Can a high-fat diet protect against statin side-effects?

In the news recently is a review of statin benefits and side-effects in the Lancet which, using a controversial modelling method to predict population effects from the variable results of clinical trials, recommends that statins be prescribed more widely to healthy people to lower their risk of future heart attacks.[1]

The claim is that side-effects are rare, but they seem to be more common, and more serious, in real life than Professor Rory Collins, lead author of the review, admitted when interviewed by the BBC. In our opinion, it’s not ethical to try to trivialise the side effects of any drug that can kill or cripple the people taking it, as Professor Collins did, whether or not the benefits outweigh the risks at a population level.

It’s also worth taking into account how these statin trials are typically designed and what that means for side effects, exclusion and interpretation. We’ve written about that before here.

A commenter on the What The Fat blog sent us this link to an Official Information Act request about the number of statin-related deaths and injuries in New Zealand.
https://www.fyi.org.nz/request/2442-number-of-statin-related-deaths-and-reported-adverse-reactions-to-statins-in-new-zealand

Over the period 01 January 2001 through to 31 December 2014, this document details 1709 reports describing 3826 reaction terms – one report may have more than one reaction described. 21 cases resulted in an outcome of death however in 3 cases death was not related to the Statin medicine and 2 cases were unclassifiable.

So we have 1709 reports of statins causing injury, and 21 deaths of which 15 were considered to be caused by statins. No doubt there is considerable underreporting here, as many people prescribed a drug which produces adverse effects will stop taking it without telling the doctor, and many doctors will stop prescribing such a drug without reporting the incident, so these numbers will tend to represent serious cases that weren’t easily resolved.

Why do some people experience extreme toxic reactions from statins while others tolerate them? A simple explanation for some types of harm might be, that statins reduce the synthesis of cholesterol, which lowers LDL in the blood, but everyone with a raised LDL cholesterol who is prescribed statins may not have an excessive rate of cholesterol synthesis to begin with, as cholesterol synthesis is regulated by insulin.[2] Someone with hyperinsulinaemia due to carbohydrate intolerance will tend to have an increased cholesterol synthesis, but this will often be accompanied by low or normal LDL levels. This may be why, in modern guidelines, LDL is no longer used as the sole guide to statin prescribing (the TG/HDL ratio is a better guide to insulin status).

Potentially, statins could cause enough of a cholesterol deficiency in cells to cause harm. This is how the NASA doctor Duane Graveline, who died recently, explained his own adverse reaction to statins, which caused him to suffer from amnesia. Professor Collins denies that amnesia is caused by statins; however all cases of amnesia in the New Zealand report (39) relate to the two statins, atorvastatin (Lipitor) and simvastatin (Zocor) which are fat-soluble and cross the blood brain barrier, just as Duane Graveline predicted.[3] Of course it is likely that amnesia in elderly patients prescribed statins is often missed as a drug side-effect, with resulting under-reporting.

A more complex mechanism for harm is that statins can be metabolised to lactones in some people, and these statin lactones are three times more toxic than the statins themselves, especially to muscle cells. Statin lactones inhibit mitochondrial respiratory complex III, reducing its activity by 84% in this experimental paper, and smaller but significant reductions in CIII activity were found in muscle biopsies from patients suffering from statin myopathy.[4]

In conclusion, we demonstrate that the Qo site of respiratory CIII is inhibited by several statin lactones and provide evidence for an association between this off-target effect and statin-induced myopathies. Consequently, polymorphisms of UGTs, the enzymes converting statin acids into lactones, and CIII could be predisposing factors in statin-induced myopathies. We showed that both G3PDH and b-oxidation stimulation can prevent statin-induced respiratory inhibition, providing a rationale for therapeutic intervention.

c3

CIII shown in context – the beta-oxidation fed electron transfer flavoprotein complex (ETF or CETF) that saves the day is, as usual, not shown here.

CIII is part of the mitochondrial electron transfer complex or ETC (also known as the respiratory complex) which is part of the machinery cells use to generate ready-use energy units (ATP) from food. Its inhibition has the effect of reducing the muscle cell’s ability to generate ATP, with apoptosis (self-destruction) of cells as an outcome. Fortunately the beta-oxidation step of fatty acid oxidation contributes to ATP through a separate mitochondrial transporter (not usually shown in diagrams, because “glucose is the most important energy source”), and this input is able to restore CIII activity – “Beta-oxidation also contributed to convergent electron flow into CIII (i.e. it stepped around the statin blockade) and reversed the effects, restoring CIII activity to 89% of normal”.

