Tuesday, November 06, 2012

Dalcetrapib fails as it should

Still no time to post but this one liner is another gem. Dalcetrapib, another (yawn) HDL raising drug has bombed. Who is surprised?

Funnily enough Dr Nissen (Rentaquote-you-have-a-statin-deficiency) feels dacletrapib failed because it was too weedy to do any good, only a 30% increase in HDL.

Evacetrapib (Nissen's gravy train) and anacetrapib will REALLY work because they double HDL and slash LDL.

No they won't. They will do exactly what torcetrapib did as they are as potent as torcetrapib was. Body count will rise. Dalceptrapib killed no one as it is not potent enough to do so!

Peter

43 comments:

George Henderson said...

Surely if people still want this effect they can take niacin.

Interesting study posted by Carbsane where PUFAs were significantly more ketogenic that SFAs: http://jcem.endojournals.org/content/89/4/1641.full.pdf
not for long-term use, perhaps, but maybe a way to kick-start ketosis.
Amazingly, zero fish were in the POLY diet in this study, focusing more on soy and other crap.
What the hell was "crystal light"?
Sounds like hippy food.

tess said...

crystal light is koolaid for grown women. yuk.

Gladina said...

Just eat seafood. Easy.

I don't eat soy. Period. Not if I care about my thyroid. Never.

Crystal LIght. Ew.

I do find from personal experience that 'pufa' but from seafood sources does do a nice job in providing ketone bodies for fuel.

M said...

Could I ask for some advice/sugestions regarding dairy?

With the current economic crisis I've been trying to make the most rational choices possible within our family's tight budget, so I've gone back to using my yogurt maker to make yogurts at home, as it's such an inexpensive way of stretching money a bit more, and yogurts (at least to me) are pretty filling. Just two are basically a meal for me.

I do remember Peter saying that dairy (both on account of its sugar and its proteins) is insulin promoting, and should therefore be avoided by those to whom this is a problem (I have weight issues and the auto-immune disease psyorisis).

I was wondering: if I stick to full fat milk and full fat yogurt, and don't eat more than two yogurts a day, would this cause problems? And secondly, would straining the yogurt, thus getting rid of some of the protein, be a smart move? Would that make the yogurt have a higher percentage of fat and less protein in it, and therefore make it less insulin promoting?

Thanks for any suggestions you're kind enough to offer.

Gladina said...

M. Of course this question is directed to Peter,but I have opinion on this.

I think firstly for someone with AI you answered your own question---and you should not consume dairy at all.

Secondly, one needs to have attitude of experimenting. Try to have everything the same and record some metrics along the way. For example you can try to recall some things you noticed from the past with 'regular whatever you buying yogurt'. Then you record again with the home made yogurt. Do you still have weight trouble? Do you still have psoriasis?

I personally think experimenting is not needed in this case since AI determines to simply avoid it at all costs. The casein proteins do not react well with anti-bodies and inflammation.

There must be alternative low cost and filling snacks/meals for you to enjoy. Heck you might even find something a. cheaper b. actually 'helps' towards AI instead of making it worse...you never know...

OK good luck. For me 'budget' never ruins nutrition. I know what is most important elements for my diet and as long as I get those, the rest is just 'extra'.

karl said...

There is another way to raise HDL (not that I think it should be a goal by itself).

That would be consumption of non-ductched cocoa (don't add sugar). ( Dutching destroys this property). It appears to really work. Is it really good for you? I don't know.

There are likely 100 types of HDL (depending on just what protein is attached) - some have been show associated with more arteriosclerosis - not less.

This insane hunt for a HDL raising drug is the problem of junk health science - (attributing causation to a mere correlation - and not even specifying which type of HDL!).

HDL can act as part of the innate immune system and can bind and inactivate unstable L-forms of Staphylococcus aureus. IMO most arteriosclerosis and CAD is an autoimmune disease - not a disease of lipoprotien levels.

What is totally bizarre is that they know quite a bit about interleukins, inflammation, Lox-1, etc, but the cholesterol mantra marches on. They appear more interested in treating lab tests rather than the disease.

