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Statin Treatment in Multiple Sclerosis: A Systematic Review and Meta-Analysis

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Abstract

Background

Multiple sclerosis (MS) is a chronic inflammatory disease that leads to progressive disability. Statins [hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors] are widely prescribed drugs in hypercholesterolemia. They exert immunomodulatory and neurotrophic effects and are attractive candidates for MS treatment due to reliable safety profiles and favorable costs. Studies of statins in a murine MS model and in open-label trials in MS have shown decreased disease severity.

Objective

Our objective was to assess current evidence to support statin treatment in MS and clinically isolated syndrome (CIS).

Methods

We conducted a systematic literature review of EMBASE, PubMed, and CINAHL databases, clinical trials registries, and unpublished conference meeting abstracts as well as reference lists between 1 and 8 June 2014 and repeated it on 1 December 2014. Randomized controlled trials (RCTs) of statins, in any form or dosage, as monotherapy or add-on to established therapy in relapsing-remitting MS (RRMS), progressive MS, and CIS were included. Data were extracted using pre-defined fields to measure study quality. Meta-analysis was performed with regards to pre-defined outcome measures of relapse activity, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) progression, and adverse events using a fixed-effects model due to low heterogeneity between studies.

Results

Eight trials were included in the review [five of statin add-on to interferon (IFN)-β treatment in RRMS, one of statin monotherapy in CIS, one of statin monotherapy in optic neuritis (ON)/CIS, and one of statin monotherapy in secondary progressive MS (SPMS)]. Three trials with eligible characteristics had not been published in peer-reviewed journals and were therefore not included. Due to the low number of trials in CIS and SPMS, meta-analysis of primary outcomes was only performed for RRMS studies. Meta-analysis showed no significant effect of statin add-on to IFNβ therapy. Indeed, a trend towards an increase in disease activity was shown in the statin group with regards to new T2 lesions, proportion of patients with relapse, and whole brain atrophy but not for EDSS progression. In SPMS, statin monotherapy showed significant reduction in brain atrophy and disability progression but no effect on relapse rate. In CIS, a phase II trial showed no difference in relapse activity, MRI activity or risk of MS between statin monotherapy and placebo. In acute ON, statin monotherapy produced better visual outcome but no difference in relapse activity, MRI activity, or risk of MS.

Conclusions

The pleiotropic effects and effects in the murine model of MS could not be converted to a proven effect in relapsing MS and hence statin therapy either as a monotherapy or in combination with IFNβ treatment for RRMS, and statin monotherapy for CIS cannot at present be recommended. However, indications are that statins may be beneficial in SPMS. The benefit thereof and whether this is due to a direct immunomodulatory and neuroprotective effect warrant further studies.

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Acknowledgments

No sources of funding were received related to the preparation of this article.

Dr. Pihl-Jensen reports no conflicts of interests. Dr. Tsakiri received simvastatin medication from the pharmaceutical company Alpharma (now named Xellia) to be used in a simvastatin trial [37]. Other than this, there are no conflicts of interest to disclose. Dr. Frederiksen received simvastatin medication from the pharmaceutical company Alpharma (now named Xellia) to be used in a simvastatin trial [37]. Other than this, there are no conflicts of interest to disclose.

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Authors and Affiliations

  1. Clinic of Optic Neuritis and Clinic of Multiple Sclerosis, Neurological Department, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, 2600, Glostrup, Denmark

    Gorm Pihl-Jensen, Anna Tsakiri & Jette Lautrup Frederiksen

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  1. Gorm Pihl-Jensen
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Correspondence to Gorm Pihl-Jensen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

40263_2015_239_MOESM1_ESM.jpg

Supplementary material 1: Forrest plot depicting pooled analysis of the secondary outcomes. a) Patients with new T2 lesions. (JPEG 77 kb)

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Supplementary material 2: Forrest plot depicting pooled analysis of the secondary outcomes. b) Change in T2 lesion volume. (JPEG 89 kb)

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Supplementary material 3: Forrest plot depicting pooled analysis of the secondary outcomes. c) Change in total brain volume. Patients experiencing adverse events in the form of myalgia. (JPEG 90 kb)

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Supplementary material 4: Forrest plot depicting pooled analysis of the secondary outcomes. d), elevated alanine aminotransferase. (JPEG 98 kb)

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Supplementary material 5: Forrest plot depicting pooled analysis of the secondary outcomes. e), flu-like symptoms. (JPEG 101 kb)

40263_2015_239_MOESM6_ESM.jpg

Supplementary material 6: Forrest plot depicting pooled analysis of the secondary outcomes. f) during the study. (JPEG 98 kb)

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Pihl-Jensen, G., Tsakiri, A. & Frederiksen, J.L. Statin Treatment in Multiple Sclerosis: A Systematic Review and Meta-Analysis. CNS Drugs 29, 277–291 (2015). https://doi.org/10.1007/s40263-015-0239-x

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