Treating lipid disorders

Overview of lipid management for cardiovascular disease prevention

Lipid-lowering treatments are recommended for pharmacological management of dyslipidaemias and to reduce the risk of atherosclerotic cardiovascular disease. Treatment options have expanded considerably over the past decade. In addition to statins, fibrates and bile acid sequestrants, lipid-lowering treatment options now include¹:

• selective cholesterol absorption inhibitors such as ezetimibe
• monoclonal antibodies, including alirocumab and evolocumab, that target PCSK9
• the small interfering RNA (siRNA) molecule inclisiran, which inhibits PCSK9 synthesis
• the cholesterol synthesis inhibitor bempedoic acid
• the angiopoietin-like 3 (ANGPTL3) inhibitor evinacumab
• antisense oligonucleotides, such as volanesorsen

According to the 2021 European Society of Cardiology (ESC) cardiovascular disease (CVD) prevention guidelines, decisions to initiate lipid-lowering treatment should be based on consideration of the individual’s risk of atherosclerotic cardiovascular disease (ASCVD), as well as risk modifiers, comorbidities and their preferences¹. However, for people who are at high or very high risk of CVD, including those with established ASCVD, lipid-lowering treatment is recommended to reduce the risk of CVD and/or recurrent events¹. For people with familial hypercholesterolaemia or other rare/genetic lipid disorders, treatment is recommended without the need for ASCVD risk assessment irrespective of their estimated CVD risk¹.

Subsequent decisions for stepping-up treatment from monotherapy to combination treatments are based on their impact on lipids, with treatment targets largely based on low-density lipoprotein cholesterol (LDL-C)^1-3. Secondary goals are also provided for non-high-density lipoprotein cholesterol (HDL-C) or apolipoprotein B (ApoB), which  are considered more accurate predictors of ASCVD than LDL-C in those with high triglyceride levels, such as patients with diabetes mellitus or obesity^1,3-6.

Despite differences between guidelines, including recommended goals for lipid reduction, they agree that lipids should be lowered to reduce overall CVD risk⁷

Options for lipid-lowering treatment

The European Medicines Agency (EMA)-approved indications for currently available options for lipid-lowering treatment, as well as their effects on lipids, are summarised in Table 1.

Table 1. EMA-approved lipid-lowering treatments for dyslipidaemia and/or atherosclerotic cardiovascular disease^3,8-10.

Treatment selection and sequencing for CVD prevention

The European Society of Cardiology (ESC) 2021 cardiovascular prevention guidelines recommend a stepwise approach to lipid-lowering treatment for atherosclerotic cardiovascular disease (ASCVD)¹. This resembles the approach taken in clinical practice, whereby treatment intensification is considered on the basis of anticipated benefit, side effects and patient preferences, using a shared decision-making approach in collaboration with the patient¹.

Generally, this stepwise approach consists of progressing from statins to combination therapy with ezetimibe, followed by addition of PCSK9 inhibitors if low-density lipoprotein-cholesterol (LDL-C) levels remain above recommended goals^1,3.

While expected LDL-C reductions from lipid-lowering treatment vary between individuals¹, average LDL-C reductions of up to 85% can be expected for some patients with triple-combination treatment of high-intensity statin, ezetimibe and PCSK9 inhibitors¹

The ESC 2021 guidelines recommend this stepwise treatment-intensification approach (Figure 1) for

• apparently healthy people at high or very high CVD risk
• people with established ASCVD
• people with diabetes mellitus and established ASCVD or severe target organ damage (which may be indicated by estimated glomerular filtration rate [eGFR] levels, albuminuria, proteinuria, and microvascular damage in at least three different sites)

As part of the stepwise treatment intensification approach, the individual’s CVD risk, treatment benefit, risk modifiers, comorbidities and preferences should also be considered¹.

