempedoic acid for patients with severe hypercholesterolaemia and who are at high risk of cardiovascular complications, but who have not achieved their treatment goals on lower doses. In this situation, a risk: benefit assessment should be done in order to decide whether to use this combination. Although weak interactions between bempedoic acid and atorvastatin or rosuvastatin have been seen, they are not clinically significant, so dose adjustments are not required. This is also the case when combining bempedoic acid with ezetimibe (Ballinger et al, 2021).
No dose adjustment is needed for older people but there are limited data in people with an eGFR below 30 mL/min/1.73 m2 and none in people with end-stage renal disease (ESRD) on dialysis. However, the SmPC merely recommends extra monitoring of these patients if bempedoic acid is prescribed, rather than suggesting that this is a contraindication to its use. In clinical trials, alterations in liver enzymes were noted. As a result, the SmPC recommends that liver function tests should be performed before treatment is started but that bempedoic acid should only be discontinued if an increase in transaminases of more than three times the upper limit of normal is detected and persists (EMC, 2020a). Although bempedoic acid can be used in mild and moderate hepatic impairment, there are no data for its use in severe hepatic impairment and extra monitoring is once again recommended (EMC, 2020a). It is contraindicated in pregnant and breast-feeding women but there is no interaction with the contraceptive pill.
Adverse drug reactions
Although statins and bempedoic acid both interfere with the liver’s ability to produce cholesterol, the activity of bempedoic acid is not expressed in skeletal muscle tissue, meaning that myalgia should not be a side effect of taking it, unlike with some statins. However, as mentioned above, bempedoic acid increases plasma concentrations of statins so patients taking the two drugs together should be monitored for the side effects associated with higher doses of statins, such as myopathy, rhabdomyolysis and/or acute kidney injury. Anyone with muscle pain or weakness should be advised to report it and a lower dose of the same statin or an alternative statin should be considered. Alternatively, the bempedoic acid can be discontinued and replaced with an alternative lipid-lowering therapy. Ongoing monitoring of lipid levels and symptoms should be undertaken. If myopathy is confirmed by a creatine phosphokinase (CPK) level of 10 times the upper limit of normal or higher, bempedoic acid should be discontinued immediately along with any statin that the patient is taking (EMC, 2020a).
Bempedoic acid may also cause a rise in uric acid levels, which might lead to the onset of gout. This rise is thought to occur because bempedoic acid is a weak inhibitor of organic anion transporter 2 (OAT2). Treatment should be discontinued if gout is diagnosed.
The most commonly reported adverse reactions with bempedoic acid were hyperuricaemia (3.8%), pain in extremity (3.1%), and anaemia (2.5%). More patients on bempedoic acid compared to placebo discontinued treatment due to muscle spasms (0.7% versus 0.3%), diarrhoea (0.5% versus <0.1%), pain in extremity (0.4% versus 0), and nausea (0.3% versus 0.2%), although differences between bempedoic acid and placebo were not significant (Ballantyne et al, 2021; EMC, 2020a).
Specific populations
The pharmacokinetics of bempedoic acid are not affected by age, gender, ethnicity or weight. Apart from the effect of bempedoic acid on statin levels described above, drug interactions are likely to be minimal as it is not metabolised via cytochrome P450 enzyme.
In people with diabetes, treatment of dyslipidaemia with bempedoic acid resulted in a small reduction in HbA1c. This reduction was only seen in people with diabetes and bempedoic acid was not linked to an increased risk of hypoglycaemia (EMC, 2020a).
In people age 60-plus who are also taking corticosteroids or fluoroquinolones with renal failure and a history of tendon rupture, advice should be given as to the increased risk of tendonitis and rupture and the drug should be stopped if any joint pain, swelling or tendon rupture occurs (Ballantyne et al, 2021).
The NICE technology appraisal
In 2021, NICE published a technology appraisal (TA) which supports the use of bempedoic acid with ezetimibe in certain situations (NICE, 2021b). Once a TA has been published, healthcare organisations have 3 months in which to make the intervention available. This means that bempedoic acid with ezetimibe should now be freely available to prescribe. Taking into account the available evidence, and blending this with NICE’s responsibility for making financial decisions, NICE advised that bempedoic acid with ezetimibe is a suitable option for treating hypercholesterolaemia as an adjunct to diet in adults for whom statins are contraindicated or not tolerated, and ezetimibe alone does not adequately control LDL-C.
The NICE TA states that bempedoic acid is an inexpensive, oral preparation that is easy to use and suitable for people who cannot tolerate statins. It also reminds prescribers that when bempedoic acid is used with ezetimibe, the combination treatment will be cheaper than prescribing each drug separately. This will not only be more cost-effective but will reduce the tablet load. The EMC SmPC on bempedoic acid with ezetimibe gives more information on this combination therapy (EMC, 2020b)
In order to carry out the TA, cardiovascular risk was assessed by taking the results of the individual’s European Society of Cardiology (ESC) SCORE assessment and converting the results into the UK’s QRISK3 risk assessment algorithm (NICE, 2021b). This was then used to estimate the person’s annual risk for different cardiovascular events in the same way as NICE had done for its guideline on cardiovascular disease: risk assessment and reduction, including lipid modification (NICE, 2021a). The primary efficacy outcome of all relevant bempedoic acid trials was percentage change from baseline LDL-C at 12 weeks although the CLEAR Harmony study showed a mean LDL-C reduction from baseline in CLEAR Harmony of -14.9% and -14.4% at 12 and 78 weeks respectively, suggesting that the benefits were sustained over longer periods of time than 12 weeks (NICE, 2021b). As a result of the recommendations from the NICE TA, if a patient has primary hypercholesterolaemia or mixed dyslipidaemia and the clinician responsible for their care thinks that prescribing bempedoic acid with ezetimibe is appropriate, NICE has approved its use.
Putting theory into practice
Many prescribers will be involved in prescribing lipid lowering drugs for both primary and secondary prevention. Prescribers may be involved in lipid lowering medication in different ways: as the primary prescriber, via repeat prescribing, as part of a medication review or if the individual expresses concerns about side-effects of current lipid lowering therapies. All of these situations provide opportunities to re-evaluate the most suitable treatment for people who require lipid lowering therapy. Consideration should be given to the indication for treatment – primary or secondary prevention, high risk or very high risk – and a review of adherence and the impact of any existing drugs should be completed. Lipid targets should be reconsidered in line with latest evidence and guidelines and the appropriate place for new therapies such as bempedoic acid should be established. Local guidance should reflect the NICE TA and algorithms such as those from the AAC can be implemented with confidence, whether to optimise lipid management in general, or to ensure that patients previously coded as statin intolerant can be offered evidence-based care. The aim of the AAC is to ensure that new therapies are fast-tracked for use by highlighting where they play a part.
Summary
Bempedoic acid is a new once daily oral therapy which can be used to complement the action of statin therapy in lipid management. It can also be used for statin intolerant patients with or without ezetimibe.
Bempedoic acid acts on the liver to reduce cholesterol synthesis and upregulate LDL receptors leading to lower LDL-C levels. It is generally well tolerated with few drug interactions, although clinicians should be aware of the propensity of bempedoic acid to raise plasma levels of simvastatin and pravastatin. It may also lead to hyperuricaemia which may lead to gout. It can be used in renal and hepatic impairment and no dose reductions are needed in the elderly.
NICE has published a technology appraisal on bempedoic acid which supports its use.
The Accelerated Access Collaborative has produced clear and concise guidance on how and when to prescribe bempedoic acid.