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Emerging High-Density Lipoprotein-Targeted Therapies: Cholesteryl Ester Transfer Protein Inhibitors, Apolipoprotein A-I Mimetics
*Corresponding author: Ritu Bhatia, Department of Cardiology, N.M.Wadia Institute of Cardiology, Pune, Maharashtra, India. ritudhawanbhatia@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Bhatia R, Dhawan V, Bhatia A, Gupta R, Gupta M. Emerging High-Density Lipoprotein-Targeted Therapies: Cholesteryl Ester Transfer Protein Inhibitors, Apolipoprotein A-I mimetics. Indian J Cardiovasc Dis Women. 2025;10:325-33. doi: 10.25259/IJCDW_50_2025
Abstract
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.
Keywords
Apolipoprotein A-I mimetics
Cholesteryl ester transfer protein inhibitors
High-density lipoprotein-targeted therapies
INTRODUCTION
Brief overview of high-density lipoprotein cholesterol (HDL-C) and its role in cardiovascular (CV) health
Dyslipidemias have emerged as prevalent disorders among patients across various age groups, causing significant risks for the development and progression of CV diseases along with various metabolic disorders, which are characterized by elevated levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C).
Dyslipidemia prevalence has increased over the last many years due to numerous factors, and it often happens to be the starting point of CV disease.[1]
This has led to increased CV and all-cause mortality and morbidity.
Dyslipidemia and their impact
Multifactorial etiology
Dyslipidemias arise from a complex interplay of genetic predisposition, lifestyle factors (like diet and physical inactivity), and comorbid conditions such as diabetes, obesity, and hypothyroidism. Table 1 highlights the risk factors for cardiovascular diseases and categorizes the patients for the need of intervention. The red colour depicting very high risk group and light green being the least.
| CV risk | Risk factors | Upper target level of plasma LDL-C cocn |
|---|---|---|
| Low | Score <1% | 3.0 mmol/L (116 mg/dL) |
| Moderate | Score 1–5% Young patients |
2.6 mmol/L (100 mg/dL) |
| High | Score >5% and <10% Markedly elevated RF BP - >180/110 HF without major risk factors Moderate CKD DM >10 years |
1.8 mmol/L (70 mg/dL) |
| Very high | Score >10% HF with ASCVD Severe CKD DM and EOD |
1.4 mmol/L (55 mg/dL) |
CV: Cardiovascular, DM: Diabetes Mellitus, HF: Heart Failure, CKD: Chronic kidney disease, BP: Blood Pressure, RF: Risk Factors. Red colour depicting the very high risk, yellow colour showing high risk, green moderate risk and light green colour depicting low risk category of cardiovascular risk
Atherogenic lipid profile
Beyond elevated TC, TGs, and LDL-C, dyslipidemia often includes reduced HDL-C, which further exacerbates CV risk due to impaired reverse cholesterol transport (RCT).
Subclinical progression
Dyslipidemias often remain asymptomatic for years, silently contributing to endothelial dysfunction, arterial plaque formation, and systemic inflammation, which are precursors to major CV events.
Age-independent risk
Although traditionally associated with middle-aged and older adults, dyslipidemias are increasingly being diagnosed in adolescents and young adults, largely due to rising rates of obesity and sedentary lifestyles.
Cardiometabolic link
Dyslipidemia is a central component of metabolic syndrome and is closely linked with insulin resistance, hypertension, and visceral adiposity, forming a vicious cycle that accelerates CV deterioration.
Global health burden
According to the WHO and other global health bodies, dyslipidemia contributes significantly to the global burden of ischemic heart disease and stroke, making it a priority target for preventive strategies.
Therapeutic challenges
Despite the availability of statins and other lipid-lowering agents, achieving optimal lipid control remains challenging due to issues such as statin intolerance, poor adherence, and residual CV risk.[1]
Emerging biomarkers
Novel lipid markers such as non-HDL-C, apolipoprotein B (ApoB), and lipoprotein (a) are gaining importance in risk stratification and guiding personalized therapy.