However, treatments that target PCSK9 (inclisiran, evolocumab and alirocumab) or the non-statin cholesterol synthesis inhibitor bempedoic acid may be considered for earlier lines of treatment, depending on individual patient characteristics^1,3,11-14. For example, inclisiran, evolocumab, alirocumab and bempedoic acid (±ezetimibe) are European Medicines Agency (EMA)-approved as monotherapy or in combination with other lipid-lowering medicines in people who are contraindicated to or intolerant of statins^11-14, or in those with homozygous familial hypercholesterolaemia (evolocumab only)¹³.

Figure 1. A stepwise approach to lipid-lowering treatment intensification for CVD prevention and expected LDL-C reductions (ESC 2021, ESC/EAS 2019)^1,3.
LDL-C, low density lipoprotein C; MTD, maximum tolerated dose; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor.

Treatment considerations for CVD prevention in specific populations

When considering lipid-lowering treatment, particular considerations for treatment selection, goals, and treatment sequencing, and additional considerations apply for specific populations including those with familial hypercholesterolaemia, chronic kidney disease and older persons¹, as outlined in Table 2.

Table 2. Considerations for lipid-lowering treatment in specific populations at risk of atherosclerotic cardiovascular disease^1,3,7.

Assessing response to lipid-lowering treatment in CVD prevention

Assessment of LDL-C levels is recommended to monitor response to treatment at 4–6 weeks after any treatment strategy initiation or change¹. If lipid goals are not achieved, treatment intensification should be considered, depending on patient characteristics, comorbidities, preferences, and the safety profile and tolerability of lipid-lowering medicines¹.

Subsequent follow-up monitoring usually takes place every 6–12 months; however, LDL-C should be assessed whenever available³. To inform management, this may involve a full lipid profile, including non-HDL-C and ApoB as secondary treatment targets³.

Lipid-lowering treatment targets

For those receiving lipid-lowering treatment, lipid goals are used to guide management for both primary and secondary prevention of ASCVD^1,3,15, particularly regarding decisions to intensify lipid-lowering treatment¹.

While specific goals for lipid levels vary between guidelines and regions^2,3,7, those recommended by the ESC 2021 guidelines are based on an individual’s CVD risk, summarised in Figure 2¹.

Figure 2. Recommended LDL-C treatment goals for lipid-lowering treatment for primary and secondary prevention of CVD – ESC/EAS 2019/ESC 2021/2023 ^1,3,16.
ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; FH, familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol; MTD, tolerated dose; SCORE, Systematic Coronary Risk Estimation; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
^*Markedly elevated single risk factors confer higher CVD risk, in particular total cholesterol >8 mmol/L (>310 mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or blood pressure ≥180/110 mmHg³.
^†In particular, triglyceride >8 mmol/L (>310 mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or blood pressure >180/110 mmHg³.

These guidelines recommend a ‘more aggressive’⁷ LDL-C treatment goal of <1.4 mmol/L (55 mg/dL) for those at very high CVD risk, compared with the previously recommended goal of 1.8 mmol/L (70mg/dL) in the 2016 ESC guidelines¹. This goal was revised downwards on the basis of evidence from Mendelian randomisation studies, meta-analyses and outcomes of randomised controlled trials for ezetimibe (IMPROVE-IT; Improved Reduction of Outcomes: Vytorin Efficacy International Trial) and the landmark PCSK9 inhibitor trials (FOURIER and ODYSSEY)^1,17.

In FOURIER and ODYSSEY, LDL-C reductions to below 1.4 mmol/L were associated with further benefits in CVD outcomes^17-20, and those at higher risk were reported to achieve most benefit from treatment¹⁷

While ESC considers there is a strong level of evidence supporting this low target for secondary prevention, the evidence for its use in primary prevention was considered lower¹.

ESC encourage treatment to focus on achieving LDL-C levels as close as possible to these recommended goals, considering anticipated benefit, availability, tolerability and cost of lipid-lowering treatments¹. Patients should be involved in shared decision-making with clinicians¹.

Variation in lipid goals across guidelines and regions for CVD prevention

While guidelines are aligned on the requirement to reduce lipid levels as much as possible, the specific lipid-lowering treatment goals can vary depending on which guideline is being followed in clinical practice^2,3,7.

