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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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August 30, 2012

Niacin: How Does It Work, Anyway?

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Posted by Derek

Here's yet another chance to play the human biology game that might as well be called "Now what?" That's when we find that what we thought we knew is actually wrong, more complicated, or a sign of something else entirely.

Today's entry is niacin. As many readers know, it looks like it should be a promising therapy for patients whose lipoproteins are out of whack. It lowers LDL, raises HDL, lowers free fatty acids, and lowers triglycerides, and all those things are supposed to be good. (As came up in the comments yesterday's post, though, the evidence is pretty strong for that first proposition, but not as solid for the others). Still, if you went around to thousands of cardiologists and asked them if they'd be interested in a therapy that did those four things, you'd get a resounding "Yes".

So why hasn't niacin taken over the world? Because of the side effects. It has to be taken in rather stiff doses to show the lipid effects, and those tend to cause a nasty skin flush reaction, which is apparently unpleasant enough that most people won't put up with it. Various attempts have been made to abrogate this, with the most direct assault being Merck's (failed) Cordaptive.

The flushing is thought to be mediated through the receptor GPR109A, via a prostaglandin pathway. Unfortunately, it's also believed that niacin's beneficial effects are mediated through that receptor, too, via some mechanism that starts with the lowering of free fatty acids. If you knock out the receptor in mice, you get no skin flushing, but no FFA lowering, either.

We must now revise that idea. A new paper tests that hypothesis with two non-niacin agonists, MK-1903 (a compound via Arena Pharmaceuticals, I believe) and SCH900271, and their effects in humans. They also report niacin's effects in the receptor knockout mice, claiming that although the FFA lowering does indeed disappear, that the downstream lipid effects remain. (That surprises me; I'd thought that had already been studied).

But the human data are especially revealing. The two new agonists do indeed show FFA effects, as you'd expect from compounds hitting GPR109A. But they do not show chronic free fatty acid lowering, nor do they have the desired downstream effects on blood lipids. So it appears inescapable that niacin's effects are going through some other pathway, one that doesn't depends on GPR109A or its (transient) free fatty acid lowering. Back to the drawing board everyone gets to go.

But niacin has been heading there already. Readers may remember a trial of a niacin-and-statin combination had to be stopped early because the cardiovascular effects were (alarmingly) going in the other direction. Not only was there no benefit, but there seemed to be active harm. Taken together, all this tells us that we have an awful lot to learn about some things that we thought we were starting to understand. . .

Comments (21) + TrackBacks (0) | Category: Cardiovascular Disease


COMMENTS

1. Nate on August 30, 2012 11:35 AM writes...

Hmm, now I'm glad I never bothered to take it when my Doctor told me to...

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2. Marilyn Mann on August 30, 2012 12:15 PM writes...

Merck has an ongoing trial, HPS2-THRIVE, testing Cordaptive.

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3. Watson on August 30, 2012 5:09 PM writes...

ChromaDex also has seen recent action with nicotinamide riboside, which doesn't produce the flushing reaction but is supposed to show some efficacy in reducing LDL and increasing HDL.

As far as outcomes are concerned, what I want to see is a reduction in LDL particle number instead of lower LDL-cholesterol, since it seems that the former is the only significant biomarker for improvement of overall risk.

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4. Watson on August 30, 2012 5:13 PM writes...

As an aside, the best primer I've yet run across that explains the state of the current research on lipid measurements and what we can interpret from them is a nine-part blog over at http://eatingacademy.com/nutrition/the-straight-dope-on-cholesterol-part-i

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5. clinicaltrialist on August 30, 2012 6:41 PM writes...

I tried to post earlier but it didn't seem to go through so I am re-posting.

It is not clear that lowering cholesterol lowers CV risk. Statins lower CV risk, but many other drugs that lower cholesterol doesn't. The simplest, most logical explanation for this would be that statins work via a different mechanism, and that lowering cholesterol doesn't really help. (In fact, it may be detrimental - remember all the debate about why people with low cholesterol have high mortality?)

