Overview of Lipid-Lowering Therapies and Emerging Treatments for Dyslipidemias Management

Dyslipidemias are common disorders in patients that significantly increase the risk of developing and worsening cardiovascular diseases. These conditions are marked by high levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C).

Conventional lipid-lowering therapies (LLTs) such as statins, ezetimibe, and PCSK9 inhibitors, combined with a healthy lifestyle, are essential for managing cholesterol levels. Statins work by inhibiting HMG-CoA reductase, thereby reducing cholesterol production in the liver. However, meta-analyses of various trials indicate that statins can have side effects, including muscle pain, liver dysfunction, and increased risk of diabetes, which may lead to therapy discontinuation. Ezetimibe is typically used alongside statins to further lower LDL cholesterol if targets are not met, as it reduces cholesterol absorption in the intestines. Despite the benefits of combined therapy, studies like GOULD have shown that only a small percentage of patients achieve recommended LDL targets after two years of treatment.

Moreover, the effectiveness of traditional LLTs can be hindered by genetic factors and metabolic processes that affect cholesterol metabolism. This highlights the need for further understanding of lipid metabolism to identify potential targets for new therapies. Several emerging drugs, including alirocumab, bempedoic acid, antisense oligonucleotides, angiopoietin-like protein (ANGPTL) inhibitors, apolipoprotein C3 (apoC3) inhibitors, lomitapide, and cholesteryl ester transfer protein (CETP) inhibitors, offer alternative mechanisms for lowering lipid levels.

Alirocumab: This monoclonal antibody increases the liver's uptake of LDL cholesterol by blocking PCSK9, leading to significant decreases in LDL levels. It is administered subcutaneously every two weeks and is indicated for patients on maximum statin doses or those with familial hypercholesterolemia.

Evolocumab: Similar to alirocumab, this antibody targets PCSK9 and is used in various forms of dyslipidemia. It has shown substantial LDL reductions and a favorable cardiovascular risk profile.

Bempedoic Acid: Approved in 2020, this pro-drug lowers LDL cholesterol by inhibiting ATP citrate lyase. It is well tolerated and does not affect muscle tissue, making it a safer option compared to statins.

Antisense Oligonucleotides (ASOs): These synthetic molecules target specific RNA to inhibit protein production involved in lipid metabolism, such as apolipoprotein(a), demonstrating significant reductions in lipid levels.

Angiopoietin-like Protein (ANGPTL) Inhibitors: Evinacumab, a monoclonal antibody targeting ANGPTL3, has shown promise in lowering triglycerides and LDL cholesterol, especially in patients with familial hypercholesterolemia.

Apolipoprotein C3 (apoC3) Inhibitors: These drugs, including volanesorsen and olezarsen, block the synthesis of apoC3, which regulates triglyceride metabolism, leading to substantial reductions in triglycerides and apoC3 levels.

Lomitapide: This drug inhibits the microsomal triglyceride transfer protein and has been shown to significantly lower LDL cholesterol levels, although it can cause gastrointestinal side effects.

Cholesteryl Ester Transfer Protein (CETP) Inhibitors: Although these drugs aim to increase HDL cholesterol while lowering LDL cholesterol, their effectiveness in reducing cardiovascular risk has been inconsistent, leading to concerns over safety.

In summary, while traditional LLTs are crucial for cholesterol management, the development of new drugs with diverse mechanisms of action provides additional options for patients who struggle to reach their lipid goals. Further research is necessary to fully understand long-term safety and effectiveness.

Source: Dybiec J, Baran W, Dąbek B, Fularski P, Młynarska E, Radzioch E, Rysz J, Franczyk B. Advances in Treatment of Dyslipidemia. Int J Mol Sci. 2023 Aug 27;24(17):13288. doi: 10.3390/ijms241713288. PMID: 37686091; PMCID: PMC10488025.