For example, the 2018 US² and 2021 Canadian²¹ dyslipidaemia management guidelines consider an LDL-C level of ≥1.8 mmol/dL as the threshold to guide intensification of lipid-lowering treatment. UK CVD guidance⁶ has shifted away from LDL-C in favour of non-HDL-C, in part due to the fasting requirements for accurate measurement of LDL-C; however, this has not been updated since 2016.

Secondary treatment goals for CVD prevention

ESC 2019/2021/2023 guidelines also recommend alternative treatment goals (summarised in Table 3) for non-HDL-C and apolipoprotein B (ApoB)^1,3,16, noting that triglyceride measurements provide useful information about CVD risk³.

Table 3. Secondary goals for lipid-lowering treatment for cardiovascular disease prevention^1,3.

Non-HDL-C captures information on ApoB-containing lipoproteins and, unlike LDL-C, does not require the triglyceride concentration to be <4.5 mmol/L (400 mg/dL)³. ESC 2021 guidelines suggest non-HDL-C as a reasonable alternative treatment goal for all patients, particularly those with hypertriglyceridaemia or diabetes mellitus¹.

ApoB provides a direct estimate of the total concentration of atherogenic lipid particles, particularly relevant for those with elevated triglycerides³. It is considered to provide a similar amount of information to that of calculated LDL-C¹.

Evidence for newer classes of lipid-lowering medicines for CVD prevention

A brief summary of lipid-lowering medicine classes that have been approved by the EMA since 2015 is provided below.

Treatments that target PCSK9

A key step in the metabolism of LDL-C is recycling of LDL receptors on the surface of liver cells, where they bind and clear LDL-C²². PCSK9 is an enzyme that facilitates degradation of LDL receptors, thereby reducing uptake and clearance of LDL-C by liver cells and increasing serum levels²².

Alirocumab and evolocumab are human monoclonal antibodies (mAbs) against PCSK9 that reduce serum levels of LDL-C by selectively binding PCSK9 and preventing degradation of LDL receptors²³

Both mAbs were approved by the EMA in 2015 for hypercholesterolaemia and dyslipidaemia, and in 2018 (evolocumab) and 2019 (alirocumab) to reduce CVD risk in people with established ASCVD⁸. PCSK9 mAbs can decrease LDL-C by up to 60% as monotherapy, or as part of combination therapy with statins and/or ezetimibe. Their lipid-lowering effects appear to be largely independent of background therapy¹.

Another approach to targeting PCSK9 is inhibiting its synthesis through RNA interference.

Inclisiran is a small interfering RNA (siRNA) molecule and a long-acting inhibitor of hepatic PCSK9 synthesis¹, which has been shown to reduce LDL-C by 50─55% when administered via subcutaneous injection twice per year¹¹

Inclisiran received EMA approval for treatment of primary hypercholesterolaemia and mixed dyslipidaemia in 2020⁸, and has been incorporated into ESC 2021 guidelines.

Bempedoic acid

Bempedoic acid inhibits cholesterol synthesis via inhibition of adenosine triphosphate citrate lyase (ACL), an enzyme that lies upstream from 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA)²⁵. It is a prodrug administered orally and converted to bempedoyl coenzyme A (CoA)²⁶. Bempedoic acid received EMA approval in 2020 for treatment of heterozygous familial hypercholesterolaemia or mixed dyslipidaemia in combination with maximally tolerated statin therapy, or for treatment of people who are statin intolerant or for whom statins are contraindicated^26,27. The cardiovascular outcomes trial (CLEAR Outcomes) for bempedoic acid is expected to be reported in 2023^1,28. A fixed-dose combination of bempedoic acid and ezetimibe has also been approved by the EMA for treatment of primary hypercholesterolaemia and mixed dyslipidaemia²⁹.

