Wednesday, November 14, 2018

A brief aside in to statins and FH and all cause mortality

I must admit that I have not read this paper, just the abstract. My excuse is, once again, that I have no access to any ondansetron.

Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality

As always the results of statin therapy are, to say the least, dramatic.

"In patients with heterozygous FH, moderate- to high-intensity statin therapy lowered the risk for CAD and mortality by 44%".

Wow. But why the need for a composite end point?

If we leave aside soft end points which include coronary re-vascularisation (never influenced by serum lipid levels. No laughing at the back there!) and concentrate on the hard end point of all cause mortality we end up with, for non statinated people:

9 deaths per 4,892 person-years, which I make 1.8 deaths per 1000 person-years.

On a statin we have 17 deaths per 11,674 person-years, 1.5 per 1000 person-years.

That looks like a reduction in mortality of 0.3 people per 1000 person-years.

Or, being more whole numberish, 1 person saved by treating for 3,300 person-years on a statin.

Does that convert to treating 100 people for 33 years to avoid one premature fatality? We're all going to die one day so no one avoids death permanently, even by taking a statin. Unbelievable as that sounds.

If you have heterozygous FH your chances of dying tomorrow are rather low but not quite zero. If you take a statin it will reduce this chance by a vanishingly small amount.

Taking the difference between "rather-low-but-not-quite-zero" and "a-vanishingly-small-amount less than rather-low-but-not-quite-zero", dividing this difference by "rather-low-but-not-quite-zero" and multiplying by 100 we get a massive 17% reduction in all cause mortality. Which means diddly squat, but sounds good if you are a statinator. Admittedly not as good as 44% for the composite end point but hey... Neither means anything.

The main benefit of a statin appears to be that the number it gives you on a lab report might just influence a cardiologist to leave your coronary arteries alone.

Peter

27 comments:

Unknown said...

Peter - No FH trial has succeeded by lowering mortality because bhigh LPDL.C is not the cause of CVD; mrfead our coming paper ib Med Hypothesis:
Inborn Coagulation Factors are More Important Cardiovascular Risk Factors Than High LDL-Cholesterol in Familial Hypercholesterolemia
https://www.sciencedirect.com/science/article/pii/S0306987718304729
Uffe

Peter said...

Absolutely Uffe,

Over the years I'd looked at the short term success of aphersesis and decided it was probably to do with the heparinisation needed to anti-coagulate the patient for connection to the machine. Never really followed it through but I read you last paper mentioning the removal of clotting factors during apheresis with great pleasure.

Peter

ctviggen said...

I wanted to break in here to mention that Dr. Ravnskov's book, The Cholesterol Myths, was the first book I read in this area, and caused my subsequent fall into the "dark side".

I also think Dr. Ranshkov's (along with the other authors) idea of coagulation being important is very interesting and makes the most sense to me. (Which doesn't mean much -- I also thought the idea that insoluble fiber helped prevent colon and other cancers made sense, but sadly the RCTs did not show this.)

Unknown said...

I've had "that talk" just recently with my doctor, wich reminds me to get a copy of the lab values. If memory serves, HDL increased, LDL went down, but still too high. Guess I'll have to defer dementia a bit with those numbers :-)

We didn't talk about trigs at all... but the doc agreed to get a more advanced lipid test done (lipoprint or equivalent), if I manage to get an appointment to get the blood drawn at "The Big Hospital". Maybe I can get them to test Homocysteine & some coagulation factors as well. Would be interesting to see if I'm a LMHR type & will definitely trying the "inversion pattern" test of Mr. Feldman. 3 days of filling up with Yoghurt and cream... what fun!

js290 said...

But, you're ignoring all those beneficial side effects of statins...

Peter said...

js, how can a drug with no side effects have so many beneficial side effects?

Peter

Eric said...

Your last paragraph probably nails it. Unnecessary BP meds and stents are probably a silent killer that someone already on statins or having better looking lipid numbers can avoid for a longer time.

Pernickety said...

Firstly, thank you very much for your incredibly educational and interesting blog posts. I am still trying to piece together the information that I have collected from reading your posts, but I greatly appreciate the time you have put into conveying your thoughts in a manner that a layperson can understand.

If you have extremely elevated total cholesterol (>20mmol/l) and LDL (>17mmol/l) but no coagulation anomalies or any family history of cardiovascular disease, and also happen to be a hyper-responder to saturated fat consumption (i.e. tripling of LDL on a low carbohydrate diet), do you think it is more sensible to remain eating a low-carbohydrate, low-polyunsaturated fat and moderate protein diet, or to focus on lowering your cholesterol to a more typical level (e.g. <12mmol/l) by switching to more monounsaturated fats rather than saturated fats (so less dairy) or by introducing a few more carbohydrates? If so, are there any safer sources of carbohydrate that you'd recommend? Considering my high cholesterol, would it be more pertinent that I avoid hyperglycaemia than the average person? What other situations are best avoided if I don't want to end up with a large percentage of oxidised lipoproteins?