High-density lipoprotein (HDL) dysfunction
Recent research suggests that not just the quantity but the quality and functionality of HDL particles are crucial, with dysfunctional HDL contributing to pro-inflammatory and pro-atherogenic states.
HDL-C level is a vitally important therapeutic target. Clinical evidence from major cholesteryl ester transfer protein inhibitor (CETPi) RCTs (e.g., ILLUMINATE and DAL-OUTCOMES) and genetic studies (Mendelian randomization) demonstrates that raising HDL-C alone does not consistently translate into reduced CV events. This emphasizes the need to target the quality and function of HDL rather than its cholesterol content (quantity). The Cholesterol Efflux Capacity CEC measures HDL ‘s ability to extract cholesterol from cells especially macrophages and transport it away. Table 2 shows how different interventions like diet,exercise and drugs influence cholesterol efflux.
| Intervention | Impact on cholesterol efflux capacity |
|---|---|
| Diet | High |
| Vigorous exercise | High |
| Cholesteryl ester transfer protein inhibitors | High |
| Statins | Low |
| Low-density lipoprotein apheresis | No change/transient decrease/no effect on intrinsic high-density lipoprotein function |
| Novel therapeutics | High |
Public health implications
Early screening, lifestyle interventions, and public awareness campaigns are essential to curb the rising tide of dyslipidemia-related complications, especially in low- and middle-income countries.
Recently, for dyslipidemia, the use of ezetimibe, or a combination of statins with ezetimibe, has increased. The initial inertia of adding other molecules to statins has gone down and physicians are more and more focusing to improve the lipid profile of their patients. There are many other molecules introduced in the last decade like monoclonal antibodies binding with proprotein convertase subtilisin/kexin type 9 (PCSK9), such as alirocumab or inhibitors of adenosine triphosphate citrate lyase, like bempedoic acid.[2]
The other classes of molecules, such as antisense oligonucleotides, angiopoietin-like protein inhibitors, CETPis, microsomal TG transfer protein inhibitors such as lomitapide, or apolipoprotein C-III inhibitors, play an important role in improving dyslipidemia.
Limitations of HDL-C as a biomarker
Mendelian randomization studies (e.g., Voight; Lancet, 2012) show that genetically elevated HDL-C does not confer protection against acute coronary syndrome.[2]
This undermines the assumption that simply increasing HDL-C levels will reduce CV events.
CETPis (e.g., torcetrapib, dalcetrapib, and evacetrapib) raised HDL-C significantly but failed to reduce CV events in large trials. Table 3 highlights the key molecules of this group and the outcomes of several major clinical trials using CETPis. This suggests that HDL-C elevation alone is insufficient for clinical benefit.
| Torcetrapib | Failed due to off-target effects. |
|---|---|
| Dalcetrapib | Modest high-density lipoprotein increase, no CV benefit. |
| Anacetrapib | Improved lipid profile, modest CV benefit (REVEAL trial). |
| Evacetrapib | Discontinued due to lack of efficacy. |
CV: Cardiovascular
CETPis (e.g., torcetrapib, dalcetrapib, and anacetrapib) were designed to raise HDL-C and lower LDL-C as a synergistic effect.
The trials for these agents yielded inconsistent results: Torcetrapib was harmful due to off-target effects; dalcetrapib was safe but ineffective; and only anacetrapib demonstrated a modest CV benefit in the randomized evaluation of the effects of anacetrapib through lipid modification (REVEAL) trial. Table 4 shows the summary of all the major trials conducting on this group of medications and their outcomes.