Evinacumab

Angiopoietin-like 3 (ANGPTL3) is a liver protein that regulates lipid metabolism and increases serum lipid levels by inhibiting lipoprotein lipase and endothelial lipase, enzymes that are involved in the degradation of lipids^30,31. The finding that loss-of-function variants of the ANGPTL3 gene are associated with decreased levels of LDL-C and triglycerides, as well as a 41% lower risk of coronary artery disease, compared with the general population^30,31, led to the development of evinacumab, an anti-ANGPTL3 monoclonal antibody. Evinacumab was evaluated in clinical trials for treatment of homozygous familial hypercholesterolaemia, a rare condition that has proved difficult to treat and often requires multiple lipid-lowering medications³⁰. In clinical trials, evinacumab reduced LDL-C levels in adults and adolescents aged 12 years and older and had an acceptable safety profile^30,31. Although studies assessing long-term benefits are needed, the EMA approved the use of evinacumab in 2023 for the treatment of adults and adolescents aged 12 years and older with homozygous familial hypercholesterolaemia³². The LDL-C reducing effect of evinacumab is independent of LDL-receptor activity³⁰.

Volanesorsen

Volanesorsen is an antisense oligonucleotide that selectively binds ApoC-III messenger RNA to prevent translation^33,34. An elevated ApoC-III level is a key risk factor for hypertriglyceridaemia. Pilot studies in people with familial chylomicronemia (FCS), a rare autosomal recessive disorder characterised by hypertriglyceridaemia, showed reductions in triglyceride levels of 56–86%³⁴. Subsequent phase 3 trials, APPROACH³⁴ and COMPASS³⁵, showed that volanesorsen reduced triglyceride levels by 77% and 71.2%, respectively, in people with FCS. In 2019, the EMA approved the use of volanesorsen as an adjunct to diet in people with genetically confirmed FCS and at risk of pancreatitis in whom diet and triglyceride-lowering therapies have been inadequate³⁶.

A summary of these EMA-approved lipid-lowering treatment options that have been approved since 2015, along with key efficacy and safety data from clinical trials, are summarised in Table 4.

Table 4. Clinical trial evidence for classes of lipid-lowering medicines approved by the EMA since 2015 for atherosclerotic cardiovascular disease^{3,30,35,37-41}.

Current conversations in the field about CVD prevention

Lipid targets for CVD preventiuon - the lower the better? 

While guidelines support the idea that ‘lower is better’ for LDL-C levels² or treatment targets¹ to lower an individual’s CVD risk, some have raised concerns about uncertainties relating to the risks/harms of lowering LDL-C too much⁴², and the long-term safety of low LDL-C levels^42,43.

In particular, concerns have been raised about potential harms and risk of dementia for those who achieve low levels of LDL-C⁴². However, previous studies of individuals with genetic variants or genetic conditions affecting LDL-C suggest that low levels of LDL-C are not associated with significantly increased risk of other comorbidities or impaired cognitive function⁴². A longitudinal study of over 7,000 adults in the USA indicated low levels of LDL-C (<70 mg/dL, especially <55 mg/dL) were associated with significantly slower cognitive decline⁴⁴. A slightly increased risk for type 2 diabetes mellitus was reported in one study, but not confirmed in others⁴². There were no reports of adverse events relating to low LDL-C in the PCSK9 inhibitor trials; however, long-term follow-up data may provide additional evidence on the safety of PCSK9 inhibitors¹⁵.

Guidelines consider marked reductions in ASCVD risk from treatment with cholesterol-lowering medications in people at high risk, particularly for PCSK9 inhibitors, as support for the general principle that ‘lower is better’ for LDL-C^1,2,15. In addition to the treatment target of <1.4 mmol/L (55 mg/dL) in people at very high risk with documented ASCVD, a further target of <1.0 mmol/L (40 mg/dL) may be considered in those with a second vascular event within 2 years while on lipid-lowering treatment¹.

ESC 2021 CVD prevention guidelines encourage liberal intensification of treatment, particularly if submaximal doses of low-cost generic statins are used and side effects are not apparent¹

Lipid lowering for ASCVD: ‘Strike effective and strong’ – the earlier the better?

