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Lipid management in ASCVD Learning Zone

Treating lipid disorders

Last updated:13th Oct 2022
Published:11th Dec 2023

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 obesity1,3-6.

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 disease3,8-10.

ASCVD, atherosclerotic cardiovascular disease; DHA, docosahexaenoic acid; EMA, European Medicines Agency; EPA, eicosapentaenoic acid; FH, familial hypercholesterolaemia; HDL-C, high-density lipoprotein cholesterol; IV, intravenous; LDL-C, low-density lipoprotein cholesterol; mAbs, monoclonal antibody; MOA, mechanism of action; SC, subcutaneous; siRNA, small interfering RNA; TG, triglyceride; VLDL, very low-density lipoprotein.
Note: EMA-approved indications were current as of 19 December 2023.

Medicine class/approved medicine EMA indication
Route and frequency of administration
Effects on lipids
Statins
Atorvastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
Fluvastatin
Lovastatin
• Moderate or severe hypercholesterolaemia
 (heterozygous familial
  and non-familial)
• Mixed dyslipidaemia

Oral administration, once daily
• LDL-C reduction is dose-dependent and varies between the different statins
• High-intensity regimens reduce LDL-C by ≥50%; moderate-intensity therapies can reduce LDL-C by 30–50%
• Reduction of TG levels by 10–20% from baseline values
• Increases in HDL-C levels vary with dose
Cholesterol absorption inhibitors
Ezetimibe • Primary hypercholesterolaemia
  (heterozygous familial
   and non-familial)
• Mixed dyslipidaemia

Oral administration, once daily
• Ezetimibe reduced LDL-C by 18.5%, compared with placebo
• 3% increase in HDL-C
• 8% reduction in TGs
• Ezetimibe added to statin therapy can reduce LDL-C levels by 21–27%
• Ezetimibe and bile acid sequestrants can reduce LDL-C levels by 10–20%, compared with bile acid sequestrant regimen
Bile acid sequestrants
Cholestyramine
Colestipol
Colesevelam
• Primary hypercholesterolaemia
  (heterozygous familial
   and non-familial)  

Oral administration
Colestipol, once or twice daily
Colesevelam, 4–6 tablets daily
• Reduction in LDL-C of 18–25%, following a top daily dose
• No major effect on HDL-C
• TGs can increase in predisposed patients
• Colesevelam reduces glucose levels in hyperglycaemia
Antisense oligonucleotides
Volanesorsen • Familial chylomicronaemia syndrome (FCS) and at high risk for pancreatitis


SC injection (once weekly for 3 months, then once every 2 weeks)

• Reduces plasma triglycerides by ∼70%, and apolipoprotein C-III by 80–90%
Fibrates
Bezafibrate
Ciprofibrate
Fenofibrate
Gemfibrozil
• Mixed hyperlipidaemia
• Severe hypertriglyceridaemia

Fibrates are not recommended as first-line therapy

Gemfibrozil should not be used in combination with statins because of an increased risk of myotoxicity

Oral administration
Bezafibrate, one tablet daily
Ciprofibrate, one tablet daily
Fenofibrate, one tablet daily
Gemfibrozil, 1,200 mg dose is taken as 600 mg twice daily

• 50% reduction of TG levels
• A ≤20% reduction in LDL-C level
• A ≤20% increase in HDL-C level
n-3 fatty acids
Omega-3 acid ethyl esters • Hypertriglyceridaemia
  (icosapent ethyl only)

n-3 fatty acids (2–4 g/day) affect serum lipids and lipoproteins (VLDL concentrations), MOA is poorly understood

Oral administration
Icosapent ethyl, 2 g/twice a day
• n-3 fatty acids can reduce TG levels
• Recommended doses of total EPA and DHA to lower TGs vary between 2–4 g/day
• EPA can reduce serum TG levels up to 45% (dose-dependent)
• Icosapent ethyl can reduce TG levels by 18%
PCSK9 inhibitors
Alirocumab
Evolocumab
(mAbs)
• Primary hypercholesterolaemia (heterozygous familial
   and non-familial)  
• Mixed dyslipidaemia 
• Established ASCVD 
• Statin intolerance/ contraindication
• Homozygous familial hypercholesterolaemia (evolocumab only)

SC injection, once every 2–4 weeks 
• Alirocumab and evolocumab, alone or with statins, and/or other lipid-lowering therapies, can reduce LDL-C levels by 60% (depending on dose)
• Evolocumab can lower TG levels by 26%, and raise HDL-C (9%) and Apolipoprotein A-I (4%)
PCSK9 synthesis inhibitors
Inclisiran
(siRNA)
• Primary hypercholesterolaemia (heterozygous familial
   and non-familial)
• Mixed dyslipidaemia
• Statin intolerance/ contraindication

