ArticleProceedings of the National Academy of Sciences of the United States of America2019
Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 38 citations in OpenAlex.
- Serum neurofilament light and MRI predictors of cognitive decline in patients with secondary progressive multiple sclerosis: Analysis from the MS-STAT randomised controlled trial.Multiple sclerosis (Houndmills, Basingstoke, England) · 2022Trial
- Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial.Neurology(R) neuroimmunology & neuroinflammation · 2022Trial
- Lower- Versus Conventional-Sodium Dialysate and Left Ventricular Mass in Patients Receiving Hemodialysis: Causal Analyses of a Randomized Clinical Trial.Kidney medicine · 2026Article
- The role of lipid metabolism in neuronal senescence.FEBS open bio · 2026Review
- Examining the role of systemic inflammation as a mediator of the glycaemia-brain volume associations in women.PloS one · 2026Article
- Altered Lipid Metabolism in CNS Demyelination and Remyelination Are Key Elements Driving Progressive MS.International journal of molecular sciences · 2025Review
- Article
- Dysregulated lipid metabolism networks modulate T-cell function in people with relapsing-remitting multiple sclerosis.Clinical and experimental immunology · 2024Article
- Blood metabolomic and transcriptomic signatures stratify patient subgroups in multiple sclerosis according to disease severity.iScience · 2024Article
- Pilot Study of the Total and Phosphorylated Tau Proteins in Early-Stage Multiple Sclerosis.Medicina (Kaunas, Lithuania) · 2024Article
- Review
- Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study.Neurology · 2023Article
- Integrated Approaches to Identify miRNA Biomarkers Associated with Cognitive Dysfunction in Multiple Sclerosis Using Text Mining, Gene Expression, Pathways, and GWAS.Diagnostics (Basel, Switzerland) · 2022Article
- Novel Drugs in a Pipeline for Progressive Multiple Sclerosis.Journal of clinical medicine · 2022Review
- Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics.Journal of neuroinflammation · 2022Review
- Lowering blood cholesterol does not affect neuroinflammation in experimental autoimmune encephalomyelitis.Journal of neuroinflammation · 2022Article
- Statins in Neuro-ophthalmology.Neuro-ophthalmology (Aeolus Press) · 2021Review
- Disrupted Lipid Metabolism in Multiple Sclerosis: A Role for Liver X Receptors?Frontiers in endocrinology · 2021Review
- Protein arginine methyltransferase 5 promotes cholesterol biosynthesis-mediated Th17 responses and autoimmunity.The Journal of clinical investigation · 2020Article
- Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells.Frontiers in molecular neuroscience · 2019Article
Corrections and comments
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Authors and funding
15 authors at 8 institutions in 3 countries.
Funding
Abstract
Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [β = -0.037; 95% credible interval (CI) = -0.075, -0.010]. This suggests that simvastatin's beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.