Residual atherosclerotic cardiovascular disease risk in statin-treated patients: mechanisms, therapeutic strategies, and future directions—a scoping review

Abstract

Statins remain the cornerstone of pharmacological prevention for atherosclerotic cardiovascular disease (ASCVD) because of their proven ability to reduce low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE). However, many patients continue to experience ASCVD events despite achieving guideline-recommended LDL-C targets with maximally tolerated statin therapy, highlighting the persistence of residual ASCVD risk. This scoping review synthesized current evidence on residual ASCVD risk in statin-treated patients, focusing on its epidemiology, underlying mechanisms, clinical evidence, therapeutic strategies beyond statins, and barriers to optimal risk reduction. A scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Electronic databases were systematically searched, yielding 1,240 records. After duplicate removal and screening, 195 full-text articles were assessed for eligibility, and 35 studies were included in the final qualitative synthesis. The included evidence comprised randomized controlled trials, observational cohort studies, registry-based investigations, and systematic and narrative reviews. The included studies were synthesized into five major themes: epidemiology of residual ASCVD risk, underlying mechanisms, clinical evidence from landmark trials and real-world studies, therapeutic strategies beyond statins, and challenges limiting effective risk reduction. Evidence consistently demonstrated that residual ASCVD risk persists despite substantial LDL-C reduction because of multiple interacting factors, including elevated triglyceride-rich remnant lipoproteins, lipoprotein(a), persistent inflammation, metabolic comorbidities, vascular aging, treatment-implementation barriers, and behavioral factors. Landmark clinical trials, including IMPROVE-IT, FOURIER, ODYSSEY OUTCOMES, REDUCE-IT, CANTOS, LoDoCo2, and CLEAR Outcomes, demonstrated incremental cardiovascular benefit from combination lipid-lowering and selected anti-inflammatory therapies, while emerging therapies targeting lipoprotein(a), IL-6 signaling, and RNA-based pathways offer promising strategies for further reducing residual ASCVD risk. Residual ASCVD risk remains a major challenge despite guideline-directed statin therapy. Effective risk reduction requires a comprehensive approach that extends beyond LDL-C lowering to include combination lipid-lowering therapy, inflammation-targeted interventions, lifestyle optimization, improved treatment adherence, and individualized risk assessment. Continued evaluation of emerging therapies and precision medicine approaches is essential to further reduce the global burden of ASCVD.