Also, I was wondering whether you normally consume your creamy cocoa drink cold or warmed up? If you have it cold, do you know if heating the cream up would be detrimental in any way? Also, I know you said a couple of years ago (?) that you have moved away from eating 100g of 90% lindt each day, instead having more macadamia nuts - would you mind explaining why you chose to do this?

Peter said...

Hi Pernickety,

Sorry for the delay, lots on the go. Just had my Bouldering induction. Very cool!

My cocoa is warmed, I think I’m probably back to 100g/d 90% choc per day, macadamias have drifted to probably a couple of 100g packets per week. No real reason, life drifts! I try not to stress about the small stuff.

The cholesterol issue is interesting. Why would you want to lower your cholesterol level? Are there any data I’m missing that suggest that lowering cholesterol might prolong either life or health? If we consider the lipid hypothesis was pure garbage in the 1950s, is there any particular time point at which it became valid?

I think your biggest problem is that you have measured your lipid levels. This is one the the surest signs of Cholesterolophobia, a pathological problem promulgated in large by cardiologists and now pervasive world wide. I have suffered myself (very) transiently in the past.

I think I’m probably right if I loosely quote Dr Ravenskov when I cite the best cholesterol level as the one which has not been measured. I stand open to being corrected.

Peter

Smileybro said...

Cholesterolphobia? More like Lipochondria... LOL

Peter said...

THAT is a word I wish I had coined!!!!!!!!

Peter

Smileybro said...

I can't claim an neologism as it is defined as lipid vacuoles of the Golgi Apparatus: but I agree it is worth adding a catchy phrase "raving lipochondriac" as an epithet to those obsessed with what is actually a minor discipline.

SM said...

Lipochondria - Medical Definition from MediLexicon
www.medilexicon.com/dictionary/50753
lipochondria[lip′ō-kon′drē-ă] Type:Term. Definitions. 1. Temporary storage vacuoles of lipids found in the Golgi apparatus.

Passthecream said...

I was reading about Dave Feldman's latest ldl lowering experiment ( I couldn't care less about hdl/ldl values etc but interested in lipoprotein function and mechanism.) He slightly increased his carb intake for 3 days and got dramatically lower ldl values. He explains it as part of energy metab. in 'lean mass hyper responders' Hmm. What is the signal which makes his explanation work? Do these people have extremely low insulin levels? Ie no lipid being driven into cells, ldl receptor dialled down somehow by low insulin so ldl remains high in circulation? => Pulse the insulin and ldl rapidly delivers its payload and circulating levels go down. QED.

Googling around, this paper seems to suggest it might be the case, once you ignore the usual chol. theory of disease boolsheet in the preamble:

https://journals.sagepub.com/doi/abs/10.1177/1479164111430243

Peter said...

Pass, a friend sent me the link to Dave Feldman's work but at the time I never really paid attention because, well, it's the lipid hypothesis and... The one passing thought was, as you suggest, insulin is what drops the very high LDL here. What you might enjoy is this one https://www.ncbi.nlm.nih.gov/pubmed/18167317, I'll probably put a post up about it someday... I think you are in the correct area of speculation.

Peter

Peter said...

Pass, a friend sent me the link to Dave Feldman's work but at the time I never really paid attention because, well, it's the lipid hypothesis and... The one passing thought was, as you suggest, insulin is what drops the very high LDL here. What you might enjoy is this one https://www.ncbi.nlm.nih.gov/pubmed/18167317, I'll probably put a post up about it someday... I think you are in the correct area of speculation.

Peter

Passthecream said...

Ta. Mention of Cho cells is a strange coincidence - I was reading a modelling paper last night about cho cell metabolism during antibody manufacture. My wife says she has some in the freezer at work so perhaps the era of diy cell metab. experiments is not quite over, outside of bio-hacking I mean.

It ocurred to me that those l.m.h.r people might also be a little insulin resistant due to their high calorie high fat diet. There has to be some glucagon splashing around there too up until the 5 to 10 slices of bread per day are consumed.
Yuk.

Paul L said...

Peter, Peter, Peter, you really ought to know, clever fellow that you are, that "The _main_ benefit of a statin appears to be" that it funds the sixty-million-pound annual bonuses of pharmaceutical company executives. Let us not get sidetracked by issues of the welfare of patients who, if they were well, after all, would fail to meet their obligation to contribute to the bottom line.

Bob said...

Hi, Peter.

The paper you mentioned to PassTheCream (https://www.ncbi.nlm.nih.gov/pubmed/18167317) says,

"In cardiac and skeletal muscles, insulin regulates the uptake of long-chain fatty acid (LCFA) via the putative LCFA transporter CD36."

Okay, I'm trying to reconcile "insulin-induced translocation of CD36" with the line from this post:

"The rate of fatty-acid uptake and oxidation by the heart is controlled by their availability [33]"

Seems contradictory. Thanks.

