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However, it is unknown whether treating vascular risk will lead to a disease modifying effect. Given the established role of simvastatin as a modifier of vascular risk, we aimed to investigate whether randomization to simvastatin could mitigate the relationships between serum cholesterol profiles and disease worsening, compared with placebo, in the MS-STAT2 trial. MS-STAT2 (NCT03387670) recruited 964 patients with secondary progressive multiple sclerosis, who were randomized to simvastatin (80\u2005mg) or placebo for 3 years. 246 participants additionally underwent yearly magnetic resonance imaging (MRI). Vascular risks were systematically assessed at trial baseline. In this exploratory analysis, the relationships between cholesterol ratio (total cholesterol\/high-density lipoprotein) and longitudinal clinical and MRI outcomes were assessed, comparing simvastatin to placebo groups. At baseline, median (IQR) age was 55 (50\u201360) years and median cholesterol ratio 3.4 (2.8 to 4.3). 73% were female, and 72% required a walking aid. Higher cholesterol ratio was associated with more severe baseline disability. No longitudinal relationships were observed between cholesterol ratio and clinical or brain atrophy outcomes. However, for each unit increase in cholesterol ratio, T2 lesion volume increased by +2.47% (95% CI: +0.03 to +4.97) from baseline in the placebo group. This relationship was significantly reduced in those randomized to simvastatin (\u22123.10% [\u22120.06 to \u22126.06]). Randomization to simvastatin appeared to mitigate the relationship between higher cholesterol ratios and longitudinal increases in T2 lesion volume in patients with secondary progressive multiple sclerosis. Further multi-modal interventional studies targeting vascular risk in patients with multiple sclerosis are warranted.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag240","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T11:40:23Z","timestamp":1781955623000},"source":"Crossref","is-referenced-by-count":0,"title":["Investigating the treatment of vascular risk with simvastatin in secondary progressive multiple sclerosis: analysis from the MS-STAT2 randomized controlled trial"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8197-0177","authenticated-orcid":false,"given":"Thomas","family":"Williams","sequence":"first","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London , London WC1N 3BG 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