| Trials | ILLUMINATE Trial (Torcetrapib) | DAL-OUTCOMES Trial (Dalcetrapib) | REVEAL Trial (Anacetrapib) |
|---|---|---|---|
| Drug | Torcetrapib+Atorvastatin versus Atorvastatin alone | Dalcetrapib versus placebo | Anacetrapib+statin versus statin alone |
| Population | ~15,000 | ~15,000 | ~30,000 |
| Outcome | Did not complete | No significant CV events | Modest reduction in major coronary events (10% relative risk reduction). |
| Keu issues | ~30% | ~100%; LDL-C reduction: ~17% | |
| Conclusion | Despite a 72% increase in HDL-C, torcetrapib was harmful. | Dalcetrapib was safe but ineffective in reducing CV risk. | Anacetrapib showed benefit but was not pursued commercially due to long half-life and tissue accumulation. |
HDL-C: High-density lipoprotein cholesterol, LDL-C: Low-density lipoprotein cholesterol, CV: Cardiovascular
This underscores that the pharmacological manipulation of lipid exchange may not fully restore or enhance the protective, functional properties of HDL and may have adverse effects.
Rationale for targeting HDL functionality rather than just levels
Although HDL-C levels have been linked to CV protection, they do not reliably reflect HDL’s biological functions such as cholesterol efflux, anti-inflammatory effects, or endothelial support. Therefore, targeting HDL functionality offers a more promising approach to reducing CV risk than simply raising HDL-C levels.[3]
HDL-C remains a standard marker of CV risk. Way from the classical report by Miller and Miller,[4] followed by confirmation in a Prospective Study,[5] lesser levels of HDL-C have been indicated as a significant factor in raising CV risk.
Robinson et al. showed an inverse relationship between HDL2 and coronary risk[6] while the Framingham group revealed the role of reduced HDL as a risk factor, particularly in women.[7] The inverse relation between HDL-C and coronary heart disease was reported in Japanese middle-aged men.[8]
Behavioral and therapeutic interventions affect cholesterol efflux capacity.
HDL BIOLOGY AND FUNCTION
HDL structure and subclasses and their roles
HDL is a heterogeneous group of particles composed of apolipoproteins A-I (ApoA-I) (primarily ApoA-I), phospholipids, cholesterol, and enzymes. Structurally, HDL exists in various sizes and densities, broadly classified into HDL2 (larger and less dense) and HDL3 (smaller and denser).
HDL is made of diverse proteins and lipids and is classified into different subclasses based on size, shape, density, and charge and can change dynamically in disease states.[9]
These subclasses differ in their cholesterol efflux capacity, antioxidant activity, and anti-inflammatory properties. HDL particles also contain enzymes such as paraoxonase-1 and lecithin-cholesterol acyltransferase (LCAT), which contribute to their protective functions. Importantly, the functionality of HDL particles – rather than their cholesterol content – is increasingly recognized as a key determinant of their atheroprotective potential.
RCT
RCT is a key protective mechanism by which excess cholesterol is removed from peripheral tissues, especially from macrophages in the arterial wall, and transported back to the liver for excretion. This process is primarily mediated by HDL particles, particularly those containing ApoA-I.
Major constituents of RCT include acceptors such as HDL and ApoA-I, and enzymes such as LCAT, phospholipid transfer protein, hepatic lipase, and cholesterol ester transfer protein (CETP).
RCT and cholesterol efflux play a major role in anti-atherogenesis, and modification of these processes may provide new therapeutic approaches to CV disease.[10]
CETPIS
Early CETPis torcetrapib, dalcetrapib, and evacetrapib did not demonstrate reduced risk of Atherosclerotic Cardiovascular Disease (ASCVD) in multiple Phase III clinical trials. The ILLUMINATE trial in 2007 was terminated as torcetrapib caused more death and CVD events;[11] at that time, the mechanisms were unknown.
Torcetrapib had structure-related off-target effects and caused increased blood pressure, as well as augmented aldosterone, cortisol, and endothelin-1 levels, in addition to profound changes in serum potassium and bicarbonate.[12,13] It also impaired endothelial function in hypertensive patients.[12,13] and significantly increased systolic and diastolic blood pressures.[14]
None of the CETPis developed later after torcetrapib had similar off-target side effects, and all have shown favorable safety profiles.[15-20]
However, as demonstrated by recent studies in animal models and human cohorts, there is a new focus on lowering the concentrations of LDL-C, non-HDL-C, and ApoB.
Mechanism of action
CETP’s role in lipid exchange between HDL and low-density lipoprotein (LDL)/Very LDL (VLDL).
