While statins remain the cornerstone of cholesterol management, a significant proportion of patients either experience adverse effects or do not reach their cholesterol targets with statins alone. In these cases, European healthcare providers turn to a range of non-statin therapies, which employ different mechanisms to lower harmful LDL-C. These advanced medications represent a move toward more personalized medicine, offering alternative or complementary approaches to manage hypercholesterolaemia.
Ezetimibe: The Oral Cholesterol Absorption Inhibitor
Ezetimibe is an oral medication taken once daily that works by blocking the absorption of dietary and biliary cholesterol in the small intestine. By inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) protein, it forces the liver to use more cholesterol from the bloodstream, thereby lowering overall blood cholesterol levels.
Ezetimibe is a key component of European guidelines for dyslipidaemia. It can be prescribed as a monotherapy for patients who cannot tolerate statins, or as an adjunct therapy alongside statins to achieve lower LDL-C levels. When used alone, it can lower LDL-C by 15-22%. In combination with a statin, it provides an additional 13-25% reduction. Ezetimibe is generally well-tolerated, with side effects that can include headache and gastrointestinal issues.
Bempedoic Acid: Targeting Liver Cholesterol Production
Bempedoic acid (brand name Nilemdo in Europe) is another oral therapy that specifically reduces cholesterol synthesis in the liver. It works by inhibiting adenosine triphosphate citrate lyase (ACLY), an enzyme in the cholesterol pathway that operates upstream of the statin target. A key advantage of bempedoic acid is that it is a prodrug, activated only in the liver, which prevents the muscle-related side effects often associated with statins.
The European Medicines Agency approved bempedoic acid in 2020 for patients with primary hypercholesterolaemia or mixed dyslipidaemia. It is used alone in statin-intolerant patients or in combination with ezetimibe, with or without a maximally tolerated statin dose. Monotherapy can lower LDL-C by 17-28%, and when combined with ezetimibe, the reduction can be up to 50%. The landmark CLEAR Outcomes trial showed that bempedoic acid significantly reduced major cardiovascular events in statin-intolerant patients.
PCSK9 Inhibitors: Powerful Injectable Monoclonal Antibodies
PCSK9 inhibitors are a class of injectable medications that offer a potent option for reducing cholesterol. Evolocumab (Repatha) and Alirocumab (Praluent) are two monoclonal antibodies available in Europe. They work by binding to the PCSK9 protein, which typically degrades LDL receptors on liver cells. By blocking this protein, PCSK9 inhibitors dramatically increase the liver's ability to clear LDL-C from the blood.
Prescribed for patients at very high cardiovascular risk who do not achieve their LDL-C goals despite maximally tolerated statin and ezetimibe therapy, these medications are administered via a subcutaneous injection every two to four weeks. PCSK9 inhibitors can lower LDL-C by an impressive 50-70% when used alongside statins, providing a powerful tool for aggressive lipid-lowering.
Inclisiran: A Twice-Yearly RNA Therapy
Inclisiran (Leqvio) is a first-in-class small interfering RNA (siRNA) therapy approved for use in Europe. It provides a sustained and long-lasting reduction in LDL-C by inhibiting the synthesis of the PCSK9 protein at the genetic level. This prevents PCSK9 production, allowing LDL receptors to remain on the liver cell surface for a longer period, resulting in greater LDL-C clearance.
Administered as an injection only twice a year after an initial dose, inclisiran offers a major benefit in terms of adherence. It is recommended for high-risk patients with high cholesterol despite statin therapy or who are statin-intolerant. Trials have shown inclisiran can reduce LDL-C by around 50%.
Comparison of Non-Statin Cholesterol Therapies in Europe
| Feature | Ezetimibe | Bempedoic Acid (Nilemdo) | PCSK9 Inhibitors (e.g., Repatha) | Inclisiran (Leqvio) |
|---|---|---|---|---|
| Mechanism | Inhibits cholesterol absorption in the intestine. | Inhibits ATP citrate lyase (ACLY) in the liver to reduce cholesterol synthesis. | Monoclonal antibodies that inactivate the PCSK9 protein. | siRNA therapy that prevents PCSK9 protein production. |
| Administration | Oral tablet, once daily. | Oral tablet, once daily. | Subcutaneous injection every 2-4 weeks. | Subcutaneous injection, twice yearly (after initial dose). |
| LDL-C Reduction | 15-22% (monotherapy). | 17-28% (monotherapy). | Up to 60-70% (adjunct to statins). | Up to 50% (adjunct to statins). |
| Key Indication | Statin intolerance, adjunct therapy. | Statin intolerance, adjunct therapy. | High-risk patients not at goal with statins + ezetimibe. | High-risk patients not at goal with statins or statin-intolerant. |
| Compliance Factor | Daily oral pill requires consistent adherence. | Daily oral pill requires consistent adherence. | Requires self-injection or clinic visit multiple times a month. | Requires only twice-yearly clinic visit for injections. |
| Side Effects | Headache, GI upset. | Gout, hyperuricaemia, renal injury. | Injection site reactions, flu-like symptoms. | Injection site reactions. |
Lifestyle and Other Considerations
Alongside pharmacological interventions, lifestyle modifications are an essential part of cholesterol management in Europe, as they are elsewhere. A healthy diet low in saturated fats and regular physical activity are fundamental to treatment, regardless of medication. European guidelines also emphasize the importance of dietary supplements like plant sterols, which have some data to support their modest LDL-C-lowering effects. Less commonly used for LDL-C are older drugs like bile acid sequestrants and fibrates, which have been largely superseded by newer, more effective options with better safety profiles.
Conclusion
Europe offers a diverse and evolving set of therapeutic options for managing high cholesterol beyond statins. The arsenal of non-statin medications—including oral ezetimibe and bempedoic acid, as well as the potent PCSK9 inhibitors and innovative inclisiran—reflects a modern, multi-faceted approach to cardiovascular risk reduction. These drugs are prescribed based on patient-specific needs, particularly for those with statin intolerance or for very-high-risk individuals who need to achieve very low LDL-C targets. This provides a broader pathway to meeting cholesterol goals, ensuring more patients receive effective treatment and ultimately lowering the risk of heart attacks and strokes.
