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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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In the Pipeline

« The Ethics of Avastin | Main | Memorial Day »

May 27, 2011

Niacin's Unexpected Flop

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Posted by Derek

Let's add to the uncertainty about whether we understand cardiovascular disease, OK? The NIH has been conducting a large statin-plus-niacin trial, which is definitely a combination worth looking at. The statin will lower your LDL, and niacin will raise your HDL and lower your triglycerides (albeit with some irritating side effects). An earlier trial of niacin versus Zetia (ezetimibe) made the former look pretty good (and Zetia look pretty bad) using an endpoint of arterial examination by ultrasound.

But now the NIH trial has been stopped, a full 18 months early. Not only did the addition of niacin show no benefit at all, but that treatment group actually had a slightly higher rate of ischemic stroke. This despite the combination working as planned, from a blood-marker standpoint. No, we really still have a lot to learn, particularly when we're trying to raise HDL and lower triglycerides. These results, together with the fenofibrate data, really make a person wonder.

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


COMMENTS

1. Rick on May 27, 2011 11:44 AM writes...

Let the spinning begin!

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2. Pharmaheretic on May 27, 2011 11:55 AM writes...

So who here still believes that lipid profiles are anything other than a poor proxy marker for an underlying condition- chronic inflammation linked to insulin resistance?

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3. You're Pfizered on May 27, 2011 12:09 PM writes...

These results, together with the fenofibrate data, really make a person wonder.

...and Miles White weep

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4. Gambler on May 27, 2011 1:25 PM writes...

Pretty naive to this field, but could this relate to PK? One presumes that with extended release niacin, Cmax is lower thus reducing the flushing effect. Maybe the beneficial effects observed in previous outcome studies are Cmax driven? Maybe they have little to do with HDL? If I'm not mistaken, the mechanism of action of niacin is still elusive.

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5. Hap on May 27, 2011 1:28 PM writes...

Why does this make me think of someone waking up from a dream to find themselves on the middle of a tightrope over the Grand Canyon with no balancing rod?

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6. NoDrugsNoJobs on May 27, 2011 1:55 PM writes...

What we've learned from all the combo statin studies so far is that so far, it is hard to improve on a baseline that is now much better with regards to lipids. The LDL in the statin treated group was a remarkably low 70 or 71.

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7. barry on May 27, 2011 3:12 PM writes...

so has anyone run a trial with ApoA1-Milano long enough to judge mortality? Dramatic reversions of plaque were reported, but maybe that's not a meaningful endpoint? If all the small-molecule efforts to boost HDL bomb out, the (really expensive-looking)large-molecule approach (or gene therapy??) may look more attractive

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8. johnnyboy on May 27, 2011 3:29 PM writes...

@4 Gambler: the key here is that niacin did have the expected effect, increasing HDL. The problem is that this increase was not associated with better clinical outcomes, which throws a monkey wrench in the generally accepted idea that increasing HDL should be a therapeutic goal, along with decreasing LDL.

This isn't my field and i'm no epidemiologist or statistician, but before throwing away the HDL hypothesis based on this, I'd look long and hard at the numbers (which are not currently available). The rates of bad outcomes (ischemic stroke and myocardial infarct) cited in the study are pretty low, at around 1%, which means that a few random bad outcomes on one side can throw the study out; waiting it out for the longer term may have produced a switch in results. The study of niacin vs Zetia that Derek cites did show an improvement in arterial plaques with niacin, so if that study is to be trusted niacin should have an overall clinical effect. However the mechanisms whereby a cholesterol plaque acutely ruptures and causes arterial occlusion (the MI or stroke events) are still not well understood; something else beside plaque size may be a risk factor. One thing for sure, this field continues to defy simple explanations.

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9. Anonymous on May 27, 2011 5:25 PM writes...

@8 Johnnyboy

I suppose my question really was whether the HDL raising effect of niacin is actually not the only thing contributing to the outcome benefits that have been demonstrated. A Cmax driven ('off-target?') effect on some other pathway could theoretically explain a difference between extended release and standard niacin.

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10. anonymous on May 27, 2011 7:32 PM writes...

"So who here still believes that lipid profiles are anything other than a poor proxy marker for an underlying condition- chronic inflammation linked to insulin resistance?"
....So are you suggesting the magic bullet is rosiglitzone????