In this cell-culture experiment beta-oxidation was stimulated by adding palmitoyl-l-carnitine to the mixture; this is a molecule of saturated fat attached to a molecule of l-carnitine, which is the molecule that carries fatty acids into the mitochondria for beta-oxidation. Co-enzyme Q10 is the molecule that carries the electrons between complexes. It has been proposed that Co-enzyme Q10 and l-carnitine be used together to treat statin myopathy.[5] However, increased beta-oxidation is also something that happens naturally in people eating the LCHF diet – it’s called fat-burning. (on the other hand G3PDH, interestingly, is activated by fructose, but also by glycerol, part of the fat molecule).

A further way in which statins can cause damage, this time to brain and nerve cells, is by inhibiting the synthesis of vitamin K2. Many plant foods contain vitamin K1, which the body converts to K2 (mostly in the liver, but also in the brain).
When this occurs in the brain the MK4 form of K2 produced is an essential co-enzyme for the synthesis of special sulfur-containing lipids called sulfatides. Low CNS sulfatide levels are associated with cognitive decline and seen in the early stages of Alzheimer’s disease.[6]

The MK4 form of vitamin K2 is produced with the same enzyme (HMG-CoA reductase) that is targeted by statins.

From all these facts and hypotheses, we can arrive at a number of factors likely, at least in theory, to be protective to people using statins.

One is a fat-burning metabolism. Of course this is associated with low insulin levels and therefore unlikely to cause excessive cholesterol synthesis in the first place.
Another is l-carnitine. This is made in the body, but we get extra from animal foods, especially red meat. Another is co-enzyme Q10, we make this in the body but by using the same HMG-CoA reductase enzyme that makes cholesterol and vitamin K2. Co-Q10 is found in animal foods and also in vegetable oils.

Vitamin K2 is found in animal foods such as liver and eggs, in cheeses, and in other fermented foods such as natto and sauerkraut.
And cholesterol itself, of course, is only found in significant amounts in fatty animal foods, especially eggs, offal, and shellfish.

The irony is that the diet most likely to protect against statin side-effects (if that is in fact possible), is a high-fat diet with plenty of rich and tasty animal foods. Exactly the sort of diet you’ll be told to avoid by most of the doctors prescribing them.

We do have quite a few studies of carbohydrate-restricted diets in people taking statins showing that the combination is safe and results in added improvement.[7]

In conclusion, these findings demonstrate that individuals undergoing statin therapy experience additional improvements in metabolic and vascular health from a 6 weeks CRD as evidenced by increased insulin sensitivity and resistance vessel endothelial function, and decreased blood pressure, triglycerides, and adhesion molecules.

And our favourite, the “high saturated fat and no-starch” diet.[8]

An HSF-SA diet was prescribed for all patients; they were instructed to attempt to consume one half of all calories as saturated fat, primarily as red meat and cheese. Eggs and other low-fat forms of protein were allowed, regardless of cholesterol content. Fresh fruit and nonstarchy vegetables were prescribed in restricted amounts at each meal.
Starch was forbidden.
In patients with atherosclerotic cardiovascular disease, an HSF-SA diet results in weight loss after 6 weeks without adverse effects on serum lipid levels verified by nuclear magnetic resonance, and further weight loss with a lipid-neutral effect may persist for up to 52 weeks. All patients were obese (mean +/- SD body mass index [BMI], 39.0+/-7.3 kg/m2) and had been treated with statins before entry in the trial.

This diet contains every element that (in theory at least) should protect against statin side-effects. It’s high enough in fat and low enough in carbohydrate to stimulate beta-oxidation (and even supplies some fructose to activate G3PDH), it supplies vitamin K2, l-carnitine, Co-enzyme Q10 and cholesterol.

Take home points

  • Statins inhibit the synthesis of cholesterol, excessive production of which is an effect of high insulin levels. Therefore, if statins do reduce heart attack risk, diets which lower insulin secretion by restricting carbohydrate should do so too. However, statins are only specific for one effect of excess insulin, whereas carbohydrate restriction reduces its effect on multiple pathways.
  • Statins can damage muscles, with life-altering consequences, by inhibiting the mitochondrial CIII complex involved in the production of energy (ATP). Diets which activate fat-burning in muscles by restricting carbohydrate can restore energy production (in theory, based on experimental evidence).
  • Statins can cause memory loss and neuropathy, probably by depleting vitamin K2 and cholesterol in the brain and nerves. High-fat, animal based diets are good sources of these nutrients, and also supply extra l-carnitine and Co-enzyme Q10 that may help to protect muscles.

