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Atherosclerosis; Cardiovascular disease; PCSK9 inhibitors; Anti-inflammatory agents; Lipid-lowering therapies; Bempedoic acid; Monoclonal antibodies; RNA-based therapies; Plaque stabilization; Combination therapies; Personalized medicine

Introduction

Atherosclerosis is a chronic, progressive disease that remains a leading cause of morbidity and mortality worldwide due to its critical role in the development of cardiovascular diseases such as heart attacks, strokes, and peripheral arterial disease. Traditionally, management strategies have focused on lifestyle interventions and the use of statins to lower low-density lipoprotein cholesterol (LDL-C) levels. While these approaches have proven beneficial in reducing cardiovascular risk, residual risk remains high for many patients, prompting the need for innovative pharmacological solutions. This article reviews emerging drug therapies designed to target atherosclerosis more comprehensively, addressing lipid accumulation, inflammation, and plaque stability [1].

Traditional therapies and their limitations

Statins, a cornerstone in the management of atherosclerosis, have been highly effective in lowering LDL-C and reducing the incidence of cardiovascular events. However, many patients fail to achieve optimal LDL-C levels or suffer adverse effects such as statin intolerance, necessitating alternative therapies. Moreover, atherosclerosis is a multifactorial disease influenced by inflammatory processes, lipid metabolism, and genetic predispositions, which cannot be adequately controlled through lipid-lowering alone. These limitations have driven research into newer pharmacological agents capable of providing broader and more potent effects in preventing disease progression.

Innovative drug therapies for atherosclerosis

PCSK9 Inhibitors Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab and evolocumab, represent a major advancement in lipid-lowering therapy. These monoclonal antibodies target the PCSK9 protein, preventing it from degrading LDL receptors in the liver, thus enhancing LDL clearance from the bloodstream. Clinical trials such as FOURIER and ODYSSEY have demonstrated that PCSK9 inhibitors significantly reduce LDL-C levels by up to 60%, offering an effective option for patients who cannot tolerate statins or require additional lipid-lowering beyond what statins can provide. Importantly, these therapies have also been shown to reduce the risk of major cardiovascular events [2].

Bempedoic Acid Bempedoic acid is an oral ATP citrate lyase inhibitor that provides another alternative to statins for lowering LDL-C. By inhibiting cholesterol biosynthesis upstream of the statin target, it reduces LDL-C without the muscle-related side effects associated with statins. The CLEAR Outcomes trial demonstrated that bempedoic acid effectively reduces LDL-C levels and offers cardiovascular protection, making it particularly beneficial for statin-intolerant patients.

Inclisiran Inclisiran is a small interfering RNA (siRNA) therapy that lowers LDL-C by targeting PCSK9 production at the gene expression level. Administered biannually, inclisiran provides long-term, sustained reductions in LDL-C, offering a convenient and potent option for managing hypercholesterolemia. Clinical studies, such as ORION-4, have shown that inclisiran significantly reduces LDL-C levels and has the potential to reduce cardiovascular events with minimal dosing frequency, which may improve patient adherence.

Anti-inflammatory Therapies Inflammation plays a pivotal role in atherosclerosis progression, contributing to plaque instability and rupture. The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) demonstrated that targeting inflammation independent of cholesterol levels could reduce cardiovascular risk. Canakinumab, a monoclonal antibody targeting interleukin-1β (IL-1β), significantly reduced recurrent cardiovascular events in patients with previous heart attacks. This finding opened new avenues for exploring anti-inflammatory therapies, such as colchicine and methotrexate, which are currently under investigation for their role in reducing atherosclerotic inflammation and improving cardiovascular outcomes [3].

Lipid-Lowering Therapies Beyond LDL-C In addition to targeting LDL-C, therapies that address other lipid components, such as high-density lipoprotein (HDL) and triglycerides, have shown promise. Agents like pemafibrate, which selectively modulates peroxisome proliferator-activated receptor α (PPARα), are designed to reduce triglyceride levels and enhance cardiovascular protection. Similarly, therapies targeting lipoprotein(a), an independent risk factor for cardiovascular disease, such as antisense oligonucleotides like pelacarsen, are being explored to address residual cardiovascular risk in patients with elevated levels of lipoprotein(a).

