#ResearchSpeak: high-dose simvastatin for all?

Is MS a dementing illness or not? Preventing MS dementia makes sense. #ResearchSpeak #BrainHealth #MSBlog

The analysis of the cognition in the high-dose simvastatin in SPMS (STAT-1) trial shows us several things. 
  1. MS is a dementing disease. Almost half the study subjects had significant cognitive impairments at baseline. 
  2. Cognitive impairment is progressive; over the trial cognition worsened in subjects.
  3. Simvastatin slowed down progressive cognitive impairment and had a positive impact on QoL
What this study doesn't show is how simvastatin works in MS. Is it via MS specific mechanisms or non-MS mechanisms such as vascular disease or ageing? This has implications on how we use the drug. Should it be added onto existing DMTs?

Unfortunately, the treatment effect of simvastatin is small and waiting for someone to enter a more advanced stage of the disease may be too late for the drug to make much of a difference. Saying that the good news is that the small treatment effect in this trial was linked to a positive outcome on quality of life. 

Should all pwMS with more advanced MS being on high-dose simvastatin? I suspect yes, but before we make this recommendation we should wait for the outcome of the phase 3 STAT-2 trial, which will start later on this year. My only reservation about this study is that it was not an add-on study, i.e. on top of existing DMTs, but a monotherapy trial. The latter goes against most of the evidence and scientific insights we have about more advanced MS. I hypothesised many years ago that to tackle more advanced MS we would need combination therapies; it is simply not plausible that one therapeutic strategy will be sufficient to make a difference in progressive MS. 

I have always been borderline in relation to needing a statin myself. I wonder if I should take-up my GPs offer of a statin? If I did I wouldn't go with simvastatin, but pravastatin. The latter choice is based on the opinion of a close colleague who works in the field of cardiovascular prevention. Pravastatin doesn't cross the blood-brain-barrier and is associated with less cognitive side effects. He has told me that the cognitive side effects of statins have been played down by industry, but there is sufficient evidence to warrant caution and to avoid them. Clearly the latter may not be relevant to MS, CNS penetration of simvastatin may be what is required to target neurodegeneration in MS. 


Chan et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurology  http://dx.doi.org/10.1016/S1474-4422(17)30113-8.

Background: In the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures.

Methods: We did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348.

Findings: Baseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6–7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8–8·7; p<0·0001). At 24 months, the FAB score was 1·2 points higher in the simvastatin-treated group than in the placebo group (95% CI 0·2–2·3). The simvastatin group also had a 2·5 points better mean physical component score of the SF-36 (95% CI 0·3–4·8; p=0·028). A treatment effect was not noted for any other outcomes.

Interpretation: To our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials.

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