As always, we are not cardiologists and are not qualified to prescribe statins or advise against using them. Those are decisions for your doctor and you (yes you!) to make when you weight up the likely benefits and harms and what weight to give to all of these combined.

References

[1] Interpretation of the evidence for the efficacy and safety of statin therapy.
Collins R, Reith C, Emberson J et al. Published Online September 8, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)31357-5
http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)31357-5.pdf

[2] Insulin and glucagon modulate hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity by affecting immunoreactive protein levels.
Ness GC, Zhao Z, Wiggins L.
J Biol Chem. 1994 Nov 18;269(46):29168-72.

[3] Adverse Effects of Statin Drugs: a Physician Patient’s Perspective.
Graveline D.
Journal of American Physicians and Surgeons Volume 20 Number 1 Spring 2015
http://www.jpands.org/vol20no1/graveline.pdf

[4] Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition.
Schirris TJJ, Renkema GH, Ritschel T, et al.
Cell Metabolism 22, 399–407, September 1, 2015.
http://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(15)00393-9

[5] CoQ10 and L-carnitine for statin myalgia?
DiNicolantonio JJ.
Journal Expert Review of Cardiovascular Therapy. 2012: 10(10); 1329-1333

arduini2004

[6] Age- and brain region-specific effects of dietary vitamin K on myelin sulfatides.
Crivello NA, Casseus SL, Peterson JW, et al.
J Nutr Biochem. 2010 November; 21(11): 1083–1088.

 

[7] Dietary carbohydrate restriction improves insulin sensitivity, blood pressure, microvascular function, and cellular adhesion markers in individuals taking statins.
Ballard KD, Quann EE, Kupchak BR, et al.
Nutr Res. 2013 Nov;33(11):905-12. doi: 10.1016/j.nutres.2013.07.022. Epub 2013 Sep 18.

[8] Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease.
Hays JH1, DiSabatino A, Gorman RT et al.
Mayo Clin Proc. 2003 Nov;78(11):1331-6.

 

 

 

13 comments

  1. excellent post George! a lot to think about here…although it’s not on-topic, i’d love to know your thoughts on people who get rid of their hyperinsulinemia but see higher LDLc (or LDLp). my hunch is, no problemo, but i’m still at a loss as to how.

    Cheers!

    PS: tiny typo ==> “…muscle cell’s ability to generate APT, with apoptosis…”

    1. Thanks Raphi, fixed now.
      Correcting hyperinsulinaemia usually lowers LDL, but elevates it in a minority of cases. Dr Sarah Hallberg has a good discussion of this on YouTube, and there’s an additional possibility, that apoCIII clearance is insulin-mediated, so that low insulin in some people with a more persistent form of apoCIII or a higher output of this protein could make LDL more persistent,
      My hunch is high LDL with lower insulin is not doing much to increase risk in someone without preexisting CVD, but as disease progresses you might see more LDL involvement and want insulin or LDL lower.

  2. Lindsay Rowe · · Reply

    Hi,

    Thanks for your always insightful posts.

    Three years ago I came across your recommendations regarding a LCHF diet and after some further research and reading decided to adopt this approach to my diet. I lost ~8kg dropping from 86kg to 78kg in a straight line over six months and have now maintained this weight for the past 2½ years. On the basis of this drop in weight and girth size had reduced my risk of cardiovascular disease (and after some more reading around the benefit vs risk of statins) I decided to discontinue with the statins I had been taking for the previous 10 or so years. Unfortunately my GP has “washed his hands” of me simply recording that the patient refuses to take statins and failing to offer me any support on diet, exercise or lifestyle that could help to further reduce my risk. At this stage I have still not had the courage to visit my cardiologist who in the past has largely diagnosed my risk from blood test results and offered nothing other than further medication. My search is now to find a medical clinic, GP and or cardiologist who is willing to incorporate a LCHF approach to diet and to support me in managing my cardiovascular health without resorting to the use of statins – can someone please provide some direction as to where I might find this type of professional medical support, ideally in the lower half of the North Island.

    Thanks

    Lindsay R

    1. Hi Lindsay,
      there is a list of practitioners who use a LCHF-friendly approach on the What The Fat website
      http://whatthefatbook.com/lchf-health-network/
      I don’t know that I’ve ever had a GP who looked like they could advise me on exercise!

  3. Richard Lehman, a smart critic of the medical journals whose BMJ blog is well worth following, has a good discusion of the Collins paper here
    http://blogs.bmj.com/bmj/2016/09/12/richard-lehman-where-next-with-statins/
    I have added a summary of this blog in comments (awaiting approval), I believe that Malcolm Kendrick has also commented.

