Sunday, 11 June 2017

#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. 



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.

12 comments:

  1. How about a low fat diet at onset? Followed the Brain Health guidelines all my life even though they didn't exist at my diagnosis, it's just common sense. Just had a cognitive test and the results were better than expected. This is after 40 years of the disease and now SPMS and a high EDSS score. How about a study on patient's life styles that have had the disease for 30+ years? Could save the NHS some money in the long term and less side effects.

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    1. RE: 'How about a low fat diet at onset?'

      I think the evidence that a high-fat diet is bad for you is non-existent. What is bad for you is excessive intake of processed carbohydrates.

      There is an emerging body of evidence that a high-fat, low carbohydrate diet, improves your metabolic profile, including reducing your cholesterol. The hypothesis is that if you can keep your insulin levels down, without yo-yoing, you improve all your metabolic outcomes.

      Based on these insights I would not recommend a low-fat diet. Please stick to the Mediterranean diet, or variations on it, as it has the best evidence-base behind it in terms of cardiovascular and potentially cerebrovascular outcomes.

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    2. I'm very impressed Jane that you have allowed for cognitive functioning testing having lived with this disease for so many years. I have previously stated on this site that I do not want any such tests as I'm loathe to know about any annual decline in my mental faculties. I've chosen to approach it as something of a life-style matter: Med diet, exercise and brain training etc.
      I have even more respect for you having done some reading recently that reminded me of something that I feel influences my resistance to cognitive testing: what psychologists call 'stereotype threat' - e.g: girls expect to perform poorly in a maths test - call it maths and this is bourne out, but call it problem solving and the gender gap in performance disappears. Knowing that MS causes neuro degeneration, I will be concerned that impacts on how I perform in any tests. You went ahead and gained a positive result!

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    3. Life is a neurodegenerative disease and cognition falls off with age. You need to keep this in mind when you contemplate testing yourself. However, I agree that it is everyone's responsibility to look after their brain's health.

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    4. Good one Professor i have tried myself hi fat low carb diet and the lipid profile improved a lot (and i have genetic predisposition to high triglicerides) I doc was amazed...

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    5. How about fasting?
      https://www.ncbi.nlm.nih.gov/pubmed/27239035
      Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355

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    6. Sorry Prof G, I wasn't specific. I meant a diet low in saturates with Essential oils, such as oily fish, olive oil etc. A Mediterranean diet really. I did a food diary for my neurological dietician and she didn't change anything. I only had the cognitive test because I thought my memory wasn't as good as it used to be. So my friends weren't being kind after all when they told me I better memory than them. The worry made me worse. Not for everyone, but fine for me.

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    7. Saw a Vascular consultant yesterday who told me not to eat any fats at all including oily fish. The doctors seem to be singing from different hymn sheets. Who do we believe?

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  2. What's the significance of this?

    https://www.ncbi.nlm.nih.gov/pubmed/25795002

    "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."

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    1. Maybe statins don't perform their neuroprotective functions in the midst of active inflammation. Maybe you'd get a better result in RRMS if it was after inflammation was extinguished by Alem or HSCT.

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    2. Possibly. But it makes little sense using statins in isolation without addressing the underlying inflammation.

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  3. What about possible danger of taking simvastatin to pwMS having an already low cholesterol level? My 'natural' total cholesterol measure is 3.1 and my GP has advised against me taking any statins. We tried a dose of 10mg/day for a month and it fell to 2.7, which he said was entering the zone of increased cancer risk. I have since stopped taking it. It seems to me that pwMS already with low cholesterol can't benefit from this potential route to decreasing MS accelerated brain atrophy, but then, depending on simvastatin's mode of action, perhaps we don't need to.

    Richard S

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