After an acute ischaemic event, it has been suggested that early and strong LDL-C reductions may help to prevent recurrent thrombo-ischaemic complications and improve long-term prognosis⁴².

Using the current stepwise intensification of lipid-lowering therapy, treatment adjustments are recommended every 4–6 weeks (if and as required)¹. However, this can delay achievement of treatment targets when the response to each line of lipid-lowering treatments is not adequate⁴².

Emerging evidence has shown that early initiation of lipid-lowering treatments after an ischaemic event can achieve substantial LDL-C reductions and reduce the risk of recurrent events⁴². Favourable outcomes have been reported from early initiation of statins following acute coronary syndrome, even before percutaneous coronary intervention⁴². Further studies are underway to assess the effects of early treatment with PCSK9 inhibitors on overall mortality and ischaemic events, with results expected in late 2023⁴².

Current unmet needs in dyslipidaemia management for CVD prevention

Despite numerous updated guidelines, treatment options and advances in lipid-lowering therapies over the past decade, various unmet needs remain for lipid management in the context of primary and secondary prevention of CVD in clinical practice^{1,3,7,17,42,45,46}. These unmet needs are summarised in Figure 3.

Figure 3. Key unmet needs in lipid management for CVD prevention^7,17.
CVD, cardiovascular disease; HCP, healthcare professional; Lp(a), lipoprotein(a); MTD, maximum tolerated dose.

Real-world registry data from Europe, the UK and the USA show that lipid-lowering treatments, including combination treatments, are underutilised in practice for primary and secondary prevention, even in those at high or very high risk of CVD^7,17

This underuse of lipid-lowering treatments includes low uptake of statins, and infrequent use of maximum-tolerated doses of statins or initiation of combination therapy¹⁷. In Europe, the DA VINCI study reported high-intensity statin therapy was used in only 20% and 38% of patients at very high risk (primary vs secondary respectively), while combination therapy was used in 9% of patients, and PCSK9 inhibitors in only 1%⁴⁷.

Registry data indicate that the majority of patients are not achieving recommended low-density lipoprotein-cholesterol (LDL-C) goals¹⁷ or reductions in cholesterol/non-high-density lipoprotein-cholesterol (HDL-C) in the UK⁷. The European DA VINCI study indicated that LDL-C targets set by the 2016 dyslipidaemia guidelines were not achieved in more than half of patients, and in more than two-thirds of patients when 2019 recommendations were implemented¹⁷.

What factors might contribute to suboptimal lipid lowering in practice? 

Patient adherence to prescribed lipid-lowering treatments and healthcare professional adherence to guideline recommendations^7,17 are considered as key contributing factors to suboptimal lipid-lowering. Limited access to potent lipid-lowering therapies and combination treatments in areas such as Central and Eastern Europe, as well as treatment cost or lack of reimbursement for medications, may also play a role^17,48.

For healthcare professionals, differences between guidelines in recommended lipid-lowering goals, and emphasis placed on LDL-C versus non-HDL-C, may contribute to variability in patient management in practice. here is evidence to suggest that not all healthcare professionals agree with guideline-recommended LDL-C goals and targets, or on safety considerations relating to use of statins or low LDL-C values⁷.

From the patient perspective, statin intolerance, statin reluctance and the nocebo effect are well recognised as factors that contribute to low adherence to statin therapy^7,17. Although statins are generally well tolerated, they can be associated with specific adverse effects, including muscle symptoms. The true incidence of these effects, however, is thought to be overestimated because of a possible nocebo effect from patients’ negative perceptions of statins⁷.  Therefore, when considering management of patients who report statin-associated tolerability issues, it is important to distinguish between true statin intolerance and the nocebo effect⁷.  

Can new treatments for CVD prevention help to address unmet needs?