  4. Thanks for the info. I have been damaged by 2 months on statins over 7 years ago and my condition has progressively worsened such that I am bed bound. I am interested in the “take home point” that perhaps a high fat/low carb diet can help reverse/overcome ( not just prevent) statin damage. Could you point me to any other data on this or elucidate any further? Thanks in advance.

    1. Hi Barry,

      the experiments I looked at for this post used a supplement called l-carnitine to increase beta-oxidation. i-Carnitine is the molecule that shuttles fatty acids into mitochondria is often used by athletes to increase fat-burning, it is considered very safe. I will edit the post to add at the bottom – after reference 5 – a link to a paper, Arduini 2004, in which l-carnitine improved rats with statin toxicity. This paper also states that statins have depleted l-carnitine in rabbits. One cause of l-carnitine deficiency in humans is vitamin C deficiency, but people can also be born with a reduced ability to make this chemical.
      Here is a MedScape article about Co-enzyme Q10 and l-carnitine for statin myopathy.
      http://www.medscape.com/viewarticle/776243
      In NZ you can buy a supplement called mito Q which is probably the best form of co-enzyme Q. I would suggest trialing the LCHF diet at around 70g carbohydrate to minimise any adaptation period that might worsen fatigue. This hasn’t been used in any published literature as far as we know, and we can’t offer this as medical advice, it’s more in the line of “what I would try in this situation”.
      I suggest searching on low carb forums to see if anyone has experience of recovering from statins in this way, it is very likely that you will find some useful support. All the best, George

      1. From the MedSpace article –

        Muscle biopsies and blood samples were tested in 132 patients who developed statin myalgias.[18] The results of this trial were presented at the American College of Rheumatology in 2004. Patients experiencing muscle pains on statins were 11-times more likely to be a heterozygous carrier for the carnitine palmitoyltransferase-2 deficiency, and 31% of muscle biopsies evaluated had carnitine abnormalities. Moreover, patients were 20-times more likely to be carriers for McArdle’s disease (a glycogen storage disease), and a third had lipid storage problems. This trial suggests that people who experience muscle pains on a statin are more likely to have an underlying metabolic muscle disease with the symptoms of statin muscle pain being brought out in these carriers. Furthermore, almost 50% of the analyzed samples had CoQ10 (ubiquinone) levels that were 2–4 standard deviations below normal. Therefore, supplementing with both CoQ10 and l-carnitine may be a rationale approach to treating certain statin myalgias.[18] Despite the high prevalence of carnitine abnormalities in patients with statin myalgia, there are no randomized controlled trials showing that l-carnitine treats this adverse reaction.

        In summary, it has been proposed that CoQ10 can help to treat statin myalgia. While this is not conclusive, there are two randomized controlled trials showing significant improvements in the severity of muscle pain with the use of CoQ10 in patients treated with statins. Thus, it is not unreasonable to supplement a patient who is experiencing muscle pains on a statin with CoQ10. While there are no clinical trials showing improvements in muscle pain with the use of l-carnitine, patients who experience statin myalgia frequently have carnitine abnormalities. It is too soon to recommend l-carnitine for statin myalgia, but future trials should test this supplement to see if it has any place for this adverse effect. Other common alternatives for treating statin myalgias are supplementation with vitamin D or vitamin B12, especially in the setting of suboptimal serum levels.

        The reference is
        Vladutiu G, Isackson P, Wortmann R et al. Metabolic muscle disorders and cholesterol-lowering drugs. Abstracts of: The American College of Rheumatology 2004 meeting. San Antonio, TX, USA, 16–21 October 2004 (Abstract 1784).

  5. George/Puddleg58
    Thank you for your info. Fyi….I have been trying acetyl l carnitine and coq10 among other supplements but I will investigate a higher dose, along with a HFLC diet, to see if I can get any improvement. Thanks again.
    Barry

  6. Hi Barry,

    I notice the reference in the MedScape article to vitamin D; if you’re in NZ, and bedbound, this could be an issue at this time of year. From my experience vitamin D deficiency increases pain and fatigue from other causes (the probable mechanism is increased autoimmune reaction to the damage already done), so this is worth checking out.

    George

    1. I am in California, but am bed bound so the Vit D is a good suggestion.

      There are so many people suffering from statin damage it would be great if we could find something to help.

      Barry

      1. One tip – beware of using supplements with excessive amounts of pyridoxine (vitamin B6). This is often added freely to other supplements and will make symptoms of muscle weakness worse if you become overloaded.
        https://www.ncbi.nlm.nih.gov/pubmed/3630649

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