GP cardiovascular specialist Dr Paul Ferenc provides an update on current and emerging therapies for lipid management
Statins have been the mainstay of lipid-lowering treatment since the late 1980s, but some exciting new therapies have recently become available. Most can be prescribed in primary care, so it is important to be familiar with them.
NICE guidelines recommend five main lipid-lowering medications: statins, ezetimibe, bempedoic acid, the small interfering RNA (siRNA) PCSK9 inhibitor inclisiran and the monoclonal antibody PCSK9 inhibitors evolocumab and alirocumab (see Table 1 below).1
GPs should consider multiple medications where needed to help patients achieve target low-density lipoprotein (LDL) or non-high-density lipoprotein (non-HDL) cholesterol level, as with hypertension management where it is common for patients to require more than one agent.
The main focus is still on achieving a greater than 40% reduction in non-HDL cholesterol from baseline for both primary and secondary cardiovascular disease (CVD) prevention. A more pragmatic approach for secondary prevention, where a baseline lipid level may not be available, is to aim for a non-HDL cholesterol of below 2.5mmol/l (equivalent to LDL cholesterol below 1.8mmol/l).
If high-intensity statin therapy does not achieve the cholesterol target reduction, one of the newer medications may be added. NHS England has produced guidance that includes algorithms explaining how and when to prescribe them.2
It is important to consider referring patients with very high cholesterol to a specialist familial hypercholesterolaemia service, as reflected in Network DES Investment and Impact Fund (IIF) targets; refer patients with a total cholesterol greater than 7.5mmol/l (if aged 29 or under) or greater than 9.0mmol/l (if aged 30 or over).3 The IIF also incentivises us to ensure those with a QRISK2 or QRISK3 score above 20% are on statins.
• While not new, ezetimibe is underused despite its attractive pricing. It works by blocking the reabsorption of cholesterol from the intestine and, when combined with statin therapy, can achieve up to a 30% reduction in LDL cholesterol.4 It has been shown to reduce CVD events as secondary prevention.5
• A relatively new agent that inhibits ATP citrate lyase, reducing cholesterol synthesis. In conjunction with ezetimibe (as a combination tablet, to be more cost-effective) it results in up to a 38% reduction in LDL cholesterol, although no long-term outcomes data are available yet.6,7
• This new injectable therapy is a siRNA that reduces PCSK9 protein synthesis, thereby increasing LDL cholesterol uptake in the liver. It has been shown to reduce LDL cholesterol levels by around 50%,8 but again no long-term outcomes data are yet published. It is given as a six-monthly subcutaneous injection once established (after a second dose at three months). It is available at a discount to its list price and NHS England is promoting its initiation in primary care.9 I recommend prescribing it where possible. This can help patients avoid long waits to be seen in lipid clinics and the injection appears to decrease LDL cholesterol levels very quickly – something that can offer reassurance to patients. Also, studies have shown it is very well tolerated. The main side-effects are mild to moderate injection site reactions, so it does not require special precautions or monitoring.
Note, however, that inclisiran is only licensed in secondary prevention in patients whose LDL cholesterol is over 2.6mmol/l despite maximal tolerated statin therapy.10 It is thought the average practice will have roughly 46 eligible patients over the next three years.11 Also be aware there is a mechanism for ordering inclisiran to obtain the discounted price via a specific wholesaler.12 It is prescribed as a personally administered item. Your local academic health science network (AHSN) should be able to support you to offer inclisiran, as part of the national lipid optimisation programme.12
Evolocumab and alirocumab
• These monoclonal antibody PCSK9 inhibitors are also injectable therapies, given every two to four weeks. However, these are only prescribed in secondary care. They have been shown to reduce LDL cholesterol by over 50% and reduce CVD events, but eligibility criteria are stricter than for inclisiran (LDL cholesterol persistently above 3.5mmol/l and ‘very high risk for CVD’).
How should they be prescribed?
Patients who are unable to achieve a greater than 40% reduction in non-HDL cholesterol on maximal tolerated statin therapy, and who have been checked for adherence as well as timing of doses and diet and lifestyle modification, may be offered ezetimibe 10mg daily on top of maximum tolerated statin therapy.2 Alternatively, if a patient is confirmed to be statin intolerant or statins are contraindicated, they should be offered ezetimibe 10mg daily instead of a statin. If ezetimibe as monotherapy does not achieve control, the combination of ezetimibe 10mg and bempedoic acid 180mg daily can be tried. Patients who fail to achieve target cholesterol reductions can be referred to a lipid clinic.