SC injection; 2nd dose after 3 months, then once every 6 months
• Can lower LDL-C between 50–55% as early as 90 days
• On average, LDL-C levels were reduced by 52% over 1 year with twice yearly dosing
• In people with FH, LDL-C was reduced by 48%, compared with placebo
ATP citrate lyase inhibitor
Bempedoic acid • Heterozygous familial hypercholesterolaemia
• Mixed dyslipidaemia
• Statin intolerance/ contraindication

Oral administration, once daily
• Bempedoic acid has been shown to reduce LDL-C by 18% on a background of moderate-to-high dose statins, 25% with low-dose or no statins, and 38-40% as a fixed dose combination with ezetimibe
Angiopoietin-like 3 (ANGPTL3) inhibitor
Evinacumab • Homozygous familial hypercholesterolaemia

IV infusion, every 4 weeks
• Evinacumab can reduce
   LDL-C by 49±23%

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 goals1,3.

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 characteristics1,3,11-14. 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 statins11-14, or in those with homozygous familial hypercholesterolaemia (evolocumab only)13.

A stepwise approach to lipid-lowering treatment intensification for CVD prevention and expected LDL-C reductions

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 disease1,3,7.

ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; DM, diabetes mellitus; LDL-C, low density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; PUFA, polyunsaturated-fatty acid; TG, triglyceride; TOD, target organ damage; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. *If no evidence of vascular damage (particularly microalbuminuria), it seems reasonable to delay initiation of statins in individuals with diabetes who are asymptomatic until the age of 303.

Population Considerations for lipid-lowering treatment
CKD Non-dialysis-dependent, stage 3–5 CKD:
• Statins or statin/ezetimibe combinations are recommended

If on dialysis:
• For those already on statins ± ezetimibe at the time of initiating dialysis, consider continuing treatment, particularly in those with ASCVD
• For those without ASCVD who are dialysis-dependent (end-stage renal disease), initiation of statin therapy is not recommended
Diabetes mellitus • Statin therapy is recommended in patients with T1DM who are at high or very-high CVD risk
• Statin therapy may be considered in both T1DM and T2DM patients aged ≤40 years with evidence of TOD and/or an LDL-C level >2.6 mmol/L (100 mg/dL), as long as pregnancy is not being planned
• Consider intensification of statin therapy before introduction of combination therapy
• If the goal is not reached, statin combination with ezetimibe should be considered
• Statin therapy is not recommended in premenopausal patients with diabetes if considering pregnancy or not using adequate contraception
Familial hypercholesterolaemia (FH) Heterozygous FH (HeFH)
• Initiate cholesterol-lowering treatment as soon as possible after diagnosis
• Use high-intensity statin therapy, in most cases in combination with ezetimibe

Treatment with a PCSK9 inhibitor is recommended for:
• Patients with FH at very high risk, if the treatment goal is not achieved on maximal tolerated statin plus ezetimibe
• Those who cannot tolerate statins

Homozygous FH
• Intensive LDL-lowering treatment is recommended (with lipoprotein apheresis, when available)
• Maximally tolerated pharmacological therapy must be maintained

If severe FH and planning pregnancy, pregnant or breastfeeding:
• Bile acid sequestrants and/or LDL apheresis may be considered
High-risk with hypertriglyceridaemia For individuals with TGs >2.3mmol/L (200 mg/dL) and at high risk in whom TG cannot be lowered by lifestyle measures alone, TG-lowering medications may be considered

Options include:
• Statins (first choice)
• Fibrates (consider adding fenofibrate or bezafibrate if at LDL-C goal with TGs >2.3 mmol/L [200 mg/dL])
• n-3 PUFAs (consider adding icosapent ethyl [2 x 2 g/day] in high-risk [or above] patients with TGs >1.5 mmol/L [135 mg/dL] despite statin treatment and lifestyle measures, in combination with a statin)
• PCSK9 inhibitors
People aged ≥70 years Primary prevention:
• Initiation of statin treatment may be considered if at high or very high risk

Secondary prevention:
• For individuals with ASCVD, treatment with statins is recommended in the same way as for younger patients
• If significant renal impairment and/or potential for drug interactions, start statin on a lower dose
Planning pregnancy, during pregnancy or breastfeeding Lipid-lowering treatments should not be given if planning pregnancy, during pregnancy or breastfeeding

For severe FH:
• Bile acid sequestrants (which are not absorbed) and/or LDL-apheresis may be considered during pregnancy
Statin intolerance Statin intolerance may be due to statin-related adverse effects including muscle symptoms, although the true incidence of these events may be overestimated and true statin intolerance is rare

For confirmed statin intolerance, options for management include:
• Changing the statin or reducing the dose
• PCSK9 inhibitor (if at very high CVD risk, or in those with HeFH)
• Bempedoic acid ± ezetimibe

Assessing response to lipid-lowering treatment in CVD prevention

Assessment of LDL-C levels is recommended to monitor response to treatment at 46 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 ASCVD1,3,15, particularly regarding decisions to intensify lipid-lowering treatment1.