There is major debate starting to brew in the CV community (see Harlan Krumholz's editorial in Circulation, "Three Reasons to Abandon Low-Density Lipoprotein Targets") about using cholesterol and LDL.

Even if lowering cholesterol lowers CV risk, it is not clear that lowering it aggressively is better than lowering it moderately.

The problem is this: there has been no trial that shows that lowering cholesterol more lowers risk more. What the trials have shown is that in patients who take statins and end up with very low cholesterol have lower risk than patients who take statins and end up with moderately low cholesterol.

It may sound like the same thing, but it isn't. It's an illusion. For example, among people with high cholesterol, there may be people who have high risk of CV and some with low risk of CV. It may be that people with higher risk of CV are more resistant to statin's anti-cholesterol effects. In other words, it is impossible to tell whether the lower cholesterol is lowering CV risk or the lower CV risk is making it easier to lower cholesterol.

A more intuitive example would be patients who take an anti-diarrheal drug. If you measure plasma levels of the drug, you may find that the patients with highest levels of drug have lowest amount of diarrhea. But maybe the patients who are the least sick are simply able to absorb more drug.

This illusion is what Harlan is talking about in his Circulation editorial "Three Reasons to Abandon Low-Density Lipoprotein Targets."

To establish that aggressive statin lowering lowers risk more than less aggressive statin lowering, what you'd need to to is to run a trial where the statins are administered not with a fixed dose but titrated to a target cholesterol level, with different targets in different arms. That has not been done.

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6. Anonymous on August 30, 2012 6:47 PM writes...

I have metabolic syndrome and my lipids are all screwed-up except my cholesterol levels are fine. I take a gram of niacin in the morning with 80mgs of aspirin and gram niacin at night w/o aspirin. Side-effects are minimal to not noticeable at all, assuming I am not torching my liver. Clinically it does exactly what it is supposed to do for my lipid profile pushing all of them towards the normal levels/ratios.

The question of up most importance for me is the one Derek has raised. Does this change in my lipid profile have any meaningful impact on my cardiovascular destiny?

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7. Watson on August 30, 2012 8:39 PM writes...

@6 - the link I gave above addresses the issue of lipid profile measurements and what they mean. If you are talking about a standard blood profile, it's equivocal. If you get one of the more advanced profiles, with LDL-P or apoB numbers, you may have at least some idea of your overall risk. I'm not sure if anyone has done a large study with niacin and LDL-P, though.

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8. ScientistSailor on August 30, 2012 9:30 PM writes...

Diet? Exercise?

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9. Morten G on August 31, 2012 7:23 AM writes...

Problem with diet and exercise is that as soon as you have people eat fewer calories they crave junk more.
And telling them that 16 carbon fats are bad but 12 and 18 are good, independently of whether they are saturated or monounsaturated and that they need to choose their polyunsaturated fats based on how far the first double bond is from the tail of the fatty acid (if the acid moeity is the head) is not making things easier. Then telling them to eat a maximum amount of carbohydrate based on their physical activity level and lean body mass isn't very helpful either.

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10. drug_hunter on August 31, 2012 9:23 AM writes...

Yes, but Morton, what about keeping it really simple:

Exercise 150 minutes a week.
Eat a lot of fruits and vegetables.
Don't eat junk food.
Try to minimize sugar in your diet.
Get enough sleep.

If everyone did that, I wonder what the rate of cancer, heart disease, and Alzheimer's would be.

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11. Watson on August 31, 2012 12:29 PM writes...

Here's the takeaway message from the articles that I linked to, which pretty much echo @10:

"The consumption of sugar (sucrose, high fructose corn syrup) increases plasma levels of triglycerides, VLDL and apoB, and reduces plasma levels of HDL-C and apoA-I.

The removal of sugar reverses each of these.