It looks like only oxLDL (not LDL ) is associated with the recruitment of monocytes - that end up as macrophages in the intima of artery walls. It is there that Lox-1 uptakes oxLDL. Statins block Lox-1 - probably why statins do a bit to reduce CAD (at a health cost) rather than reducing LDL.

BTW - oxLDL is a cheap test (about $80-90 to test HDL, oxLDL and CRP) that your doctor doesn't run.

What is associated with keeping oxLDL low? Well low BG for one.
Here is a list of things that are supposed to lower oxLDL. Will it change outcomes? I don't know.

I am pretty sure that we did not evolve LDL to cause Cardiac Disease nor did we evolve HDL to prevent it. I am also pretty sure that LDL is harmless unless it ends up oxidized. I've seen Zero papers - as in nada, nill, nun - that show LDL levels are associated with CAD IF oxLDL levels are held constant. (I've looked quite a bit - let me know if you find one. )

M said...

Hello Gladina, thanks for replying.

One of the things that worries me regarding dairy consumption is that, although I've been trying for a long time to remain paleo I nonetheless still crave carbs, especially at night - and I now find that eating yogurts curtails those cravings.

Some people might say that's wonderful news - that it's certainly a lot better to eat a yogurt than a slice of bread - but what if this indicates that my cravings are actually for the insulin spike in itself (which presumably the yogurt provides) and not so much for the carbs, which would not mean such great news.

Which is why I'm wondering if, for instance, reducing the percentage of protein by straining the yogurt, and upping the fat content, by for instance adding cream and/or butter, would not make it less insulogenic and still filling.

karl said...

@George Henderson

Another one of those studies where they lump a bunch of different variables together.

For this to provide something meaningful, I would suggest a standard synthetic diet as a base line - then test on type of fat at a time. In real experiments - real science - the idea is to have a single variable.

There are many different ω-6 and ω-3 FA - each one could be varied - one at a time.

"crystal light" is one of those food-like-substances - basically artificial sweetener( aspartame or stevia (I've seen stevia increase peoples BG) with artificial(?) flavors.

Galina L. said...

I found the most budget-friendly way to do paleo is the diet based on organ meats and eggs. I also remember reading that Peter was raised on roadkill if I am not mistaken. I never tryid it myself, but I thought about calling numbers on a graiglist to the people who adwertised themselves as a wild pigs catchers(maybe even wild racoon catcher could be an option for somebody who wants to keep pets on a paleo diet as well).

My comment is a sneaky way to be subscribed on other comments. Peter, I wish I had an option to do it by just clicking on some small square.

karl said...

A couple of papers that I think shine the light on the real cause of heart disease.

Autoimmunity in atherosclerosis: a protective response
losing control?


A new paper on an enzyme that reduces the oxydized lipids :


Low Serum Glutathione Peroxidase Activity Is Associated with Increased Cardiovascular Mortality in Individuals with Low HDLc’s

A list of things that appear to lower oxLDL ( not LDL )

A list of things that appear to lower oxLDL

Just to be clear - oxLDL levels can be elevated or low independently from the level of LDL - LDL is a very poor proxy for oxLDL. oxLDL levels appears to a function of the level of ROS.

George Henderson said...

One for Karl:
http://diabetes.diabetesjournals.org/content/54/5/1506.full

Linoleic Acid Increases Lectin-Like Oxidized LDL Receptor-1 (LOX-1) Expression in Human Aortic Endothelial Cells

karl said...

@George Henderson

There is another paper that says 16:0 palmitic acid also messing with Lox-1

Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells

I've been looking at the fats-Lox-1 connection some some time. here are a bunch of
notes I've got started. I think oxLDL is a metric that is involved in the BG + 18:2 ω-6 linoleic acid = autoimmune reaction. (also why they got distracted with LDL - which has only a poor correlation with oxLDL ).

My take-away so far is that out of control BG confounds what we know about FA. I'm also thinking there is something about the increase in 18:2 ω-6 linoleic acid in our diets that is suspect for causing the T2D pandemic.

There is a table near the top of those notes I need to fill out (hoping Petro might help).

I'm worried about lumping FA into a ω-6 group - they fooled themselves before when they grouped ω-3 - the type of ω-3 makes a difference.

