Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis.

Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis.

Publication date: May 09, 2019

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.

Eshaghi, A., Kievit, R.A., Prados, F., Sudre, C.H., Nicholas, J., Cardoso, M.J., Chan, D., Nicholas, R., Ourselin, S., Greenwood, J., Thompson, A.J., Alexander, D.C., Barkhof, F., Chataway, J., and Ciccarelli, O. Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis. 17974. 2019 Proc Natl Acad Sci U S A.

Concepts Keywords
Atrophy Magnetic resonance imaging
Brain Niacin
Cholesterol EDSS
Clinical Trials Cholesterol
Cognitive Statins
Credible Interval Simvastatin
Disability Lactones
Magnetic Resonance Imaging Multiple sclerosis
Multiple Sclerosis Merck
Physical Disability Drugs
Placebo Chemical compounds
Progressive Organic compounds
Sci MS
Serum
Simvastatin
STAT

Semantics

Type Source Name
gene UNIPROT SOAT1
drug DRUGBANK Cholesterol
disease DOID secondary progressive multiple sclerosis
disease MESH secondary progressive multiple sclerosis
disease DOID multiple sclerosis
disease MESH multiple sclerosis
drug DRUGBANK Simvastatin

Original Article

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