Emerging High-Density Lipoprotein-Targeted Therapies: Cholesteryl Ester Transfer Protein Inhibitors, Apolipoprotein A-I Mimetics

Dyslipidemia remains a major contributor to residual cardiovascular (CV) risk despite significant lowering of low-density lipoprotein cholesterol using statins, which reduce major adverse CV events by 20–30%. It is of utmost importance to know the real need gaps from the detection and management perspective. Conventional statin therapy often gets limited in complex dyslipidemias, statin tolerance and resistance-like scenarios. Emerging high-density lipoprotein (HDL)-targeted therapies, including cholesteryl ester transfer protein inhibitors (CETPis) and apolipoprotein A-I (ApoA-I) mimetics, aim to enhance HDL functionality rather than only raise HDL cholesterol levels. Major CETPi trials – ILLUMINATE (Torcetrapib), DAL-OUTCOMES (Dalcetrapib), and REVEAL (Anacetrapib) - highlighted safety concerns, lack of efficacy, or modest benefits. ApoA-I mimetics, such as CSL112 and synthetic peptides like D-4F, show promise in improving reverse cholesterol transport, reducing inflammation, and enhancing endothelial function. This in turn will have promising benefits in the management of dyslipidemias. They offer promising benefits over conventional management of dyslipidemias, which in turn leads to better therapeutic benefits and improved therapy adherence. Despite challenges, combination strategies with statins or proprotein convertase subtilisin/kexin type 9 inhibitors may offer synergistic benefits in high-risk populations. Ongoing trials like ApoA-1 Event Reducing in Ischemic Syndrome II Trial (AEGIS-II) may define future roles for these therapies in CV risk reduction. These therapies are promising for a certain cohort of patient profiles.