If we look back on the (sarcasm warning)kindly government advice to avoid fat - it was irresponsible to over simplify this and make pronouncements which has done the public great harm. Then they started making claims about PUFA as a group that was wrong. Later SFA that is wrong etc. I have grown quite distrustful of the conventional wisdom that comes out of the torrent of junk/fraud papers people pump out to keep the grant-gravy-train flowing their way.

Peter said...

Galina,

No button I know of I'm afraid.

M, we've done the Special Optimal Diet on two episodes over the last 10 years due to serious financial constraints. Special means that if it's on special offer, we buy it. Especially butter and cheese. Offal is intrinsically cheap of course.

Peter

James said...

This question of whether antioxidants are good or not seems very intersting to me. Some people are starting to say that the types of antioxidants are very important, and that more is not necessarily always better.

Im including a reference to a paper (below) that seems to show, with "compelling" evidence, that induction of the β-adrenoceptor (β-AR) signaling pathway for Mitochondrial Biogenesis leads to activation of multiple genes involved in the mitochondrial electron transport chain, increased mtDNA copy number, and increased respiratory capacity, at least in the hearts and kidneys of the cats that they tested on.

If free radicals emanating from mitochondria acts as a signal to the nuclear genome to increase MB, or to destroy damaged mitochondria, then anti oxidants are only going to disrupt this process.

http://jpet.aspetjournals.org/content/342/1/106.abstract

blogblog said...

@M,

ditch the dairy and eat some sweet potatoes instead.

Makro said...

If the Protons ever run out, I guess this should be on the observation list.

http://www.latimes.com/news/science/la-sci-statins-cancer-20121108,0,3168815.story

Adam Long said...

Karl and George Henderson,

I like the focus on atherosclerosis from an autoimmunity standpoint, but what about Dr. Attia's analysis that LDL particle number counts, not particle size? http://eatingacademy.com/nutrition/the-straight-dope-on-cholesterol-part-v

If atherosclerosis is an autoimmunity reaction, there first have to be LDL particles stuck in the endothelium - whether particle number is more important than underlying inflammation (whether it's more important that the LDL gets there, or that the LDL stays there via inflammation and oxidation, and how much it's attacked by white blood cells).

So which do you think it is?

karl said...

@James

1 -There is no agreement on how to test something to say it is an antioxidant. (Many things that are food-storage-antiox end up being pro-ox in-vivo )

2 - Some of these so called antiox the body tries very hard to remove as fast as possible. Some of these things may do some good by other means .

3 - Some may do good only at a particular dosage. Understand what they mean by "the dose makes the poison".

I think it is highly probable that some of the anti-ox sold as supplement will end up doing harm at some dose. A lot of the good is based on papers that were published only in the exporting country - many are not reproducible.

That being said - I am very interested in C60 as an antiox. It is lipophilic - likes to hang out in the membrane where the proton pumping happens.

@Adam Long

I think tracking LDL for people that don't have familiar hypercholesteremia is not useful.

I think looking at the particle size is like reading tea leaves. Here is the rub - what do you do about the wrong size? The only intervention is to reduce carbohydrate intake - it will shift the size. Is the cause of increased oxLDL due to BG or the size of LDL? The problem is they have assumed causation out of mere correlation.

They want to sell these expensive tests, but if there is no intervention that they have that is shown to change outcomes - why mess with it?

Here is a better idea. Buy a cheap glucose meter and keep your postprandial BG below 110 by modulating what you eat.

(I think it might be more useful to watching oxLDL and interleukins and modulate interventions than obsess about LDL. )

blogblog said...
This comment has been removed by the author.
blogblog said...

Attia is just another supplement pushing scammer.

Repeat after me "a doctor (MD) is a tradesman - not a scientist". The vast majority of them know NOTHING about nutrition (or exercise science) and very little about biochemistry or physiology. Why anyone listens to their opinions on nutrition (or exercise) is beyond me.

We were taught in exercise physiology classes that any mainstream nutrition book written by a medical doctor is almost certain to be BS.

Gadfly said...
This comment has been removed by the author.
karl said...