RNA-Based Therapies RNA-based therapies, including siRNA and antisense oligonucleotides, offer novel approaches to treating atherosclerosis at the genetic level. Inclisiran’s success highlights the potential for these therapies to provide long-lasting and potent effects with fewer doses, enhancing compliance. Beyond inclisiran, gene-editing technologies such as CRISPR are being investigated for their potential to provide permanent therapeutic solutions by targeting and modifying the genes involved in lipid metabolism and inflammation.

Combination therapies

Given the complex nature of atherosclerosis, a combination approach targeting multiple pathways may provide the most comprehensive protection against disease progression. Combining lipid-lowering therapies like statins or PCSK9 inhibitors with anti-inflammatory agents or drugs targeting other lipid components could address both the cholesterol-driven and inflammatory aspects of atherosclerosis. Ongoing trials are exploring these combinations, with early results showing promise in reducing cardiovascular events in high-risk populations [4].

Challenges and future directions

Despite the promise of these innovative therapies, several challenges remain in their clinical implementation. The high cost of novel agents like PCSK9 inhibitors and inclisiran can limit access for many patients, raising concerns about cost-effectiveness in routine practice. Additionally, long-term safety data is still needed for many of these therapies, particularly those targeting inflammation, to ensure their benefits outweigh potential risks. Finally, patient adherence to treatment regimens, especially those requiring frequent dosing, remains a key barrier to the success of these therapies in real-world settings.

Looking ahead, personalized medicine approaches, informed by genetic and biomarker testing, may optimize treatment selection and improve outcomes by tailoring therapy to individual patient profiles. As research continues to uncover the underlying mechanisms driving atherosclerosis, the development of even more targeted therapies will likely emerge, offering new hope for patients at risk of cardiovascular disease. Innovative pharmacological approaches to atherosclerosis are transforming the landscape of cardiovascular disease management. With the advent of PCSK9 inhibitors, RNA-based therapies, and anti-inflammatory agents, patients now have access to more targeted and potent treatment options [5]. While challenges such as cost, long-term safety, and patient adherence remain, ongoing research and clinical trials continue to refine these therapies, potentially ushering in a new era of atherosclerosis treatment. By addressing both lipid and inflammatory pathways, these emerging treatments offer the promise of reducing residual cardiovascular risk and improving long-term outcomes for patients with atherosclerosis.

Results and Discussion

Results

Emerging pharmacological therapies for atherosclerosis demonstrate significant advancements over traditional treatments, with promising outcomes in lipid-lowering, inflammation control, and cardiovascular event reduction. Below are key findings from major clinical trials:

PCSK9 Inhibitors Clinical trials like FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) and ODYSSEY (Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab) have shown that PCSK9 inhibitors reduce LDL-C levels by up to 60%, significantly outperforming standard statin therapy. Additionally, these trials reported a 15-20% reduction in major adverse cardiovascular events, including heart attacks and strokes, highlighting their potential in high-risk populations.

Bempedoic Acid The CLEAR Outcomes study reported that bempedoic acid, when used in statin-intolerant patients, lowered LDL-C levels by approximately 17-28%. Cardiovascular outcomes in patients treated with bempedoic acid also showed improved risk reduction, making it a viable alternative for individuals who cannot tolerate statins. Moreover, it demonstrated minimal adverse effects compared to statins, particularly regarding muscle-related side effects [6].

Inclisiran The ORION trials established inclisiran as a highly effective agent in maintaining long-term LDL-C reductions of 50-55%. This biannual injection also improved patient adherence due to its less frequent dosing regimen. While LDL-C reduction was similar to that achieved with PCSK9 inhibitors, inclisiran’s unique siRNA mechanism introduces the potential for sustained, durable effects with fewer interventions.

Anti-inflammatory Therapies The CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) provided groundbreaking evidence that anti-inflammatory therapy could reduce cardiovascular risk independently of LDL-C lowering. Canakinumab reduced cardiovascular events by 15% in patients with elevated inflammation, indicating that targeting inflammation represents a critical step in mitigating atherosclerotic progression. However, the therapy was associated with an increased risk of infection, raising concerns about its widespread use.