CETP plays a central role in lipid metabolism by facilitating the exchange of cholesteryl esters and TGs between different lipoproteins.
Specifically, CETP transfers cholesteryl esters from HDL to apo B-containing lipoproteins such as LDL and VLDL, in exchange for triglycerides. This process reduces the cholesterol content of HDL and enriches it with TGs, which can impair HDL functionality [Figure 1].[21]
- Function of CETP in lipoprotein metabolism. (CETP: Cholesteryl ester transfer protein, CE: Chlesteryl ester, TG: Triglycerides: TRL- Triglyceride rich lipoproteins)
Thereby, CETP indirectly lowers HDL-C levels and contributes to the atherogenic lipid profile. Inhibiting CETP aims to preserve HDL-C, enhance RCT, and potentially reduce CV risk – though clinical outcomes have varied across CETPi trials. Figure 1 shows the role of CETP in lipoprotein metabolism.
CETP inhibition raises HDL-C and lowers LDL-C by blocking the normal lipid exchange process mediated by CETP. Under typical conditions, CETP facilitates the transfer of cholesteryl esters from HDL to LDL and VLDL, and in return, HDL receives TGs.
When CETP is inhibited
HDL retains more cholesteryl esters, leading to an increase in HDL-C levels.
LDL and VLDL receive fewer cholesteryl esters, which contributes to a reduction in LDL-C levels.
This dual effect – raising HDL-C and lowering LDL-C – is the therapeutic rationale behind CETPis, although clinical trials have shown that improving lipid profiles does not always translate into reduced CV events.[22]
Provides an overview of key CETP inhibitors that have undergone clinical evaluation over the past two decades. These molecules were developed with the aim of raising HDL cholesterol and improving cardiovascular outcomes. However, their clinical trajectories have varied significantly [Table 5].
| Class | CETP inhibitors | ApoA-I mimetics |
|---|---|---|
| MOA | Block the transfer of cholesteryl esters from HDL to LDL/VLDL, raising HDL-C and lowering LDL-C. | Replicate the functional properties of native ApoA-I, enhancing cholesterol efflux, reducing inflammation, and stabilizing plaques. |
| Efficacy | Modest cardiovascular benefit in the REVEAL trial, but others (torcetrapib, dalcetrapib) failed. | Are still under investigation, with promising early data on plaque stabilization and improved HDL function. |
| Safety | CETP inhibitors faced issues like off-target effects (e.g., torcetrapib increased blood pressure). | ApoA-I mimetics generally show good tolerability, though long-term safety data are still emerging. |
HDL: High-density lipoprotein, LDL: Low-density lipoprotein, VLDL: Very low-density lipoprotein, HDL-C: High-density lipoprotein cholesterol, LDL-C: Low-density lipoprotein cholesterol, ApoA-I: Apolipoprotein A-I, CETP: Cholesteryl ester transfer protein, MOA: Mechanism of action
Some agents, like torcetrapib, were discontinued early due to safety concerns unrelated to lipid modulation
Others, such as dalcetrapib and evacetrapib, failed to demonstrate meaningful CV benefit despite favorable changes in lipid profiles
Anacetrapib stood out by showing modest CV risk reduction in the REVEAL trial, although long-term safety concerns led to its withdrawal from further development.
Overall, these outcomes highlight the complexity of translating HDL-raising strategies into tangible clinical benefits, underscoring the need for more targeted and mechanistically sound approaches.
CLINICAL TRIALS AND OUTCOMES - SUMMARY OF MAJOR TRIALS (ILLUMINATE, DAL-OUTCOMES, REVEAL)
Table 4 describes various RCT data for landmark trials.
CURRENT STATUS AND FUTURE DIRECTIONS
Potential for combination therapy or niche indications.
Although CETPis have faced setbacks in large-scale trials, their ability to favorably modulate lipid profiles – by raising HDL-C and lowering LDL-C – continues to attract interest for combination therapy with agents such as statins, PCSK9 inhibitors, or ApoA-I mimetics. Such combinations may enhance RCT and address residual CV risk more effectively.
