Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis.
Alexander, Daniel C
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
MetadataShow full item record
Eshaghi, A., Kievit, R., Prados, F., Sudre, C. H., Nicholas, J., Cardoso, M. J., Chan, D., et al. (2019). Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis.. Proceedings of the National Academy of Sciences of the United States of America, 116 (22), 11020-11027. https://doi.org/10.1073/pnas.1818978116
Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here we aimed to explore whether the simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol, using mechanistic computational models. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomised to receive placebo or simvastatin (80 mg/day). At baseline, after one and two 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 used SIENA to calculate 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 (beta=-0.037, 95% credible interval [CI]=-0.075, -0.010). This study supports the hypothesis 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.
Brain, Humans, Multiple Sclerosis, Chronic Progressive, Atrophy, Disease Progression, Simvastatin, Cholesterol, Models, Statistical, Causality, Adult, Middle Aged, Clinical Trials as Topic
Rogier Kievit is supported by the Sir Henry Wellcome Trust (107392/Z/15/Z) 638 and MRC Programme Grant (RG91365). O. Ciccarelli, A. Thompson, F. Barkhof, and J. Chataway have received funding from the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC) for this work. D. Alexander has received funding for this work from EPSRC (M020533, M006093, J020990) as well as the European Union's Horizon 2020 research and innovation programme under grant agreement No.s 634541 and 666992.
Wellcome Trust (107392/Z/15/Z)
Medical Research Council (MC_UP_1401/1)
External DOI: https://doi.org/10.1073/pnas.1818978116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292372
All rights reserved