Novel Approaches to Lipid Management: Beyond Statins and PCSK9 Inhibitors

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Genetics

Background:

• Statins are the cornerstone of lipid management, lowering LDL-C and preventing cardiovascular events.
• Guidelines recommend stepwise intensification or add-on therapies when lipid targets are unmet or statin intolerance occurs.
• Residual cardiovascular risk necessitates exploring advanced lipid-lowering strategies beyond statins.

Purpose of the Study:

• To introduce a mechanism-first, phenotype-guided framework for selecting add-on lipid-lowering therapies.
• To integrate clinical trial evidence with practical considerations for managing dyslipidemia.
• To review emerging and established add-on therapies for residual cardiovascular risk.

Main Methods:

• Literature review of clinical trials and guidelines on lipid management and add-on therapies.
• Framework development linking treatment mechanisms and lipid phenotypes to residual risk drivers.
• Categorization of therapies based on targets: LDL-C, triglycerides, lipoprotein(a), or inherited dyslipidemias.

Main Results:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies are validated for very high-risk patients.
• Bempedoic acid offers an alternative for statin-intolerant patients.
• Inclisiran provides durable LDL-C reduction with infrequent dosing.
• ANGPTL3-directed therapies and ApoC-III inhibitors address refractory dyslipidemias and severe hypertriglyceridemia.
• High-dose icosapent ethyl demonstrates ischemic event reduction in persistent hypertriglyceridemia.
• Implementation challenges including cost and access remain significant barriers.

Conclusions:

• A phenotype-guided approach optimizes add-on therapy selection for residual cardiovascular risk.
• Emerging therapies offer novel mechanisms for managing complex dyslipidemias.
• Addressing implementation barriers is critical for widespread adoption of advanced lipid-lowering strategies.