Sunday, March 29, 2015

HbA1c and Familial Hypercholesterolaemia

Ivor, over at thefatemperor, recently mentioned the lovely observational study, the Norfolk section of EPIC. That's where I live and it's HbA1c which correlates with CVD here. Cholesterol does not. At all. Tha' be 'ere in Norf'k, b'o'r. With apologies for the lapse in to the vernacular. My children are becoming experts. Computer is com-poo-er...

That nudged me to put this very brief observational post up on glucose dysregulation and CVD in the land where cholesterol is king, for people with heterozygous familial hypercholesterolaemia. There are many, many problems you could point out in this study, but those are intrinsic to a retrospective observational study. Take a group of hFH people who have survived a premature heart attack. Match a similar group of hFH people who haven't had a heart attack. How do you tell the difference between the groups? As a lipidologist perhaps you might suspect the LDL cholesterol level? That is exactly the problem in hFH after all... But:

"There was no difference in total and LDL cholesterol between the two groups. Patients with previous myocardial infarction had significantly higher levels of insulin, insulin resistance [and several other things I'm not interested in, which they would like to treat]..."

Insulin resistance is the problem, on a mixed diet. Do you think this might show in the HbA1c, just as it does here in Norfolk for us non hFH folks?

It probably does. In a similar observational study on hFH, using HbA1c itself rather than insulin/resistance parameters:

"Of special note is that HbA1c showed a significant correlation with average ATT [Achilles Tendon Thickness], independent of other parameters..."

Achilles Tendon Thickness is a marker of Badness in hFH. As your tendon thickens, so too does your carotid intima thicken.

In general, patients with hFH tend to have rather good glucose control compared to the general population. That might just be why they live as long as they do under the correct circumstances. But with hFH I suspect that, should you manage it, developing metabolic syndrome may be a very unforgiving problem. You have to wonder what side stepping the syndrome by low carb eating might do, giving chronic normoglycaemia without elevated post prandial insulin. Not holding my breath waiting for that one.

BTW, as statins worsen glycaemic control, could they actually make the CVD problems worse for hFH patients? Surely not. Surely we have stopped making booboos of this type. Of course we have. Of course.



Unknown said...

Nice post Peter. Get all those people over that way outside and into the sun and away from the blue light Peter. I bet their insulin changes with messing too badly with their diet. There is a deep reason every mammalian somatic gene has a circadian clock gene right in front of it.

Warburg is trying to tell you something about know that big series you left..........I hope you get back to it.

Tucker Goodrich said...

That's a weird correlation, between AT thickness and HbA1c.

There are some other items I've come across that might speak to a connection between tendon health and overall health.

ACL ruptures, for instance, are one of the most common knee injuries today, even in children.

They didn't exist prior to the mid-60s.

The group where ACL tears first emerged as a common injury was football players at West Point, where they'd been playing football for a very long time.

Now what could cause a change in the structure of the tendons, and is also closely related to CVD?

Hint, it's not glucose...

Puddleg said...

This is pretty much where I'm at now Peter.
All else being equal, if insulin and HbA1c are low (and HDL is a not too shabby marker for this) you can safely
- eat carbs and have higher TGs,
- eat normal fats and run higher LDL.

If, on the other hand, insulin and HbA1c are high, you'll tend to have high TGs, low HDL, high LDL anyway.

Metabolic syndrome - insulin is the king pin, sort that out and you're good to go. LCHF or fasting cuts the Gordian knot, I'm sure there are various methods of untying it too if you have the time and luxury.

Peter said...

Jack, there are so many things I want to go back to. One day.

Tucker, ACL ruptures are so common. I've long felt they were diet related. I briefly met a surgeon who had just finished her PhD on the degenerative changes in the ACL of dogs. No ligament is normal at the time it tears.

George, I had a line in there saying "It's the insulin, stupid". Probably should have left it but couldn't remember who said it.


Ash Simmonds said...

Dunno who first said it, but Andreas Eenfeldt championed it a few years ago.


I'd like to add a modifier - "It's the insulin/glucagon dance, dumbass".

FrankG said... :-)

As a person with Type 2 Diabetes, my common sense approach is that: the complications of raised Blood Glucose (BG) over the long-term, are already well established, not controversial and are not favourable to a long and healthy life. Meantime the notion that "high cholsterol" will kill you is not only grossly oversimplified, it is also subject to question and seems based more in profiteering than public health.

So, when choosing an LCHF diet which manages my BG but I am warned will "kill me" because "fat raises cholesterol", guess how hard a choice it is? Particularly when it turns out that, despite the dire predictions, I not only feel and look better but by am improved in every meaningful and measurable way.

Specious Sine said...

Hi Peter,

Thanks! A fab post. Lovely segue too.