Combination Therapies Combining PCSK9 inhibitors with statins or anti-inflammatory agents, as examined in ongoing studies, appears to provide additive benefits. For example, patients treated with both PCSK9 inhibitors and anti-inflammatory agents demonstrated further reductions in cardiovascular events compared to monotherapy. Combination therapies targeting both lipid and inflammatory pathways may become a key strategy for managing high-risk atherosclerotic patients [7].

Discussion

The results of these studies mark a pivotal shift in the pharmacological management of atherosclerosis. The success of PCSK9 inhibitors, bempedoic acid, inclisiran, and anti-inflammatory agents offers patients new, more effective options for reducing LDL-C levels and combating the inflammatory processes that drive atherosclerosis progression. These therapies have particular relevance for patients who cannot tolerate statins or do not achieve adequate results from existing therapies, addressing gaps in traditional treatments.

PCSK9 Inhibitors and Bempedoic Acid: Expanding the Lipid-Lowering Toolbox PCSK9 inhibitors and bempedoic acid provide alternatives or adjuncts to statins, offering significant LDL-C reductions with favorable safety profiles. PCSK9 inhibitors, though potent, come at a high cost, limiting accessibility for many patients. Bempedoic acid, a less expensive oral option, offers a middle ground for those who cannot tolerate statins but still require LDL-C management. These treatments can be integrated into the standard of care for patients who need more aggressive lipid-lowering beyond what statins can achieve [8].

Inclisiran: Long-Term Compliance and Convenience Inclisiran’s biannual dosing could be a game-changer in improving patient compliance, a major challenge in long-term atherosclerosis management. Its sustained efficacy over time reduces the need for frequent interventions, potentially improving adherence and outcomes. However, further studies are needed to confirm long-term safety, particularly in diverse populations.

Anti-inflammatory Therapies: Targeting the Inflammatory Pathway The discovery that inflammation plays a key role in atherosclerosis opens new therapeutic targets, as seen in the CANTOS trial. While canakinumab reduced cardiovascular events, it introduced new safety concerns, particularly infections, raising questions about its long-term viability. However, therapies such as colchicine, with fewer adverse effects, are under investigation and may provide a safer option. Incorporating anti-inflammatory treatments alongside lipid-lowering agents could create a more holistic approach to managing cardiovascular risk.

Combination Therapies: A Multidimensional Strategy Combination therapies, such as pairing PCSK9 inhibitors with anti-inflammatory agents or statins, appear to enhance efficacy by addressing multiple pathways in atherosclerosis. This multidimensional approach targets lipid accumulation, inflammation, and plaque stability, offering a more robust solution for high-risk patients. However, the challenge lies in balancing the cost and complexity of managing multiple drug regimens, which could lead to issues with patient adherence and healthcare resource allocation.

Challenges and Considerations Despite these promising developments, several hurdles remain. The high cost of novel therapies like PCSK9 inhibitors and inclisiran may restrict their use in broader populations, particularly in resource-limited settings. Addressing the cost-effectiveness of these treatments is crucial to ensure equitable access. Additionally, while short-term results are promising, long-term safety data is still required to confirm the sustainability of these novel interventions. Patient adherence, a well-known issue in cardiovascular care, must be addressed, particularly when dealing with combination therapies or treatments requiring frequent administration.

Future Directions The integration of personalized medicine based on genetic and biomarker profiling may optimize therapy selection, ensuring that treatments are tailored to individual patients’ risk profiles. The development of more accessible, less invasive therapies, such as oral or RNA-based treatments, could further expand the therapeutic landscape. Future research will likely focus on fine-tuning combination therapies, exploring gene-editing approaches like CRISPR, and understanding the full scope of the inflammatory processes that underpin atherosclerosis.

Conclusion

The evolution of pharmacological strategies for atherosclerosis represents a new frontier in cardiovascular disease management. As innovative therapies emerge, including PCSK9 inhibitors, RNA-based drugs, and anti-inflammatory agents, they offer greater efficacy and improved outcomes for patients with high cardiovascular risk. However, ensuring accessibility, managing long-term safety, and addressing patient adherence remain critical to maximizing the benefits of these therapies. Combination treatments targeting both lipid levels and inflammation may hold the key to reducing the global burden of cardiovascular disease, but cost-effective, patient-centered strategies will be essential for successful integration into clinical practice.

Acknowledgment

None

Conflict of Interest

None

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