@Makro

RE:statins-cancer

This is the actual NEJM paper

The epidemiological paper was pumped up to say more than it possibly can in the LA times. Once again correlations do not show causation.

Looks like they didn't track BG... Of course people that are on satins are likely to eat less junk food thus lower BG and lower cancer - but that would take real science.

In real experiments, statins produce a modest reduction from death via MI, but death from all causes is almost a nil improvement. If it isn't extra cancer deaths, it must be something else.

My take is statins increase BG slightly - which I would expect to increase cancer rates slightly.

Last sentence in paper: "This suggests a need for trials of statins in patients with cancer."

Which if they did have a real control - I predict would have "unexpected" results.

I'm not totally anti-statin. I just think they are hugely over prescribed, misunderstood how they work, and don't like how this paper has been covered in the press.

Jack Kruse said...

The best way to raise HDL, lower TC and TG and LDL is to eat a diet loaded in Mg, carnitine, D-ribose if your Leptin resistant, and lots of Coenzyme Q10. That will take care of lipoprotein lipase and do the job with no deaths. I think Peter has been saying that with different words for a long time. The real problem for my profession is Big pharma cant make money from it so they try to keep the recipe our of our training. If one reads enough you get how to do it because the drugs wont work. When you understand how ATP is really replenished in a mitochondria it is amazing how much better humans get across all neolithic spectrums of illness.

Jack Kruse said...

Karl nothing protect membranes from lipid peroxidation better than DHA/iodine and CoEnQ10. In fact when one looks at the molecular structure of CoenzQ10 and Vitamin K2 they look like siblings. Hockey stick shape and all.....no wonder they have the same biologic effects for the heart and for mitochindria. The PUFA in seafood is not burned in beta oxidation. It is highly conserved for neural lipids so it wont jump start ketosis. The cofactors for ATP substates are what need to be in adequate supply and they are not. PUFA's will improve eicansanoid signal (fast hormoen response system) acutely but it will not have any lasting effect if you cant sustain energy because your losing xanthine and hypoxanthine out of the cell because you cane make any D ribose to salvage them from the Pentose phosphate shunt system. It is all about energy generation........that is the final common tie to all things which leads to the mitochondria. That is how the brain uses leptin to account for electrons from the diet.

Gladina said...

It's good I can come to Peter's blogs to get the straight answers from Jack. Tricky science to understand sometimes but I find it's direct and to the point in these cases. Very appreciated.

Eva said...

Crystal light is a diet drink. Taste is not bad, main issue is safety or lack thereof of artificial sweetners and chemicals added.

For insulin, I personally don't know of the issue between AI and insulin. I know of links between leaky gut and AI. My first thought with diary is if it tends to trigger AI directly if it escapes the gut or otherwise. I am persosonally still thinking about if diary is an issue for those with healhty gut and villi and produce sufficient lactase naturally. Probs with dairy could also be related to how it is currenlty processed.

As for ketosis, I am not convinced that full time ketosis is especially good for everyone or even anyone long term. It does seem good for weightloss but some/many have probs after long term use. Not to say I think everyone should pound down sugar and crap, but is 75 to 100g of carb a day really a bad thing? You could eat diary every day and not reach 75g a day. On the flip, diary is a known potential staller of weight loss for some (but not all). Could be it depends on the individual response. Insulin response varies wildly from one individual to another.

I am also skeptical of antioxidants. Proof seems a bit flimsy to me. Likely there are lots of other benefits to eating whole foods that just happen to also have antioxidents though.

I don't think atherosclerosis is a typical AI response. Atherosclerosis happens where cells walls experience the most pressure from blood flow. To me that suggests weak cells and membranes getting damaged by hard blood flow presure but since damage doesn't happen all over, likely not a direct AI attack. Although could/likely related to inflammation issues. I am curious if they will be able to isolate any one main cause, but I guessing from what I've seen so far that sugar and rancid grain oils are likely culprits and maybe also lack of nutrition or some nutrients. But could be a complex symptom of overall unhealthy body condition in general.

karl said...

@Jack Kruse said:

"Karl nothing protect[s] membranes from lipid peroxidation better than DHA/iodine and CoEnQ10."

