BACKGROUND

Relapsing-remitting multiple sclerosis (MS) is an immune-mediated, chronic inflammatory disease of the central nervous system, characterized by progressive neuronal degeneration. Although a few disease-modifying drugs are available, they are only partially effective, require chronic injections, and are cost prohibitive for some patients. Additional drugs to help treat this significant disease process are needed. Hydroxycholesterol and cholesterol precursors may be possible markers for neurogeneration and demyelination in MS, suggesting a role for the statin drugs.¹ In addition, statins may possess anti-inflammatory and immunomodulatory effects (ie, inhibiting lymphocyte function, the entry of T cells into the central nervous system, and T-cell activation; the suppression of secretion of numerous inflammatory mediators).² In an in vitro study, simvastatin, lovastatin, and mevastatin inhibited, in a dose-dependent manner, the proliferation of stimulated peripheral blood mononuclear cells obtained from untreated or interferon beta-1b–treated patients with relapsing-remitting MS.³

PATIENT POPULATION

Adult patients with relapsing-remitting MS receiving interferon therapy

DOSAGE AND DURATION

40 mg to 80 mg daily for up to 3 years. Note: Based on negative results in controlled trials, this use is not supported.

RESULTS

The use of adjunctive simvastatin therapy (with interferon-beta) in the management of relapsing-remitting MS has been evaluated in a limited number of controlled trials enrolling approximately 400 patients and has demonstrated conflicting results, either moderate to no benefit.^4,5  Two meta-analyses of statins (atorvastatin and simvastatin) that examined the same trials found that there is no benefit of statins in regard to MS relapse rates, disease progression, or change in disability scores.^6,7

Meta-analyses

A meta-analysis evaluating the efficacy of statins in combination with interferon therapy for the management of patients with relapsing-remitting MS identified 4 unique randomized controlled trials (RCTs). The evaluated statins included simvastatin and atorvastatin, with 2 studies each. Analysis did not reveal significant benefit associated with statin use compared to control groups in regard to relapse rates (relative risk [RR] 0.99; 95% CI, 0.53 to 1.85; I² = 54.1%), risk of disease progression (RR 1.31; 95% CI, 0.73 to 2.36; I² = 38.1%), or change in Expanded Disability Status Scale (EDSS) scores from baseline (weighted mean difference -0.06; 95% CI, -0.30 to 0.19; I² = 0%).⁶

Another meta-analysis evaluated the same 4 controlled trials with the use of statins in the management of relapsing-remitting MS (2 with atorvastatin and 2 with simvastatin). Only 3 studies were considered to be of good methodological quality. The authors concluded that the evidence did not support the use of either atorvastatin or simvastatin for the reduction of MS relapses or prevention of disease progression. No serious adverse events were associated with statin use.⁷

Controlled Trials

In a double-blind, placebo-controlled trial, 85 adult patients with relapsing-remitting MS who were receiving interferon beta-1a therapy for at least 3 months were randomized to receive intramus-cular interferon (30 mcg weekly) with simvastatin (40 mg daily) or placebo for 12 months. The primary outcome at the end of one year was the number of relapses. Secondary outcomes included changes in disability as measured by EDSS and MRI findings (number of new T2 lesions and the number of new gadolinium-enhanced lesions). A total of 14 patients withdrew from the study, of whom 6 had 2 relapses (2 in the simvastatin group and 4 in the placebo group). No withdrawals were due to adverse events. The mean total number of relapses during the trial period was significantly lower in the combination interferon/simvastatin group when compared to the interferon/placebo group (0.4 vs 1.0; P = .007). Initial analysis of the ultimate EDSS mean scores appeared to be significant; but when confounders were controlled, there was no difference between the 2 groups. In addition, there were no significant differences between the 2 groups for other outcome measurements (eg, new T2 lesions, number of gadolinium lesions on MRI, or patients with EDSS exacerbation). The authors concluded that the addition of simvastatin 40 mg daily to interferon therapy may reduce the relapse rate (moderate effect size, r = 0.29).⁴