Patients who do not achieve their target cholesterol after three months of adhering to high-intensity statin treatment should be considered for either additional ezetimibe 10mg daily, or addition of one of the injectable therapies (being mindful of the eligibility criteria). This is in addition to the maximally tolerated statin dose. The choice of the additional therapy should be made after making a shared decision with the patient.2
If the patient is confirmed as statin intolerant (including not being able to tolerate high-intensity statin), they should be offered ezetimibe 10mg daily, and if this does not achieve the desired cholesterol reduction, they can try the combination of ezetimibe 10mg and bempedoic acid 180mg. If they continue to miss their target, they can be considered for addition of one of the injectable therapies.
What’s no longer recommended?
NICE recommends we do not routinely offer fibrates, bile acid sequestrants or nicotinic acid for primary or secondary prevention. NICE also states we should not prescribe the above with a statin.
What’s on the horizon?
Results from clinical trials for bempedoic acid and inclisiran are due and the expectation is they will show reductions in CVD events.
A new therapy that is coming soon is icosapent ethyl, for use on top of a statin for secondary prevention in people with CVD who have well controlled cholesterol but remain at high risk due to raised triglycerides. NICE recently recommended GPs prescribe this on the NHS; it says some 425,000 patients might be offered the treatment.13 Icosapent ethyl is a form of the omega-3 fatty acid eicosopentaenoic acid, and results from one trial showed it produced a 4.8% reduction in absolute risk for CVD events in such patients.14
Another target for treatment is Lipoprotein(a), or Lp(a), which is an independent risk factor for CVD. Therapies that inhibit Lp(a) action are being developed and further trials will establish if these improve cardiovascular outcomes.15 Oral PCSK9 inhibitors are also in development and early trials have shown they are well tolerated and effective.16
Dr Paul Ferenc is a GP partner in Worcestershire, CVD clinical adviser for the West Midlands Academic Health Science Network and council member of the Primary Care Cardiovascular Society
Please note this article was updated on 29.09.22 to correct the indication for inclisiran use, which is in patients with LDL (not non-HDL) cholesterol above 2.6 mmol/L despite maximum tolerated statin use
- NICE. CG181 Cardiovascular disease: risk assessment and reduction, including lipid modification. 2014. Link
- NHS England. Summary of national guidance for lipid management. 2020. Link
- NHS England. Network Contract DES. Investment and Impact Fund 2022/23: Updated guidance. March 2022. Link
- Gagne C, Bays H, Weiss S et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolaemia. Am J Cardiol 2002; 90: 1,084-91
- Zhan S, Tang M, Fang L et al. Ezetemibe for the prevention of cardiovascular disease and all-cause mortality events. Cochrane Database Syst Rev 2018; CD012502
- Ballantyne C, Laufs U, Ray K et al. Bempedoic acid plus ezetemibe fixed-dose combination in patients with hypercholesterolaemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol 2020;27:593-603
- Ray K, Bays H, Catapano A et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019;380:1022-32
- Fernández-Ruiz I. Twice-yearly inclisiran injections halve LDL-cholesterol levels. Nat Rev Cardiol 2020;17:321
- Novartis. Inclisiran programme in England. 2022. Link
- BNF. Drugs. Link
- AHSN Guidance to support implementation of Inclisiran within the lipid management pathway 2021. Link
- The AHSN Network. Lipid management and familial hypercholesterolaemia. 2019. Link
- NICE. TA805. Icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides. 2022. Link
- Bhatt D, Steg G, Miller M et al for the REDUCE-IT investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriyglyceridemia. N Engl J Med 2019;380:11-22
- Yeang C, Karwatowska-Prokopczuk E, Su F et al. Effect of pelacarsen on Lipoprotein(a) cholesterol and corrected low-density lipoprotein cholesterol. J Am Coll Cardiol 2022;79: 1035-46
- American Heart Association. News release: Oral PCSK9 inhibitor found to be safe, effective to lower cholesterol in first human trial. 2021. Link