Your adept game of pin-the-tale-on-the-hFH donkey stands alone, but in additional confirmation, studies(1, 2) on crohn’s indicate increase in cIMT, endothelial dysfunction, and I did read ATT, somewhere, in the context of distinct hypocholesteremia and low LDLc: HDL, trigs being unaffected. In this guise cholesterol is far from being ‘it’. Here, it’s regarded as innocuous until, under inflammation, oxidised, whereby oxysterols promote further inflammation in a fdbk loop(3). Tho, they do gravitate to figure a stymied cholesterol efflux as the generator, via low apoA1 (being displaced by CRP)> cause of atherosclerosis in CD(4). I guess its a pernicious thought-sieve? And, there needs to be a rationale for the statin-push with low TChol, LDLc.

Many studies indicate that CD shares a dark symmetry with obesity, diabetes. it really is a systemic metabolic-inflammatory disorder alongside these, just rather more macabre! Like this study(5), tho could only read abstract, has the summation of hyperinsulinemia being protective of relapse!

Hyperinsulinemia was associated with the decrease in adiponectin (r = -0.572, P < 0.001) and proved to be an independent protective factor for 6-mo maintenance of remission (P = 0.016).

Like for hFH, crohns patients seem to have good glycemic control, but with insulin resistance and hyperinsulinemia.

Seems For A1C, ATT, the link is inflammation: as viewed thru the bent of anti-tnf therapy.

The authors concluded that infliximab induction therapy is associated with a significant increase in abdominal fat tissue in CD...(!)
In addition, infliximab therapy was accompanied by a decrease in glycemia and HbA1c concentrations, probably by reversing the impairment of TNF-induced insulin-mediated glucose uptake [63].Similar results were shown in another study, where infliximab therapy in 22 IBD patients led to a significant increase in TCHOL, HDL-C and apoA1 levels after 14 weeks, while no difference was observed in TG, LDL-C, apoB100 and lipoprotein (a) levels [64].

IBD patients exhibit lower levels of LDL-C and TCHOL compared to healthy subjects with that finding being more profound in CD than UC patients. In addition, no significant alterations have been reported in these patients as far as HDL-C and TG levels are concerned. These findings remain stable independently of disease activity and are also observed post-operatively. Moreover, IBD patients exhibit lower levels of LDL-C even after intestinal resection....

In the second linked study, of the post, the other parameter was hypofibrinolysis, linked in particular to cardiac events over LDL or cholesterol...again, mediated by inflammation and syncronised to inflammation in crohn’s linearly.

I wondered about the low adiponectin, above, where chronic hyperinsulinemia is protective in CD. Less recognition by innate immune system of antibody-antigen complexes/ bacterial surface is not triggering acute phase havoc. A calm before petite adipokine storm a.k.a. disease flare? Seems tnf-a normally inhibits Ad, hypoad is a feature of inflammatory disorders, maybe just a chronic state.

So, does the increase in adiponectin via low carb/ketosis, functionally, partially inhibit TNF (homology!). Chemokine production could affect lipoprotein metabolism and might in part be held responsible for lipid derangements in patients with IBD(2). TNF regulates chemokines(7). Anti-TNF drugs increase TC and HDL-c, and reduce A1C, in inducing quiescence (temporal and prone to failure tho that it is, with a terrible NNT).

Can the hyperlipid way be palliative, by mod of hyperinsulinemia, adipokines/ cytokines which mod lipid metabolism and hence attenuating inflammation. A functional stand-in for anti-tnf therapy?

Specious Sine said...

Oh, and, struck upon a interesting dynamic and maybe answer. My recent TC, LDL, HDL rose, while CRP sank, a reversal. Could this be due to a state of high FFA, lipoproteins, where LPS is favorably bound to HDL, resulting in its inactivation and transfer to liver. Elevated lipoproteins are mediating the inflammatory response by taking up the LPS burden and deactivating it via HDL instead of being, transfered to CD14 receptors> immune cell activation(6):

HDL act as a reservoir for a series of proteins and lipids endowed with immunomodulatory activities, including lipid transfer proteins involved in the scavenging of LPS(LBP, phospholipid transfer protein [PLTP], CETP), apoproteins (apoA-I, apoE, apoL-1, apoM), and immunoactive lipids (S1P).
LBP is a plasma component (mainly associated with HDL) that binds LPS and, in the absence of lipoproteins, favours its transfer to CD14 receptors, resulting in immune cell activation. In the presence of lipoproteins, LBP facilitates the binding of LPS to HDL, resulting in its inactivation and transfer to the liver.86

Seems the changes to molecules, like cholesterol, under inflammation is the frightful bit.

(Excuse my un/miseducated ramble!)

karl said...

HbA1c may be a useful test, but it really doesn't replace teaching people to watch their postprandial BG. The problem I see is that there is an assumption that BG levels have a linear effect. Not sure this has been studied well enough - but I've seen some material that suggests that the glycation of lipids - and the consequential increase in oxLDL(the thing gets the immune system to start packing foam cells) is an exponential effect that would be missed if one only looks at the HbA1c.

