Open Access

REVIEW

Genetic Factors Influencing Response to Lipid-Lowering Therapies in Atherosclerotic Cardiovascular Disease: Systematic Review

Miguel Meñaca-Puentes^1,*, Juan-Camilo Arias-Ospina¹, Narmer F. Galeano², Reinel Tabares-Soto^1,3, Carlos Alberto Ruiz Villa¹

1 Faculty of Artificial Intelligence and Engineering, University of Caldas, Manizales, 170001, Colombia
2 Faculty of Technology, Technological University of Pereira, Pereira, 660003, Colombia
3 Departamento de Electrónica y Automatización, Universidad Autónoma de Manizales, Manizales, 170001, Colombia

* Corresponding Author: Miguel Meñaca-Puentes. Email:

Congenital Heart Disease 2025, 20(6), 743-767. https://doi.org/10.32604/chd.2025.070423

Received 16 July 2025; Accepted 04 November 2025; Issue published 10 February 2026

Abstract

Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with low-density lipoprotein cholesterol established as a primary causal risk factor. Despite widespread implementation of statin therapy, substantial interindividual variability in treatment response persists, necessitating precision medicine approaches to optimize therapeutic outcomes. This comprehensive narrative review synthesizes current understanding of pharmacogenomic determinants influencing lipid-lowering therapy efficacy, examines mechanisms underlying residual cardiovascular risk, and evaluates emerging therapeutic modalities targeting previously unexploited pathways in lipid metabolism. Genetic variants in key genes including 3-hydroxy-3-methylglutaryl-CoA reductase, apolipoprotein E, low-density lipoprotein receptor, and proprotein convertase subtilisin/kexin type 9 demonstrate significant associations with differential treatment responses, with specific polymorphisms conferring enhanced efficacy or increased intolerance risk. Beyond traditional statin therapy, novel therapeutic approaches targeting proprotein convertase subtilisin/kexin type 9, angiopoietin-like protein 3, apolipoprotein C-III, and ATP citrate lyase offer substantial low-density lipoprotein cholesterol reductions of 50–80%, while RNA-based therapies including antisense oligonucleotides and small interfering RNA provide precise molecular targeting capabilities. Despite intensive lipid-lowering interventions, residual cardiovascular risk persists through four principal mechanisms: triglyceride-rich lipoproteins, lipoprotein(a), inflammatory processes, and suboptimal treatment adherence. Integration of pharmacogenomic insights with emerging therapeutic modalities enables personalized risk stratification and treatment selection, representing a paradigm shift toward precision medicine in cardiovascular disease prevention and management.

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Keywords

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