Based on what papers? This might be the truth, but I'm long past believing blog pronouncements or even what I think I know. I've seen too many claims gets turned upside down (mega-dose vit C, calcium supplements etc ) .

I DO take very high-dose fish oil ( which may have lowered my 3xhigh Lp(a)) - I take iodine, K2-m7(the type apparently matters),magnesium - no CQ10 ( makes my coffee cup apparate in random places ), but I have lots of reasons to doubt I really know what I'm doing in spite of the papers I've looked at.

There is a pandemic of T2D that I don't think anyone really definitively knows the cause of ( as apposed to the treatment of). I don't think the pandemic is caused by a supplement deficiency.

Lusting thinks it is fructose. Others O-6. There are good reasons to suspect transfats, BUT if I throw out the garbage (epidemiological, flawed causation logic, fraud etc) papers, I'm left thinking there is much that is unknowable right now.

Does Magnesium act by protecting membranes? Or instead by effecting heart rhythms, or lower BP or several other proposed mechanisms? Do we really know which is the dominant means of Mag?

Does iodine act mainly as a membrane antiox or by normalizing thyroid function?

karl said...

@ Eva said...

"I am not convinced that full time ketosis is especially good for everyone..

Neither am I, but I am pretty sure it is better than having out of control BG or staying obese. My take is a long term ketogenic diet is better than taking meds to control T2D. I wish I knew a way to cure rather than control.

My take is that elevated BG causes all sorts of health problems - I don't think anyone disputes this. The place where I disagree with the mainstream is the BG target should be to maintain postprandial below 110 instead of the insane levels of the ADA (10 mmol/L or 180 mg/dL) ( My healthy 88 year-old father has levels below 110 on a mixed diet ).

Chip Spitter said...

This is why Hyperlipid is far and away the best nutrition/health blog in the universe. It is rare that the comment section on a blog is as informative as the main show. Thanks to all.

Re Attia (blog blog), I believe his heart is in the right place, even if his conclusions are based on leaps of faith. If you read his 'straight dope' series and have a functioning brain, toward the end you can see the massive chasm where he jumps from FH to "LDL particles are a death sentence". Hopefully his collaboration with Taubes and NUSI will see some meaningful results.

Anyone hooked up on LDL-P (like i was) may want to take a gander at http://azsunfm.blogspot.com.au/2012/09/font-definitions-font-face-font-family.html It is only an n=1 but it is interesting all the same.

Cheers.

George Henderson said...

@ Jack Kruze, maybe the fish oil PUFAs were ketogenic because they stop omega-6 going into membranes, so it has nowhere to go but oxidation.

@ Blogblog -"We were taught in exercise physiology classes that any mainstream nutrition book written by a medical doctor is almost certain to be BS."

Aren't you lucky then that there are plenty of people out there on the interweb who can give you advice without the benefit of qualifications?

I think the expression is "tall poppy syndrome".

Neil Timms said...

M,

You may want to consider fermenting Cream - really easy to do. I understand that because Cream has less milk protein and sugars to start with and the fermentation process itself there is much less harm from consuming Dairy this way. I could of course be wrong but I can tolerate fermented cream when milk or even Youghurt causes me trouble.

cavenewt said...

"they fooled themselves before when they grouped ω-3 - the type of ω-3 makes a difference."

Can you provide some elaboration, or links? Thanks.

karl said...

@cavenewt

The long chain 20:5 ω-3 eicosapentaenoic acid (EPA) and 22:6 ω-3 docosahexaenoic acid or DHA are what people take fish-oil for.
Plant oil - 18:3 ω-3 alpha linolenic acid or ALA can be converted to EPA and DHA, but with an efficiency of only a few percent.

It is claimed that the over production of arachidonic acid => PGH2 (which makes thromboxane) from ω-6 intake is either blocked or balanced by EPA and/or DHA ( I'm not sure they really understand this - I sense some hand waving ).

Anyway - EPA and/or DHA ( I've seen some disagreement/hand-waving here also about which one is more important ) appear to reduce systematic inflammation. Exactly how this works I would love to know.