In addition, niche indications such as familial dyslipidemias, statin-intolerant patients, or post-ACS settings are being explored, where CETP inhibition may offer incremental benefit. Future directions include refining patient selection, improving safety profiles, and integrating HDL functionality assays to guide therapy.
ApoA-I MIMETICS
ApoA-I - ApoA-I, the main structural and functional protein of HDL, is essential for initiating RCT. It is composed of 243 amino acids arranged into 10 amphipathic α-helices. ApoA-I features both hydrophilic and hydrophobic surfaces that facilitate lipid binding. It is positively charged residues (Lys, Arg, His) and negatively charged ones (Asp, Glu) that contribute to its structural integrity and activity. These properties give ApoA-I a high affinity for lipids and enable it to significantly enhance cholesterol efflux from peripheral cells.[23]
ApoA-I mimetics (e.g., CSL112 and D-4F) represent a more direct functional approach, leveraging the key structural protein of HDL. They work on cholesterol efflux capacity from macrophages (the first step in RCT), reduce vascular inflammation, and improve endothelial function.
This mechanism offers a greater therapeutic benefit by addressing the core biological defects of dysfunctional HDL.
In addition, a later study indicated that when apo A-I and apo B are kept constant, very high levels of HDL-C and HDL particle sizes are associated with a marked increase in CV risk.[24]
Mechanism of action
ApoA-I’s role in RCT and HDL functionality
ApoA-I is the principal protein component of HDL and plays a central role in initiating RCT. It interacts with ABCA1 transporters on macrophages to promote cholesterol efflux, forming nascent HDL particles.[25,26] ApoA-I also activates LCAT, which esterifies free cholesterol, allowing HDL maturation and efficient transport to the liver through scavenger receptor B
Type 1 (SR-BI) receptors. Beyond RCT, ApoA-I contributes to HDL’s anti-inflammatory, antioxidant, and endothelial-protective functions, making it a key mediator of HDL’s atheroprotective effects.
Apo-A1 memetics have protective effects by enhance cholesterol efflux capacity. Enhancing cholesterol efflux capacity is a key goal of HDL-targeted therapies. It may also offer greater clinical benefit than CETPis by improving HDL function rather than just raising HDL-C. Table 5 summarizes the efficacy and safety of this class of molecule and compares it with CETP inhibitors.
Reduce vascular inflammation
ApoA-I, the main protein in HDL, plays a key role in suppressing vascular inflammation by below-mentioned mechanisms
Inhibiting endothelial adhesion molecule expression (Vascular Cell Adhesion Molecule-1 [VCAM-1], Intercllular Adhesion Molecule-1 [ICAM-1])
Reducing cytokine release (Tumor Necrosis Factor alpha [TNF-α], Interleukin-1 beta [IL-lβ], Interleukin-6 [IL-6])
Modulating toll like receptor 2 [TLR2] and Nuclear Factor Kappa light chain enhancer of activated B cells [NF-κB] signaling in macrophages and endothelial cells
Enhancing cholesterol efflux, which lowers lipid raft cholesterol and dampens inflammatory signaling.[27]
Lipid-free ApoA-I and reconstituted HDL (rHDL) formulations have shown below mentioned benefits –
~40–60% reduction in joint inflammation scores in animal models
Decreased leukocyte accumulation and systemic cytokine levels
Inhibition of TLR2/MyD88/NF-κB pathways in macrophages
Improve endothelial function.
Key Molecules – below are key molecules
ETC-216 (ApoA-I Milano) – early promise, halted development
CSL112 – human plasma-derived ApoA-I, ongoing trials
D-4F and L-4F – synthetic peptides with anti-inflammatory effect.
Challenges and opportunities - Potential synergy with statins or PCSK9 inhibitors
Rationale for combination of these two API is as below mentioned
PCSK9 inhibitors (e.g., evolocumab and alirocumab) dramatically lower LDL-C by enhancing LDL receptor recycling.
