Difficulty is seeing Saving Nerves with Statins

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Statins are agents used to reduce cholesterol. When used in a UK trial called MS-STAT they found that brain loss was slowed and suggested there was a benefical effect suggesting that nerves loss is inhibited by statins. “High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe”. So we now have MS-STAT2 on the go (NCT03387670)

Yeserday NDG posted a piece on neurofilaments (nerve protein that gets released after nerve damage) and in this study they looked for neurofilaments in the blood after statin treatment in MS-STAT and found no change, suggesting no saving of nerves. Should we say Oh heck?

There are over 1000 people in MS-STAT2. Whats going to happen?

I guess we have to wait and see, but because MS-STAT2 is a phase III trial it means the outcome is clinical. They ask does it stop disability progression, does it stop loss of mobility of the lower and upper limibs?

We will have to wait and see, but can we explain the result of a seemingly beneficical effect on brain shrinkage but no evidence to saving nerve loss. You can have read to see what you think. It suggests that “slowing of brain shrinkage is occuring independently of nerve loss”. I think NDG may say the problem is they were looking for nerve loss using the blood and they should be looking in spinal taps. Also it is hard to see a difference because they were not controlling inflammation in all people and adding statin on top. A good anti-inflammatory makes the neurofilament levels drop miles more than is ever seen from the nerve loss due to progression.

At the end of the day the clinical response is important. What do you think will happen?

However, one question is how could it work. The original idea was (a) It changed the pattern of T cell cytokines and (b) It block lesion formation by stopping trafficking across blood vessels. I know because we did the pioneering work with statins, but others got of the mark to do trials in RRMS and statins were not good enough so an SPMS trial was done, but what is the working mechanism. I think both (a) and (b) are not the answer indeed I never thought (a) was the answer, but how come the steroid pathway is the number one dysregulated pathway in chronic EAE, MS and Alzheimers. It isnt about T cell lesions..surely. Some may say de and (c) remyelination. There are other possibilities. I was going to write a review but never got round to it. One I wondered about was (d) the oxysterols that can be linked to neurodegneration and neuroprotection. Can one create a hypothesis for a role, I think you can and counter the effects of toxic accumulation of sodium and calcium, which we know have the capacity to kill nerves and oligodendrocytes via excitotoxicity.

Anyway blocking sodium channels did not have an effect on neurofilaments levels in the brain, but it did slow loss of mobility (PROXIMUS) so lets keep our fingers crossed

Williams TE, Holdsworth KP, Nicholas JM, Eshaghi A, Katsanouli T, Wellington H, Heslegrave A, Zetterberg H, Frost C, Chataway J. Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial. Neurol Neuroimmunol Neuroinflamm. 2022 Jan 14;9(2):e1130. doi: 10.1212/NXI.0000000000001130.

Background and objectives: Improved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.

Methods: The MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology.

Results: A total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.

Discussion: We found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.

COI: None really

Disclaimer. This is the authors view and does not represent theviews of any institution, notably mine.

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MouseDoctor

12 comments

  • Dimethyl fumarate Is shown to lower NfL levels.

    Ketogenic diet works in a similar way to Dimethyl fumarate

    Ketogenic diet showing evidence of lowering NfL levels

    I know diet is seen as quackery on this blog. However it seams to be actually showing evidence of neuroprotection more than any of the drugs trialed so far.

    Also HIIT exercise is showing effects of lowering NfL levels.

    The best treatment possible + these lifestyle options should be the best option until something out performs them

    It would be nice to have more lifestyle trials. However as we know, they are always going to be small trials with no large trials as the end result doesn’t make money

    Hopefully there’s a positive outcome, however if the trials aim is neuroprotection then shouldn’t NfL levels in earlier trials have been observed?

    • I think a ketogenic diet might theoretically be detrimental in the long term due to a negative impact on heart health. There is more evidence that HIIT does something than that regular aerobic exercise does something but still, exercise trials are usually small and often flawed in major ways that make one wonder why anyone bothered doing them other than as a thesis project for some phd student.

      Lifestyle trials need to be funded by governments or charities, but as we know pharma are the only people who have a clue about clinical trials.

  • Thanks MD, Anonymous.
    Have had cause to consider statins in a number of contexts, and personally wouldn’t touch them with a barge pole, especially if I had an MS diagnosis- they definitely contribute to fatigue and muscle weakness. GP has advised elderly AMD spouse to come off them, SPMS D1 personally committed to providing data for MS research. I have always been slender, D1 of pretty average BMI.
    I continue to be amazed by the ever-increasing number of allegedly discrete forms of both MS and EDS. All I know for sure so far is D1 and I have firm diagnoses of EDS from different hospital rheumatology departments, D1 showed oligoclonal bands on lumbar puncture for acute encephalitis, and D2’s RRMS diagnosis was made based on documented previous optic neuritis, her then clinical presentation, and her elder sister’s firm diagnosis. I have had more allegedly rare complications of EDS than you can shake a stick at, including near death by gangrene (double-knotted caecal volvulus, brewing for years apparently- big cheese relevant surgeon, called in when registrar couldn’t cope, quite firm in writing about collagen disorder).
    So guys, never assume that blue-eyed persons have a low pain threshold, and again, 🙏

  • It’s interesting to see that MS-STAT2 is going for nocturnal doses of Simvastatin. This forum has previously discussed the use of Simvastatin over alternatives, due to it’s ability to cross the blood brain barrier. We know that pwMS have sleep problems and that statins cause insomnia. Better sleep may improve outcomes, so giving the statin at night is likely to make insomnia a significant confounding variable. Let us hope they have thought of this and are taking steps to control this confounder which could reduce the treatment effect.

  • “toxic accumulation of sodium and calcium, which we know have the capacity to kill nerves and oligodendrocytes via excitotoxicity.” Does potassium levels lowered by statins play any role for protection or disability progression, Or possibly a confusing variable? I throw this out there because In my prior working life, a geriatric nurse routinely advised to check potassium levels on elderly patients taking statins when there was sudden reduction in cognition and EDSS. Doctors generally did not feel level of low potassium explained the level of increased disability but i observed a dramatic reversal of a patient’s new symptoms within 6 hours. The patient, immobilized, weak, and confused, returned to baseline like a wilted flower perks and straightens after getting water.

    • Interesting….in my oxysterol scenario….they work via potassium levels….spooky:-) Shame we couldnt get the idea funded

    • Observed an improvement with higher potassium levels?

      Most of the population is deficient in potassium, it’s hard to eat the 4.5g recommended through foods

        • 4.7g in America. Where 98% of people are defficaint in potassium. So maybe not so ready to obtain though diet.

          The facts are, soils are over farmed and deficient in nutrients, if the soils deficient the plants not going to take up the minerals.

          • If the soils were deficient in potassium, the crops wouldn’t grow as it is an essential nutrient for plants too.

  • Oxford calling MD-Anon:
    May I be the first to nominate SchutzStaffel-CurriculumVitae-3-counting-MERS community for gold star?
    PMR via iOS

  • This might explain why I’ve been losing muscle at an alarming rate for 5 years. Already being monitored for electrolytes, and I always place a bet with GP on what the lab results will be- can usually predict what’s happening before they return

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