The consumption of fructose alone, though likely in dose-dependent fashion, has a similar, though perhaps less harmful, impact as that of fructose and glucose combined (i.e., sugar).

The addition of fat, in the absence of sugar and starch, does not raise serum triglycerides or other biomarkers of cardiovascular disease.

The higher the level of serum triglycerides, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB).

The greater the number (from 0 to 5) of inclusion criteria for metabolic syndrome, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB)."

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12. Stevedoc22 on September 1, 2012 8:11 AM writes...

Sorry, but Cordaptive hasn't actually failed yet. The FDA rejected Merck's NDA because the agency wanted outcomes data, which we will get by year end. So, stay tuned. Of course, given the negative studies utilizing Abbott's Niaspan, hopes for Cordaptive are lower than dinosaur bones. That said, Abbott's studies were generally underpowered, so this dataset should be the definitive say on niacin.

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13. clinicaltrialist on September 1, 2012 10:19 PM writes...

Watson is absolutely right. Fructose, trans fat, ethanol (high levels) and branched amino acids are what you want to avoid. Well, that is what the cutting edge metabolism researchers will tell you.

In response to drug_hunter, about 50% of cancer is attributed to obesity by mainstream cancer researchers. So there should be about 50% less cancer if no one was obese.

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14. Interested on September 3, 2012 6:07 AM writes...

@10 - Interestingly, a huge single arm open label experiiement of this kind has been run: WWII in Britain. Food was rationed according to strict calorie intake, with excerise greatly exceeding your 150 mins per week. Anecdotally (there must be studies to record this but I can't find any), by the end of the war the British had never been healtier: metabolic diseases like T2DM at an all time low. Trouble was, the the food was terrible.

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15. Morten G on September 3, 2012 8:35 AM writes...

@10.drug_hunter

I agree. I was mainly annoyed by the "diet and exercise" knee-jerk reaction from 8.ScientistSailor. For most people diet means being hungry because most diets come without hunger management tools more advanced than "suck it up". No wonder they aren't long-term useful.

I would however put it this way:
Replace your treats with fruit and nuts.
Replace your bread/pasta/rice/beans/corn with vegetables.
Eat meat that wasn't raised on bread/pasta/rice/beans/corn.
Replace your omega-6 heavy fats with omega-6 low fats (preferably something high in oleic acid or stearic acid).

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16. shohel on September 8, 2012 4:01 AM writes...

so that's why take ChromDex company's drugs which is going to take whole market as soon.

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17. universe on September 25, 2013 1:29 PM writes...

Hi,
Pharma does not like to hear anything works for us except

DRUGS.....HAHAHA ... I TOOK IT IS FANTASTIC ... I READ BOOKS ABOUT IT OVER 30 YEARS IT IS GOOD THE BEST. ANYONE WORKS FOR PHARMA WE HAVE TO LISTEN TO THEM....HAHAHAH

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18. Pat on November 16, 2013 2:22 PM writes...

Why isn't the focus ever on improving liver function to reduce lipid levels, period?- As liver function is 70-80% responsible for elevated lipid levels in people, including those with fh.

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19. Pat on November 16, 2013 2:25 PM writes...

Why isn't the focus ever on improving liver function to reduce lipid levels, period?- As liver function is 70-80% responsible for elevated lipid levels in people, including those with fh.

Permalink to Comment

20. tshann on November 20, 2013 4:16 AM writes...

I Rx wax matrix (carnauba based) slow release niacin in 500 mg TID all the time. Sure, some don't tolerate it. But many do just fine with it and it works for LP(a), upping HDL, lowering trigs. So while it's not perfect, it is helping lots of folks. Just avoid stuff like Niaspan - terrible. The wax matrix stuff does work for many folks.

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21. aviya on January 7, 2014 12:21 PM writes...

has anyone had extreme anxiety while taking niacin or systems similar to PMS ?

Permalink to Comment

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