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Intensive lowering of low-density lipoprotein cholesterol (LDL-C) has substantially reduced cardiovascular events; however, a considerable degree of residual cardiovascular risk persists even among patients achieving very low LDL-C levels. This observation has shifted contemporary cardiovascular research toward a broader understanding of atherosclerosis as a multifactorial disorder involving triglyceride-rich lipoproteins (TRLs), apolipoprotein B (APOB)-containing particles, dysfunctional high-density lipoproteins (HDLs), lipoprotein(a) [Lp(a)], endothelial dysfunction, and chronic vascular inflammation. Emerging evidence further suggests that psychological and behavioral factors, including specific personality traits and chronic psychosocial stress, may contribute independently to cardiovascular disease susceptibility and outcomes. The present review summarizes emerging risk factors associated with residual cardiovascular risk and highlights novel therapeutic strategies beyond LDL-C lowering. Collectively, current evidence supports a transition from a simplistic LDL-C-centric paradigm toward a multiple risk factor approach for atherosclerosis prevention and treatment.<\/jats:p>","DOI":"10.3390\/ph19071071","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T07:28:27Z","timestamp":1783927707000},"page":"1071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unmet Cardiovascular Risk Beyond LDL-C: A Perspective on Managing Residual Cardiovascular Risk"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6784-2710","authenticated-orcid":false,"given":"Kyriakos E.","family":"Kypreos","sequence":"first","affiliation":[{"name":"Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece"},{"name":"Gene Regulation and Molecular Therapies Laboratory, Institute of Cellular Biology and Pathology, \u201cNicolae Simionescu\u201d of the Romanian Academy, 050568 Bucharest, Romania"},{"name":"School of Sciences, Department of Life Sciences, European University Cyprus, Egkomi, Nicosia 2404, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1290-1346","authenticated-orcid":false,"given":"Anca Violeta","family":"Gafencu","sequence":"additional","affiliation":[{"name":"Gene Regulation and Molecular Therapies Laboratory, Institute of Cellular Biology and Pathology, \u201cNicolae Simionescu\u201d of the Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2011-8930","authenticated-orcid":false,"given":"Ourania","family":"Andreopoulou","sequence":"additional","affiliation":[{"name":"Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Zvintzou","sequence":"additional","affiliation":[{"name":"Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece"},{"name":"Gene Regulation and Molecular Therapies Laboratory, Institute of Cellular Biology and Pathology, \u201cNicolae Simionescu\u201d of the Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Marinos","sequence":"additional","affiliation":[{"name":"Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Mparnia","sequence":"additional","affiliation":[{"name":"Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, 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