With a lack of quality research to say definitively - my personal goal is to keep my postprandial BG below 110 - if I see it above, I know I ate the wrong thing or to much of something. This tends to keep HbA1c low - but I've seen some disconnect between the two measurements that gives me the hunch that both the average and peak levels matter. (probably the area under the curve AND the peak levels matter).

The post postprandial BG level of 140 promoted by some in the medical community is just too high IMO - I target lower than 110.

My 90 year old father can eat potatoes, some bread etc and tests at 108 -- If I eat a similar meal I would be over 165. Thus finding out what happens when you eat carbs - on a person level is quite important.

Now add to this mix the effects of PUFAs and high BG - do the effects multiply? If the QUALITY of research went up instead of the quantity - perhaps we might know someday.

OldTech said...


One of my grips is that it seems that we do not really know what is optimal behavior for blood glucose and I do not really expect this to be fixed. Studies done today are based a populations eating a modern western diet so just testing a bunch of people and determining what is normal does not really answer the question. I think that this is where the 140 number came from.

So I am taking a very conservative approach by following Dr. Berstein's advice to keep my blood glucose constant and that includes postprandial readings. In other words he says that your blood glucose should not spike. He also says that HbA1c should be below 4.7.

fff said...

Hey Peter

delighted that my mumblings inspired a post in your august organ :-)

On the FH side, I've been meaning for some time to put together the evidence for FH peeps needing to be low carb even more than the general population. My interest was piqued by the old study I used back in 2013 - just did a quick blog post on it:


Olga said...

Hi Peter,
Thanks so much for posting about hFH and bringing more evidence to the table.

I suspect the reason statins are never tested in hFH, apart from the fact they're not able to reduce cholesterol enough, is that they cause more side effects in those with hFH, than in the general population, especially of the cognitive variety.

This is purely an observation on my part, but seems to occur everytime someone in my family or an acquaintance, with hFH, resorts to statins. Present company included.

In a very nice post Zoe Harcombe mentions this as well, suggesting that if you have defective LDL receptors and then prevent cells from making their own cholesterol with statins, that you will effectively starve the cell of cholesterol.

raphi said...

I went down the FH (hetero & monozgous) rabbit hole ~3yrs ago when living in Amsterdam (NL).
It's a case in point of drunks (doctors) searching for their keys (theory) under the lamp posts (only think of you can measure, don't entertain other notions).

My cholesterol increased to 9-11mmol/mL when going LCHF-Keto ~4yrs ago & the advice I was given was = STATIN + LOW-FAT.

My genetic FH test came back negative & the advice remained. Even had it not, advice was still = STATIN + LOW-FAT.

My cholesterol profile (20/08/2014) went back down to: TC 7,42 mmol/l, HDL-c 1,98 mmol/l.LDL-C 5,20 mmol/l, Trigs 0,53 mmol/l. [This trend correlated with: more ketogenesis & lower BG (measured), more spontaneous fasting, more time under the sun & more sleep (easily 8-9hrs).]

Guess what the advice still is = STATIN + LOW-FAT.

I suspect a more meaningful conversation would have been had with a brick wall.

As far as I'm concerned, this obsession with LDL-c is ridiculous & entertained ad nauseam by so scores of Twitter docs sporting their white lab coats (I get it, you've got 'authority'!).

Maybe instead of assuming LDL-c is simply inconvenient VLDL 'waste' with only downsides to it (as was put to me by one of the Twitter lab coats), we'd be better of re-appraising cholesterol BASICS. With all this talk about cholesterol, it's not clear how and why it does what it does, REALLY. Why is it always 'at the crime scene' & never found guilty? For every e.g. of cholesterol supposedly being detrimental to health, there are 10 more showing that it's fundamentally important when dealing with; immune responses, cellular membrane structure, nervous system development etc.

LDL-c is worst than Christ - it resurrects ALL THE F*CKING TIME!

[rat over]

Unknown said...

Insulin levels to me are most interesting in how they affect glucagon's action on DNA synthesis. The correlation of AT and HbA1c makes sense to me. When energy is lost in a system things will get larger. Glucagon can be both a -/+ modulator of DNA synthesis depending upon the insulin level and the temperature of the environment the animal is in.

Bea said...

My mother and I have pretty much the exact same cholesterol profile. Total around 275... LDL 175ish.....whether I eat butter or only lettuce LDL 175..

Mother is 80 no cvd.

I stupidly let a "doctor" convince me to lower it with something called red yeast rice . His patients had great success with it without side effects.