Peter said...

Bob, yes, I had no idea about the effect of insulin on CD36 receptors when I wrote that line (hence the need for a post but there is never enough time). It seems to have been looked at in the early 2000s and then forgotten. Of course it makes perfect sense. Bulk supply of FFAs is controlled at the adipocyte, intake in to cells is controlled by the action at the cell surface, controlled by insulin and ultimately by superoxide. My earlier comment is simply inadequately informed, time goes by, you read more papers and learn more stuff...

Peter

Bob said...

Peter, thanks. Yes, I understand about learning more stuff. That's all I do with your blog, after all.

I do hope you have a chance to do a post at some point. The insulin effect on LCFA intake strikes me as having lots of implications for normal physiology vs hyperinsulinemia pathology

Passthecream said...

I'm retroposting here. In addition to cd36, insulin up-regulates lipoprotein lipase (lpl) in fat tissues while it inhibits hormone sensitive lipase. It's a triple whammy wrt insulin (this is relevant to the solstice insulin/liver post too). Lpl rips the triglycerides from ldl and chylomicrons, moves them into adipocytes and mops up the lipoprotein remnants. It has a different effect in muscle cells but probably goes a long way to explaning why a burst of insulin would lower circulating ldl levels.

Passthecream said...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681393/ is relevant and the Wikipedia article on LPL is useful.

Pernickety said...

Hi and apologies, it's the lipochondriac again :-) I'd love to have a go at bouldering one day - very jealous!

I've been wondering about the various causes of elevated Lp(a), and hope you can help me understand its various functions better. Peter, back in 2007 you wrote 'Lipoprotein(a) is especially needed if you have defective LDL receptors, so in familial hypercholesterolaemia you would expect lipoprotein(a) to be high'. I suspect it's likely that I possess one allele for defective LDL receptors which may partly explain my high Lp(a), however most studies suggest that the difference between controls and FH heterozygotes is in the realm of 20-50mg/dl, and mine far surpasses this. Also, is it right to think being an FH heterozygote may potentially be positive in terms of innate immunity, however, especially with the rise in antibiotic-resistant superbugs?

Therefore I guess my question is whether having an elevated Lp(a) of >2800mg/L (>280mg/dl in units typically given) is a sign of damaged endothelium and the need for vast amounts of repair, which due to defective LDL receptors Lp(a) is relied on more to do a similar job to LDL? Is there a way to determine whether Lp(a) is elevated in order to accumulate oxidised lipids (presumably present in large amounts if Lp(a) is being secreted in response) and to deliver these to cells for carrying out emergency repair of the arterial wall (is that the correct hypothesised mechanism?), or raised from genetic factors without high oxLDL and/or endothelial damage present?

Also, Passthecream, you mentioned that the LMHR phenotype might be partially explained by lower insulin levels down-regulating LDL receptors, CD36 and LPL. Do you think the absolute insulin concentration or the relative drop from one's baseline would be more important for predicting whether someone will respond to a LCHF diet with a rise in TC and LDL?

Finally, please could you explain your concern of insulin resistance in a LMHR. What differentiates this situation from physiological insulin resistance due to high sat fat intake, which Peter has explained many benefits of in his Protons series, as long as one is not consuming both a high fat and high carbohydrate diet? Is it the high calorie aspect, or the greater glucagon secretion compared to a less active person? Sorry for all the questions, I'm just trying to gain a greater understanding!

Many thanks and I wish you all a happy new year.

Passthecream said...

Hi Pernickety there are many things I do not understand! I had a notion that DF's lmhr were not insulin resistant, rather the opposite. Lean (obviously!) eating very high fat and few carbs (in ketosis) therefore minimum insulin levels and perhaps a pulse of insulin could explain why, if one of them ate their usual high fat together with ~140 to 200g of carbs per day over three days, the temporarily higher insulin levels would quickly lower the ldl levels via lpl, asp, cd36 and the inhibition of hsl (And any other members of the zoo).

Perhaps there would also be a transient weight gain but those lmhr are very active people and for tge next three days tgey are back to their usual vlc eating. The usual hf diet of the cholesterol code supposedly produces mostly chylomicrons in the circulating lipoprotein pool which have a much shorter half life than vldl, ldl etc., hours rather than days, which is one explanation offered for the effect of DF's 'standard' protocol.

Do chylomicrons figure in LP(a) dynamics or do they have a different variety of lipoproteins? It would be handy to know but there are only ever more questions I'm afraid.

Passthecream said...

https://www.ncbi.nlm.nih.gov/m/pubmed/8729170/

(Insulin suppresses liver vldl production but not so much in the context of IR.)

Peter said...

Hi Pernickety,

I can strongly recommend bouldering. But then I think I may be addicted... On the Lp(a) front I'd have to go back and re read, it was a while ago...

All the best

Peter