In a double-blind, placebo-controlled -multicenter trial, 307 treatment-naïve patients with relapsing-remitting MS received intramuscular interferon -beta-1a (30 mcg weekly) for 3 months prior to randomization to concurrent therapy with simvastatin or placebo for at least 12 months and up to 36 months. Simvastatin was dosed as 40 mg daily for one month then increased to 80 mg daily. The primary endpoint was the annual rate of documented relapses. Secondary outcomes were time to first documented relapse, number of new or enlarging T2 lesions on MRI at 12 months compared to baseline, and the percentage of patients without disease activity during the first year and throughout the study. In the intent-to-treat (ITT) population, the annual rate of documented relapses was 0.19 and 0.14 in the simvastatin and placebo groups, respectively, with an absolute difference of 0.059 (P = .35). There was also no significant difference between the 2 groups for annual rates of all relapses (documented and undocumented, 0.44 and 0.38, respectively), time to first documented relapse (13.7 vs 21.5 months, respectively), or the number of new or enlarging T2 lesions (2.96 vs 2.52, respectively). A total of 75% of the simvastatin group and 81% in the placebo group were relapse-free throughout the study. The probability of a patient remaining relapse-free was 0.69 versus 0.76, respectively. The authors concluded that there was no beneficial effect of simvastatin as combination therapy with interferon beta-1a in the management of relapsing-remitting MS.⁵ 

SAFETY

This is a limited safety profile. Refer to package labeling for complete prescribing information (eg, Warnings/Precautions, Adverse Reactions, Drug Interactions).

In the reviewed trials, interferon with simvastatin or placebo produced similar rates of adverse events, which were typically mild. There were no significant differences between the groups for the rates of infections, creatine phosphokinase, psychiatric disorders, or musculoskeletal complaints.^4,5

THERAPY CONSIDERATIONS

The use of adjunctive simvastatin therapy (with interferon-beta) in the management of relapsing-remitting MS has been evaluated in a limited number of controlled trials, demonstrating conflicting results of either moderate to no benefit.^4,5 Two meta-analyses of statins (atorvastatin and simvastatin) examining the same trials found that there is no benefit of statins in regard to MS relapse rates, disease progression, or change in disability scores.^6,7

REFERENCES

1. Teunissen CE, Dijkstra CD, Polman CH, Hoogervorst EL, von Bergmann K, Lutjohann D. Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients. Neurosi Lett. 2003;347:159-162. 
2. Stuve O, Youssef S, Steinman L, Zamvil SS. Statins as potential therapeutic agents in neuroinflammatory disorders. Curr Opin Neurol. 2003;16:393-401.  
3. Neuhaus O, Strasser-Fuchs S, Fazekas F, et al. Statins as immunomodulators: Comparison with interferon-beta 1b in MS. Neurology. 2002;59:990-997. 
4. Togha M, Karvigh SA, Nabavi M, et al. Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: A double-blind randomized controlled trial. Mult Scler. 2010;16(7):848-854. 
5. Sorensen PS, Lycke J, Erälinna JP, et al; SIMCOMBIN Study Investigators. Simvastatin as add-on therapy to -interferon β-1a for relapsing-remitting multiple sclerosis
   (SIMCOMBIN study): A placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10(8):691-701. 
6. Bhardwaj S, Coleman CI, Sobieraj DM. Efficacy of statins in
   combination with interferon therapy in multiple sclerosis: A meta-analysis. Am J Health Syst Pharm. 2012; 69(17):1494-1499. 
7. Wang J, Xiao Y, Luo M, Luo H. Statins for multiple sclerosis. Cochrane Database Syst Rev. 2011;(12):CD008386. 

^*Editor-in-Chief, Hospital Pharmacy, and Clinical Professor, Emeritus, Department of Pharmacy Practice, University of Kansas, School of Pharmacy, Kansas City/Lawrence, Kansas, e-mail: jgeneral@ku.edu; ^†Founder and Contributing Editor, The Formulary, and Editor, Off-Label Drug Facts, e-mail: Dennis.Cada@wolterskluwer.com.