ApoA-I mimetics or reconstituted ApoA-I (e.g., CSL112) enhance HDL functionality, particularly cholesterol efflux, anti-inflammatory effects, and plaque stabilization.
Together, they target both ends of the lipid spectrum: LDL reduction and HDL optimization.
Potential benefits are as mentioned below
Table 6 shows the efficacy of these molecules against statins in reducing LDL cholesterol.
Improved outcomes in ACS: ApoA-I mimetics may stabilize vulnerable plaques, while PCSK9 inhibitors reduce recurrent events.
Enhanced vascular repair: ApoA-I supports endothelial health, complementing PCSK9’s anti-atherogenic effects.
| Agent | LDL-C reduction versus statin (%) |
|---|---|
| Ezetimibe | 20–25 |
| Bempedoic acid | 45–55 |
| Evolocumab, alirocumab | 50–60 |
| Inclisiran | 50 |
LDL-C: Low-density lipoprotein cholesterol
Future directions
Given the persistent residual CV risk despite optimal LDL-C lowering, the future of HDL-targeted therapy lies in combination strategies. Combining ApoA-I mimetics with lipid-lowering agents like statins or PCSK9 inhibitors is proposed to offer better therapeutic benefits, targeting both parameters – the reduction of atherogenic lipoproteins (LDL-C) and the enhancement of atheroprotective functions (HDL functionality). Ongoing trials like AEGIS-II are critical for defining the clinical role of this paradigm shift.
Ongoing trials like AEGIS-II (CSL112) may pave the way for combination studies
Potential use in high-risk populations: familial hypercholesterolemia, diabetes, post-ACS with low HDL function
Development of fixed-dose combinations or sequential therapy protocols.
COMPARATIVE ANALYSIS AND FUTURE OUTLOOK
Shift from HDL-C quantity to HDL functionality
Traditional focus on HDL-C levels has proven insufficient for predicting CV outcomes. Recent research emphasizes HDL functionality – including cholesterol efflux capacity, anti-inflammatory effects, and endothelial protection – as more relevant markers of atheroprotection. This shift has led to the development of therapies that enhance HDL performance, rather than just increase its cholesterol content.
New guidelines with thresholds and targets
The results of these studies further validate the fact that lowering LDL-C is fundamental to preventing ASCVD events. Based on these findings, the 2019 European Society of Cardiology and European Atherosclerosis Society guidelines defined new LDL-C targets according to patient risk; for very-high-risk patients, the LDL-C target is <55 mg/dL.[28-31]
The 2018 American Heart Association/American College of Cardiology guidelines recommend adding non-statin agents to statin in very-high-risk ASCVD patients with LDL-C ≥70 mg/dL.[32]
CETPis, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and CV risk reduction.[22]
In addition to inhibitors, active immunization (vaccination) is a promising treatment for atherosclerosis. The CETP vaccine targets lipid metabolism, focusing on cholesterol transport regulation.[33-38]
CONCLUSION
HDL-C as a biomarker has limitations, and the focus is shifting toward enhancing HDL functionality rather than simply raising HDL-C levels. CETPis has shown promise in modulating lipid profiles, but their clinical efficacy has been inconsistent, with only anacetrapib demonstrating modest CV benefit.
ApoA-I mimetics, particularly CSL112, offer a novel approach by directly improving HDL’s biological functions such as cholesterol efflux and anti-inflammatory activity, with encouraging early-phase data.
The failure of CETPis in some trials underscores the need for therapies that target HDL quality over quantity. Combination strategies, such as pairing ApoA-I mimetics with statins or PCSK9 inhibitors, may offer synergistic benefits in managing residual CV risk.
Future research should focus on standardizing HDL functionality assays, identifying ideal patient populations, and exploring long-term outcomes of HDL-targeted therapies. HDL-targeted therapies represent a paradigm shift in CV prevention, moving beyond LDL-centric approaches to a more comprehensive lipid and inflammation management strategy. Reducing lifetime exposure to LDL-C has been demonstrated to lower the risk for ASCVD. Combination therapy with statin and a non-statin LDL-C–lowering agent has been shown to be safe and effective for lowering LDL-C and CV risk reduction in clinical outcome trials.
