Beyond Statins: Are We Entering a New Era of Lipid Management?

Abstract

Statins have been the mainstay of lipid-lowering therapy for decades, dramatically reducing cardiovascular events. However, many patients fail to reach optimal LDL-C levels on statin monotherapy, experience statin-associated muscle symptoms (SAMS), or are intolerant to statins altogether. This has driven the development of novel lipid-lowering therapies, including bempedoic acid, inclisiran, and other emerging agents. This article discusses these innovative approaches, detailing their mechanisms of action, summarizing key clinical trial data, and discussing their potential role in contemporary clinical practice, marking a potential shift into a new era of lipid management.  

Introduction

Elevated low-density lipoprotein cholesterol (LDL-C) is a well-established modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD), which remains a leading cause of morbidity and mortality worldwide. For decades, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), commonly known as statins, have been the cornerstone of lipid-lowering therapy, successfully lowering LDL-C levels and markedly reducing the risk of cardiovascular events. Nevertheless, despite the demonstrated efficacy of statins, several challenges persist in attaining optimal LDL-C lowering with statin therapy alone. Despite maximally tolerated statin therapy, a considerable proportion of patients fail to reach their target levels of LDL-C. In addition, statin-associated muscle symptoms, from myalgia to rhabdomyolysis, can curtail the use of statins or even cause a patient to discontinue them altogether. These caveats have made necessary the development of new, additional lipid-lowering therapies-a new era of lipid management on the horizon. These therapies will be examined, with a focus on bempedoic acid, inclisiran, and a few other exciting agents, covering their mechanisms of action, their clinical trial data, and where they might go in clinical practice.  

Literature Review

The literature on lipid management is extensive, with decades of research supporting the efficacy of statins. However, recent research has focused on the limitations of statins and the potential of new therapies.  

• Statins: Landmark clinical trials, such as the Cholesterol Treatment Trialists' (CTT) meta-analyses, have consistently demonstrated the benefits of statins in reducing cardiovascular events across a wide range of patient populations. However, studies have also highlighted the prevalence of SAMS, which can affect adherence and limit the intensity of statin therapy.  

• Ezetimibe: Ezetimibe, a selective cholesterol absorption inhibitor, works by blocking the Niemann-Pick C1-Like 1 (NPC1L1) protein in the small intestine, reducing cholesterol absorption. Studies have shown that adding ezetimibe to statin therapy can further reduce LDL-C levels and improve cardiovascular outcomes.  

• PCSK9 Inhibitors: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as evolocumab and alirocumab, are monoclonal antibodies that inhibit PCSK9, a protein that degrades LDL receptors. These agents have been shown to dramatically lower LDL-C levels and significantly reduce cardiovascular events in high-risk patients.  

• Bempedoic Acid: Bempedoic acid inhibits adenosine triphosphate-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. Clinical trials have demonstrated that bempedoic acid effectively lowers LDL-C levels, both as monotherapy and in combination with statins.  

• Inclisiran: Inclisiran is a small interfering RNA (siRNA) that targets PCSK9 mRNA, leading to a sustained reduction in PCSK9 levels and subsequent lowering of LDL-C. Clinical trials have shown that inclusion provides long-lasting LDL-C reduction with infrequent dosing (twice yearly).  

Emerging Therapies

• Bempedoic Acid

  • Mechanism of Action: Bempedoic acid inhibits ACL, an enzyme involved in the cholesterol biosynthesis pathway upstream of HMG-CoA reductase (the target of statins). This mechanism of action allows bempedoic acid to lower LDL-C without directly affecting muscle tissue, potentially reducing the risk of SAMS.  

  • Clinical Trial Data: Clinical trials have shown that bempedoic acid reduces LDL-C by approximately 15-20% as monotherapy and by an additional 18% when added to maximally tolerated statin therapy. Studies have also demonstrated cardiovascular benefits in high-risk patients.  

  • Role in Clinical Practice: Bempedoic acid is approved for use in patients with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering despite maximally tolerated statin therapy. It may also be a suitable option for patients with statin intolerance.  

• Inclisiran

  • Mechanism of Action: Inclisiran is a siRNA that targets PCSK9 mRNA, leading to a reduction in PCSK9 synthesis. This results in increased LDL receptor availability and subsequent lowering of LDL-C. The unique mechanism of action allows for infrequent dosing (twice yearly).  

  • Clinical Trial Data: Clinical trials have shown that inclusion provides substantial and sustained LDL-C reduction (around 50%) with only two subcutaneous injections per year. Studies have also demonstrated cardiovascular benefits.  

  • Role in Clinical Practice: Inclisiran is approved for use in adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering despite maximally tolerated statin therapy. Its infrequent dosing schedule offers a potential advantage for improving adherence.  

Other Emerging Approaches

Beyond bempedoic acid and inclisiran, other novel approaches to lipid management are being investigated:

• CETP Inhibitors: Cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib and anacetrapib, raise HDL-C levels and lower LDL-C. While earlier CETP inhibitors had safety concerns, newer agents are being studied.  

• ANGPTL3 Inhibitors: Angiopoietin-like 3 (ANGPTL3) inhibitors lower LDL-C, triglycerides, and other atherogenic lipoproteins.  

• Liver-Targeted Therapies: Other liver-targeted therapies, such as antisense oligonucleotides and gene editing technologies, are being explored for their potential to lower LDL-C.

Addressing Statin Intolerance

A key aspect of the new era of lipid management is addressing statin intolerance. Strategies include:

• Re-challenging with lower doses or different statins: Often, lower doses or switching to a different statin can resolve SAMS.  

• Intermittent dosing: Taking statins every other day or once weekly may be tolerated by some patients.  

• Non-statin therapies: Using non-statin therapies like ezetimibe, bempedoic acid, or PCSK9 inhibitors as monotherapy or in combination with low-dose statins.

The Role in Clinical Practice

These new therapies are not intended to replace statins as first-line therapy for most patients. Statins remain highly effective and affordable. However, these new agents provide valuable options for patients who:

• Do not achieve target LDL-C levels with statins alone.  

• Experience SAMS or are intolerant to statins.

• Are at very high risk for cardiovascular events and require more aggressive LDL-C lowering.

Challenges and Considerations

• Cost and Accessibility: The cost of some of these new therapies, particularly PCSK9 inhibitors and inclisiran, can be a barrier to access.  

• Long-term Safety Data: While clinical trials have demonstrated short- to medium-term safety, long-term safety data is still being collected.

• Combination Therapies: The optimal use of combination therapies involving statins, ezetimibe, bempedoic acid, and PCSK9 inhibitors/inclisiran needs further investigation.

Conclusion

The landscape is rapidly changing. New therapies begin to offer an exciting hope for better LDL control and reduced risk of cardiovascular outcomes.

Bempedoic acid and inclusion represent significant steps forward, providing effective options for patients who do not tolerate or achieve adequate LDL-C lowering with statins. Although statins will remain the mainstay of therapy for most patients, these new agents provide valuable tools for personalized lipid management. They may represent a shift into a new era of cardiovascular prevention. Further research and clinical experience will refine the optimal use of these therapies in clinical practice.