For the record - I followed Dr. Davis advise to take high dose fish-oil due to his observation that over time (6mo - 2 years) as his experience is it would lower Lp(a) levels ( involved in the inflammation of artery walls ) which it appears for me (n=1) it did - I went from 3x over the 'serious-warning' level to just inside the 'some-risk' level. ( It would be nice if there was a quality controlled study on this with outcome markers besides a blood test )

George Henderson said...

EPA is anti-inflammatory, DHA is structural (insulin sensitivity and other membrane protein effects).
Mg is catalyst for glutathione syntrhesis.

Eva said...

M, might want to consider if you are getting enough protein. SOme say you should get at least 150 g of protein plus carb per day. (I'd love to hear rationals on if this is a good number) If you cut out carb, then the body uses more protein to convert to glucose for those body cells that MUST have glucose. The reason you don't need carb is because the body can make glucose out of protein. But you NEED protein. You can't live on fat alone. One serving of greek yogurt has only about 20 g of protein which is a lot more than meat but not much compared to daily needs. If you cut out too much protein for fear of insulin, you could damage your health. You might be suprised how much meat you gotta eat to get to 150 g protein per day!

George Henderson said...

Mg also required for most glycolytic reactions, splitting ATP, including generating AdoMet from Methionine, ergo required for methylation...
and so on (350 reactions approx), as well as electrolyte and neuro-electrolyte...

George Henderson said...

Mg required to activate vit D to 1,25 (OH)2 D3
Mg elevates free testosterone by competing for SHBG
http://www.ncbi.nlm.nih.gov/pubmed/21675994

In a cohort of older men, magnesium levels are strongly and independently associated with the anabolic hormones testosterone and IGF-1.

karl said...

@George Henderson

Aging seems to increase SHBG until it blocks the effects of T - thus we get grumpy and unhealthy old men.

Interesting paper - I wonder if the modulation of SHBG is part of how Mg does it's good stuff?

I've looked at SHBG in connection with TBG(Thyroid Binding Globulin) - I think there is some connection between the two that is not fully understood which might bear on the use of T4+T3 in treatment of hypothyroidism .

http://online.liebertpub.com/doi/abs/10.1089/thy.1999.9.1085


http://www.eje.org/content/104/2/253.short

High fat diets lower SHBG
http://jcem.endojournals.org/content/64/5/1083.short

My take is that These binding globulins are part of the control loop - and involved with insulin as well. These nested, duplicate control loops are quite complex.

Jane said...

@George
Yes it's interesting about vit D and Mg. People used to think everything bad was due to vit D deficiency and then they found out low vit D is just a symptom of Mg deficiency. Or Ca overload, as I think you pointed out somewhere. A friend of mine and her mother both died within a year of starting on high-dose vit D. It probably didn't kill them, but it didn't save them either. My friend was a science journalist and had done her homework on vit D. She believed the people who said you have to take enormous quantities of it.

karl said...

@Jane & George Henderson

What I find interesting about vit D is that most of the claims are based on associations with serum levels. Thus, causation is not shown.

I know there are other photo-products produced in the skin, so it could be that these other products -- or even the reduction of the feedstock precursors of these photo-products, are what should have our attention.

Without this information, it may be that getting Vit D up via sunshine is the best way.

Jack Kruse said...

Karl read Crawford, Cunnane and Kuipers works and you'll get the DHA and iodine roles (many others too that paleo refuses to examine due to dogma). George DHA is not metabolized by human neurons it is reserved for cell membrane construction. While it is a PUFA it is not physiologically treated like other PUFA's. This is also proven in the work of Cunnane, Crawford et al. Low vitamin D is proxy for mitochondrial inefficiency. Low PQQ, CoEnzyme Q10, Mg, L-carnitine, and D-ribose......all precursors of ATP synthesis in mitochondria in ox/phos.

Jane said...

@karl
Agreed.

@Jack
I've just read on your blog that you recommend IRON supplements to people on a PALEO DIET. Haven't you read Chris Kresser on this? Even Mercola is telling people about the link between iron overload and dementia.
http://articles.mercola.com/sites/articles/archive/2012/07/19/excess-iron-leads-to-alzheimers.aspx

Exceptionally Brash said...

Oh Jane, too funny. Call it women's intuition, but I'll bet Jack doesn't run everything by Kresser before he posts.