Increasing statin dose is less effective than adding a second agent to lower LDL-C levels; several options are available to personalize therapy (ezetimibe, evolocumab, alirocumab, bempedoic acid, and inclisiran).
Along with increasing dosage of statin, there comes a challenge for certain patient profiles like patients with multiple co-morbidities or statin-dosage tolerance.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
References
- Global Epidemiology of Dyslipidaemias. Nat Rev Cardiol. 2021;18:689-700.
- [CrossRef] [PubMed] [Google Scholar]
- Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomization study. Lancet. 2012;380:564.
- [CrossRef] [PubMed] [Google Scholar]
- High-Density Lipoprotein (HDL) Functionality and its Relevance to Atherosclerotic Cardiovascular Disease. Drugs Context. 2018;7:212525.
- [CrossRef] [PubMed] [Google Scholar]
- Plasma-High-Density-Lipoprotein Concentration and Development of Ischaemic Heart-Disease. Lancet. 1975;1:16-9.
- [CrossRef] [PubMed] [Google Scholar]
- High-Density Lipoprotein and Coronary Heart-Disease: A Prospective Case-Control Study. Lancet. 1977;1:965-8.
- [CrossRef] [PubMed] [Google Scholar]
- High Density Lipoprotein Subfractions and Coronary Risk Factors in Normal Men. Arteriosclerosis. 1987;7:341-6.
- [CrossRef] [PubMed] [Google Scholar]
- High Density Lipoprotein Cholesterol, Total Cholesterol Screening, and Myocardial Infarction. The Framingham Study. Arteriosclerosis. 1988;8:207-11.
- [CrossRef] [PubMed] [Google Scholar]
- High-Density Lipoprotein Cholesterol and Premature Coronary Heart Disease in Urban Japanese Men. Circulation. 1994;89:2533-9.
- [CrossRef] [PubMed] [Google Scholar]
- High-Density Lipoprotein Subclasses and their Role in the Prevention and Treatment of Cardiovascular Disease: A Narrative Review. Int J Mol Sci. 2024;25:7856.
- [CrossRef] [PubMed] [Google Scholar]
- Reverse Cholesterol Transport and Cholesterol Efflux in Atherosclerosis. QJM. 2005;98:845-56.
- [CrossRef] [PubMed] [Google Scholar]
- Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med. 2007;357:2109-22.
- [CrossRef] [PubMed] [Google Scholar]
- Torcetrapib Impairs Endothelial Function in Hypertension. Eur Heart J. 2012;33:1615-24.
- [CrossRef] [PubMed] [Google Scholar]
- Onand Off-Target Pharmacology of Torcetrapib: Current Understanding and Implications for the Structure Activity Relationships (SAR), Discovery and Development of Cholesteryl Ester-Transfer Protein (CETP) Inhibitors. Drugs. 2012;72:491-507.
- [CrossRef] [PubMed] [Google Scholar]
- Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans: A Randomized Phase II Dose-Response Study. Circulation. 2002;105:2159-65.
- [CrossRef] [PubMed] [Google Scholar]
- Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N Engl J Med. 2017;377:1217-27.
- [CrossRef] [PubMed] [Google Scholar]
- Long-Term Safety and Efficacy of Anacetrapib in Patients with Atherosclerotic Vascular Disease. Eur Heart J. 2022;43:1416-24.
- [CrossRef] [PubMed] [Google Scholar]
- Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease. N Engl J Med. 2017;376:1933-42.
- [CrossRef] [PubMed] [Google Scholar]
- Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med. 2012;367:2089-99.
- [CrossRef] [PubMed] [Google Scholar]
- Obicetrapib Plus Ezetimibe as an Adjunct to High-Intensity Statin Therapy: A Randomized Phase 2 Trial. J Clin Lipidol. 2023;17:491-503.
- [CrossRef] [PubMed] [Google Scholar]
- Tolerability Pharmacokinetics and Pharmacodynamics of TA-8995, a Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Subjects. Br J Clin Pharmacol. 2014;78:498-508.
