Investigating the treatment of vascular risk with simvastatin in secondary progressive multiple sclerosis: analysis from the MS-STAT2 randomized controlled trial

Abstract

Vascular comorbidity is associated with more severe disability in multiple sclerosis. 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 mg) 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 (50–60) 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 (−3.10% [−0.06 to −6.06]). 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.

Metadata

Item Type:	Article
Authors/Creators:	Williams, T. Magill, N. John, N.A. Bianchi, A. Blackstone, J. Braisher, M. De Angelis, F. Calvi, A. Apap Mangion, S. Wade, C. Yiannakas, M.C. Stutters, J. Ricciardi, A. Prados Carrasco, F. MacManus, D. Gandini Wheeler-Kingshott, C.A.M. Barkhof, F. Ciccarelli, O. Chataway, J. Chataway, J. Williams, T. John, N. De Angelis, F. Calvi, A. Bianchi, A. Wright, S. Shatila, M. Doshi, A. Mangion, S.A. Wade, C. Brownlee, W. Gandini Wheeler-Kingshott, C.A.M. Barkhof, F. Ciccarelli, O. Stutters, J. Carrasco, F.P. Ricciardi, A. Yiannakas, M. MacManus, D. Agiu, M. Bassan, V. Beyene, T. Conway, S. Fneich, B. Jimenez, A.H. Pullinger, S. Samdanidou, E. Wynne, M. Braisher, M. Blackstone, J. Merry, R. Barton, G. Crisp, L. Parker, J. Flight, J. Deane, L. Frost, C. Nicholas, J. Nixon, S. Beveridge, J. Pavitt, S. https://orcid.org/0000-0001-7447-440X Chandran, S. Mahad, D. Connick, P. Lyle, D. Galea, I. Jarman, E. Jacob, C. Kaninia, S. Sharrack, B. Paling, D. Ford, H. Fernandes, L. Vinjam, M. Pearson, O. Ingram, G. Rickards, C. Hill, M. Evangelou, N. Allen, C. Shehu, A. Arun, T. Belhag, M. McDonnell, G. Magill, F. Ramsay, S. Geraldes, R. Craner, M. Cullen, D. Birmingham, H. Cavey, A. Hillier, C. Dube, J. Davis, M. Ganesalingam, J. Fisniku, L. Aram, J. Newman, J. Hobart, J. Almasri, O. Lashley, D. Spilker, C. Quinn, O. Bellfield, R. Kalra, S. Ellis, S. Robertson, N. Tallantyre, E. Butcher, C. Harikrishnan, S. Guckm, N. Pluchino, S. Peruzzotti-Jametti, L. Mattoscio, M. Chaudhuri, A. Visentin, E. Fawehinmi, G. Azzopardi, L. Harrower, T. O’Reilly, C. Acres, S. Statton, S. Young, C. Mills, R. Arndt, H. Lee, M. Chhetri, S.K. Maskery, M. Ahmed, F. Khalil, M. Rog, D. Parker, V. Vinod, N. Silber, E. Dervanoulis, G. Rhule, N. Gallagher, P. Duddy, M. Robson, L. Straukiene, A. Marshall, C. Bamforth, K. Kalil, A. Nicholas, R. Cabreros, L. Rice, C.M. Minton, T.
Copyright, Publisher and Additional Information:	© The Author(s) 2026. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords:	multiple sclerosis, secondary progressive multiple sclerosis, vascular risk, cholesterol, statins
Dates:	Accepted: 27 May 2026 Published (online): 24 June 2026 Published: 24 June 2026
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Dentistry (Leeds) > Applied Health and Clinical Translation (Leeds)
Funding Information:	Funder Grant number NHS National Inst. for Health Research NIHR Department of Health 539549
Date Deposited:	14 Jul 2026 12:50
Last Modified:	14 Jul 2026 12:50
Status:	Published
Publisher:	Oxford University Press
Identification Number:	10.1093/braincomms/fcag240
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:242873

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Investigating the treatment of vascular risk with simvastatin in secondary progressive multiple sclerosis: analysis from the MS-STAT2 randomized controlled trial

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