Additional options for lipid-lowering treatment that have emerged in the past decade may help to address unmet needs for difficult-to-treat populations, including those who do not achieve adequate LDL-C lowering from maximal tolerated dose of statins and ezetimibe^1,25 (Table 4). The 2021 ESC CVD prevention guidelines currently recommend addition of a PCSK9 inhibitor in such cases, with clinical trial evidence showing an additional LDL-C lowering effect from their combination with statins ± ezetimibe¹.

Bempedoic acid is also an option for patients who are intolerant of statins, or who have not obtained an inadequate response to statin therapy^1,25.

Familial hypercholesterolaemia can be a particularly challenging condition to manage and achieving target LDL-C levels can be difficult¹⁷, increasing the risk of ASCVD in young people¹⁷.  The less frequent dosing required for treatments that target PCSK9 – once every 2–4 weeks for alirocumab and evolocumab, and twice a year for inclisiran – has been suggested as an approach to facilitate improved adherence in this patient population¹⁷.

More evidence for classes of lipid-lowering medicines for ASCVD

Lack of effective strategies that specifically target Lp(a)

There is a substantial body of evidence linking elevated levels of lipoprotein(a) (Lp[a]) to increased CVD risk^1,3,45,46. In the absence of pharmacological treatment options that specifically target Lp(a), however, it is important to manage other CVD risk factors, such as LDL-C levels and blood pressure, diabetes mellitus and chronic kidney disease, with pharmacological interventions and lifestyle changes^1,3.

Investigational treatments that specifically lower Lp(a) are being evaluated in ongoing clinical trials^18,45,46, including antisense oligonucleotides⁴⁹ and small interfering RNAs (siRNAs)^50,51. Results of these trials will help to clarify whether reductions in Lp(a) translate to reduced CVD risk^18,45,46. Future studies may also inform whether reductions in Lp(a) are of benefit to further reduce CVD risk in patients who have met LDL-C targets.

Uncertainties about newer lipid-lowering medications and barriers to uptake for CVD prevention

Although a wider range of lipid-lowering medications are now available, barriers to their uptake in the real world include variability in access^7,52 and cost^52-54, limited duration of follow-up data from clinical trials, and a lack of direct comparative data with other lipid-lowering agents^52,55-59.

For treatments that target PCSK9, longer term follow-up (>3 years) and direct comparative trials will help to better inform treatment selection and patient management, while CV outcome data are required for inclisiran^52,57,58.

Trials to determine the impact of inclisiran on CV outcomes include the ORION-4 study in people with ASCVD, due for primary completion in mid-2026⁶⁰, and the VICTORIAN-2P study in those with established CVD, due for completion in early 2027⁶¹

Although concerns have been raised over the potential association between PCSK9 inhibitors and new-onset diabetes⁶², longer follow-up data will provide more clarity around the long-term effectiveness, long-term safety and tolerability of treatments that target PCSK9⁵⁹.

For bempedoic acid, the CLEAR Outcomes study is ongoing, and will provide CV outcome data for patients with statin intolerance and established CVD, or who are at high risk of CVD^1,28. Results are expected in 2023^1,28.

Finally, there is uncertainty about the values and preferences of adults considering lipid-lowering medicines (e.g., route and frequency of administration, safety profile)⁵², which are to be considered on an individual basis.

What’s on the horizon for lipid-lowering medicines in CVD prevention?

While pharmacological options for lipid management have advanced substantially over the past decade, further developments are on the horizon. These include:

• Investigational lipid-lowering treatments that specifically target Lp(a), apolipoprotein A (ApoA), apolipoprotein B (ApoB), or peroxisome proliferator-activated receptor (PPAR)^27,46,63,64
• Biomarkers to inform a precision medicine approach to treatment, including potential for allele/gene-guided approaches⁶⁵, or use of genetic risk scores⁶⁶, to inform selection for PCSK9 inhibitor treatment; and an approach to diagnose statin intolerance using micro RNAs (miRNAs) as biomarkers⁶⁷
• Investigations into further non-invasive cardiac and inflammatory biomarkers to better inform assessment of individual risk for ASCVD⁶⁸