1 month total of taking it cholesterol was 200 and I had severe damage that took 2 years to recover from. I developed small fiber neuropothy over my whole body. Confirmed by a muscle biopsy that showed active denervation of the small muscle fibers. Very painful. Was on neurontin for 2 years for the pain. My tendons were painful in my feet. Muscle loss. My calve muscles seemed to disappear overnight.

I found a cardiologist that helped people with problems after lipid lowering. His protocol was
basically a high dose CoQ10 and lots of
fish oil. It helped but LCHF really is what eventually brought the greatest healing.

Last lipid panel about 4 years ago trigs had gone from 170 to 50 and hdl was in the 70s. LDL was ................175 and never felt better!

fff said...

Updated Blog post with two more interesting papers inserted up top - enjoy:

Unknown said...

Tucker and Peter: Tendon ruptures, ACL tears and DDD in the spine all tied to use of excessive Br and F to lower the redox potential. Higher HBA1c is also a redox measure and shows the plasma dehydration. Many ligament injuries are seen with the floxin drugs and this is a redox story related to fluoride and Br effect on water. IF you have less water in your body the effect is magnified All grains in the west are now brominated........I have been telling people about collagen water and halides for a long time as a surgeon.

Puddleg said...

True Jack, bromine gas is the fumigant whenever a shipload of grain is allowed into a country. I used to work for the Ministry in charge of such things in New Zealand - I'd forgotten all about that.

Jim said...

Off-topic from blood glucose and cholesterol: I thought I understood the whole proton thing, but now I am confused. Proton gradients at undersea hydrothermic vents created a reduced entropy in some natural mineral tubes so that systems could evolve replication and eventually encapsulate these natural hydrothermic vent processes into the machinery that is the raison d'etre of modern mitochondria. Zoom through time from these vents to the first eukaryote when an archaea engulfs some bacteria that retain both this wonderful respiration machinery and the equally wonderful photosynthetic system. But why did the archaea and many of the bacteria lose all this wonderful machinery and have to go eukaryotic to get it all back? I am missing how you might get from these way-back undersea vents to the eukaryotes.

Peter said...

Hi all, I'm a bit involved in an anaesthesia project at the moment so answers to comments are sadly lacking. Jim. Leaving the vents is not simple. It involves a sodium gradient, still retained at the eukaryote cell surface today, where as the mitochondria reverted (as did many archaea and eubacteria) once free of the vents to a proton gradient. Many bacterial ATPases are happy to use a proton or Na+ gradient. There seems to be some advantage to using H+ gradients over Na+ gradients to most modern organisms.

gets you started


Olga said...

Peter, have you seen this study?

Two of the magical fatty acids are saturated and the 3rd is monosaturated.

Peter said...

Thanks Olga, I think I saw the press report... Interesting signalling.


Peter said...

Hi Robert, request complied with


spfldo said...

In my n=1 experience, you are dead on, on this one Peter. I'm hFH, family history (father died of MI at 33), early onset heart attack, two open heart surgeries a stent for ten "blockages" as certified by angiograms, and angina. My FH is type2a, which presents with high TC, low HDL and "normal" TG, and interestingly tendonitis in the Achilles tendon. During my trials, tribulations and interventions of the medical community, I had never been tested for Blood Glucose or HbA1c. Years later, I was already on a "relatively" low carb diet, because I'd come to the conclusion that CVD was likely a form of diabetes, when I had a pretty comprehensive blood test, back in the summer of 2011. The HbA1c came in at 5.5% and the data sheet says, NORMAL. Dr. Richard K. Bernstein says he's seen diabetic complications in the mid fives. In the preceding years of a typical high carb diet, I'm sure it was much higher and is what was causing my CVD troubles. Thanks to bumping into Ivor Cummins by chance, I read an article about Dr. Kraft's research on insulin and the diabetes/heart/CVD connection and decided to go low, low carb, high fat and fast intermittently. After several months, my angina was lessening a bit, but what really came to my attention was, tendonitis, which had been bothersome for years was gone. I've gotten remarkably better over the last two years and the angina that kept me from even walking sometimes after a meal or on a cold winter day is almost completely non existent during any daily activity. AND, now I cycle up to 60 Kilometers some days. I believe that CVD is caused by high BG and insulin and that hFH especially, is a form of diabetes, which is not understood by the medical community. One key indicator is the TG/HDL ratio, which I've read on Ivor's blog is an indicator of insulin resistance. On a low fat diet my TG/HDL ratio is as high as 7 to 1, on a high fat, intermittent fasting diet/regimen, it's less than 1 to 1.

Peter said...

Hi spfldo,

That's a nice set of observations. I think I did find that most FH people had improved insulin sensitivity but if you managed, either lifestyle or genetics, to develop insulin resistance then you were in trouble. Of course the dietary recommendations for management of FH virtually guarantee metabolic syndrome. It would be interesting to see the outcomes of managing a set of FH folks with dietary normoglycaemia/insulinaemia. I'm not holding my breath waiting for that trial.........