While specific goals for lipid levels vary between guidelines and regions2,3,7, those recommended by the ESC 2021 guidelines are based on an individual’s CVD risk, summarised in Figure 21.

Recommended LDL-C treatment goals for lipid-lowering treatment for primary and secondary prevention of CVD

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 outcomes17-20, 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 practice2,3,7.

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 prevention1,3.

ApoB, apolipoprotein B; non-HDL-C, non-high density lipoprotein cholesterol.

Lipid Secondary lipid treatment goals
Non-HDL-C Very high risk: <2.2 mmol/L (<85 mg/dL)
High risk: 2.6 mmol/L (100 mg/dL)
Moderate risk: 3.4 mmol/L (130 mg/dL)
ApoB Very high risk: <65 mg/dL
High risk: 80 mg/dL
Moderate risk: 100 mg/dL
Triglycerides No goal, but <1.7 mmol/L (<150 mg/dL) indicates lower risk; and higher levels indicate a need to look for other risk factors

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 contraindicated26,27. The cardiovascular outcomes trial (CLEAR Outcomes) for bempedoic acid is expected to be reported in 20231,28. 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 lipids30,31. 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 population30,31, 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 profile30,31. 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 translation33,34. 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 5686%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 disease3,30,35,37-41.

AE, adverse event; LDL-C, low-density lipoprotein cholesterol; SAE, serious adverse event, TG, triglyceride. ORION-939, ORION-10 and ORION-1140; CLEAR Wisdom41; CLEAR Harmony37; ELIPSE-HoFH30; COMPASS35,38.

Medication Clinical study Primary and secondary study outcomes
Medications that can reduce LDL-C
Inclisiran ORION-10 and ORION 11 • At Day 510, LDL-C in the inclisiran group was reduced by 52.3% in ORION-10 and 49.9% in ORION-11
• AEs were generally similar between inclisiran and placebo groups, although injection site reactions were more frequent with inclisiran vs placebo (2.6% vs 0.9% in the ORION-10 trial and 4.7% vs 0.5% in the ORION-11 trial); these reactions were generally mild and none were severe or persistent
  ORION-9 • At Day 510, LDL-C was reduced by 39.7% in the inclisiran group
• AEs and SAEs were similar between inclisiran and placebo groups
Bempedoic acid CLEAR Harmony • Bempedoic acid added to background lipid-modifying therapy reduced LDL-C by 16.5% from baseline
• Incidence of AEs and SAEs were considered similar between bempedoic acid and placebo groups, except for a higher incidence of gout in the bempedoic acid group (1.2% vs 0.3%); the incidence of AEs leading to discontinuation was also higher in the bempedoic acid versus placebo group (10.9% vs 7.1%)
  CLEAR Wisdom • LDL-C levels were reduced by 15.1% in the bempedoic acid group, but increased by 2.4% in the placebo group
• Common AEs included nasopharyngitis (5.2% vs 5.1% for bempedoic acid vs placebo, respectively), urinary tract infection (5.0% vs 1.9%) and hyperuricaemia (4.2% vs 1.9%)
Evinacumab ELIPSE HoFH • LDL-C was reduced by 47.1% at week 24 with evinacumab, on a background of stable lipid-lowering therapy
• AEs were similar between evinacumab and placebo groups; an influenza-like illness was reported in 11% of patients in the evinacumab group and none in placebo
Medications that can reduce triglyceride-rich lipoproteins, and their remnants
Volanesorsen COMPASS • Reduced plasma TGs by ~70%, and apolipoprotein C-III by 80–90%

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 levels42,43.

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-C1,2,15. 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 practice1,3,7,17,42,45,46. These unmet needs are summarised in Figure 3.

Key unmet needs in lipid management for CVD prevention

Figure 3. Key unmet needs in lipid management for CVD prevention7,17.
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 CVD7,17

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 recommendations7,17 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 role17,48.

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 therapy7,17. 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 ezetimibe1,25 (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 therapy1,25.

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 risk1,3,45,46. 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 changes1,3.

Investigational treatments that specifically lower Lp(a) are being evaluated in ongoing clinical trials18,45,46, 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 risk18,45,46. 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 access7,52 and cost52-54, limited duration of follow-up data from clinical trials, and a lack of direct comparative data with other lipid-lowering agents52,55-59.

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 inclisiran52,57,58.

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 CVD1,28. Results are expected in 20231,28.

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
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