- [CrossRef] [PubMed] [Google Scholar]
- The Lipid Transfer Properties of CETP Define the Concentration and Composition of Plasma Lipoproteins. J Lipid Res. 2020;61:1168-79.
- [CrossRef] [PubMed] [Google Scholar]
- Comparative Effectiveness of Cholesteryl Ester Transfer Protein (CETP) Inhibitors on Lipid Profiles in Adults with Hyperlipidemia: A Comprehensive Systematic Review and Frequentist Network Meta-Analysis of Randomized Controlled Trials. Clin Cardiol. 2025;48:e70204.
- [CrossRef] [PubMed] [Google Scholar]
- Structural Properties of Apolipoprotein A-I Mimetic Peptides that Promote ABCA1-Dependent Cholesterol Efflux. Sci Rep. 2018;8:2956.
- [CrossRef] [PubMed] [Google Scholar]
- High-Density Lipoprotein Cholesterol, High-Density Lipoprotein Particle Size, and Apolipoprotein A-I: Significance for Cardiovascular Risk: The IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol. 2008;51:634-42.
- [CrossRef] [PubMed] [Google Scholar]
- The Amphipathic Helix in the Exchangeable Apolipoproteins: A Review of Secondary Structure and Function. J Lipid Res. 1992;33:141-66.
- [CrossRef] [PubMed] [Google Scholar]
- A New Generation of Ca2+ Indicators with Greatly Improved Fluorescence Properties. J Biol Chem. 1985;260:10248-55.
- [CrossRef] [Google Scholar]
- APOA1: A Protein with Multiple Therapeutic Functions. Curr Atheroscler Rep. 2021;23:11.
- [CrossRef] [PubMed] [Google Scholar]
- Combination Lipid-Lowering Therapy as First-Line Strategy in Very High-Risk Patients. Eur Heart J. 2022;43:830-33.
- [CrossRef] [PubMed] [Google Scholar]
- Highest Risk-Highest Benefit' Strategy: A Pragmatic, Cost-Effective Approach to Targeting Use of PCSK9 Inhibitor Therapies. Eur Heart J. 2018;39:2546-50.
- [CrossRef] [PubMed] [Google Scholar]
- EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care: The DA VINCI Study. Eur J Prev Cardiol. 2021;28:1279-89.
- [CrossRef] [PubMed] [Google Scholar]
- Treatment Patterns and Low-Density Lipoprotein Cholesterol (LDL-c) Goal Attainment among Patients Receiving High-or Moderate-Intensity Statins. Clin Res Cardiol. 2018;107:380-8.
- [CrossRef] [PubMed] [Google Scholar]
- Characteristics of Lipid Profile and Effectiveness of Management of Dyslipidaemia in Patients with Acute Coronary Syndromes-Data from the TERCET Registry with 19,287 Patients. Pharmacol Res. 2019;139:460-46.
- [CrossRef] [PubMed] [Google Scholar]
- Recent Advances in Immunotherapy Targeting CETP Proteins for Atherosclerosis Prevention. Hum Vaccin Immunother. 2025;21:2462466.
- [CrossRef] [PubMed] [Google Scholar]
- Long-Term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol: A Prespecified Analysis of the IMPROVE-IT Trial. JAMA Cardiol. 2017;2:547-55.
- [CrossRef] [PubMed] [Google Scholar]
- Bempedoic Acid Plus Ezetimibe Fixed-Dose Combination in Patients with Hypercholesterolemia and High CVD Risk Treated with Maximally Tolerated Statin Therapy. Eur J Prev Cardiol. 2020;27:593-603.
- [CrossRef] [PubMed] [Google Scholar]
- Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376:1713-22.
- [CrossRef] [PubMed] [Google Scholar]
- Alirocumab and Cardiovascular Outcomes After Acute Coronary Syndrome. N Engl J Med. 2018;379:2097-107.
- [CrossRef] [PubMed] [Google Scholar]
- Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382:1507-19.
- [CrossRef] [PubMed] [Google Scholar]