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11. dearieme on May 28, 2011 8:55 AM writes...

"So who here still believes that lipid profiles are anything other than a poor proxy marker for an underlying condition...": I suspect as much.

"....- chronic inflammation linked to insulin resistance?" I'm not qualified to judge.

I do wonder whether the whole fatty foods-lipids-heart disease-statins doctrine is a fandango of fraud and error.

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12. Cellbio on May 28, 2011 9:30 AM writes...

fatty foods are not bad, being fat is bad for health, but not as bad as people think in most cases. The topic has been handled well, sorry I don't have a link, both with the health impacts of low fat diets, and with the social aspects of information flow, or knowledge 'cascade'. Apparently, C Everett Koop was largely responsible for influencing our common perception that fat is bad to eat.

On the chronic inflammation linked to insulin resistance concept....where is the robust data in humans?

Statins not likely fraud or error, except the error of thinking it is a drug working through a mechanism of action we fully understand.

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13. Still Scared of Dinosaurs on May 28, 2011 10:31 AM writes...

Koop certainly had a lot of help from Dean Ornish.

I don't believe that the counterintuitive results are due to bad luck in the combo arm. Stopping rules for trials are supposed to be powered to prevent that. It could happen but that would be really, really, really bad luck.

On the other hand, it could have been that in the short term the safety profile of niacin increases risk whereas in the long run the overall risk may be different. Guess we won't get that answer from this trial.

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14. Rick on May 28, 2011 12:41 PM writes...

Speaking of unexpected results from statins paired with something else, check out the latest news on possible side effects of taking a statin (pravachol) and an SSRI (paxil), published in today's Boston Globe: http://www.boston.com/news/local/massachusetts/articles/2011/05/28/study_cautions_on_combining_two_commonly_prescribed_drugs/

If confirmed, this would be a very significant finding, considering how many people how many old, fat, depressed, verging-on-diabetic people probably take a combo like this. If my quick scan is correct, it could number in the 10s of millions in the US alone.

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15. hse on May 30, 2011 11:15 AM writes...

Get the heck out of cardiovascular. And metabolic.

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16. anonymous on May 30, 2011 2:00 PM writes...

Yes, get out of metabolic. The solution to our obesity/diabetes crisis is not in drugs. We evolved to seek, consume, and digest as much food as we could possibly get. There are multiple mechanisms in place to assure that we remain motivated to get off of our butts and seek and digest food so that we don't blissfully starve to death. A superabundance of food was probably not even encountered by humans in an evolutionarily significant way until the 20th century. And there was little evolutionary pressure to avoid chronic illnesses after the age of 50. Is it any surprise that everything goes to hell when we stuff our faces with Ben and Jerry's or Coca Cola, while sitting at desks or on couches?

Once we're out of metabolic, I think the most rational field to work in is infectious diseases, followed perhaps by oncology. ID is unattractive commercially--for now. But I bet people will be willing to pay a lot for a course of a new antibiotic or antiviral when a drug-resistant M. tuberculosis or a new 1919-like influenza virus shows up in town. In the meantime, it would make sense for the US government to tackle several problems at once.

1) drastically decrease NIH funding
2) Focus the research efforts on the largest public health needs
3) Retrain most of the very capable people currently doing (or unemployed from) biomedical research to focus on various aspects of renewable energy
4) Give people the incentives, and the time, to walk or bike to work

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17. pal raghavan on May 30, 2011 4:41 PM writes...

comment 16 is right on the money. As Mark Twain said
" The only way to stay healthy is to eat what you don't want, drink what you don't like and do what you rather not do ."

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18. Vader on May 31, 2011 10:01 AM writes...

deariemie,

"I do wonder whether the whole fatty foods-lipids-heart disease-statins doctrine is a fandango of fraud and error."

Error, possibly. Fraud? There's no call for that kind of talk. Epidemiology is hard enough to get right that no darker explanation is required.

Incidentally, I have no connections with the drug industry. I just really like Derek's blog. It's not myself I'm defending.

anonymous 16:

"3) Retrain most of the very capable people currently doing (or unemployed from) biomedical research to focus on various aspects of renewable energy"

Bzzzt, dumb answer. I was once deeply involved in the directed energy business. It's not something you pick up casually on weekends. And I am deeply, deeply skeptical that even solar, the best of the renewables, will ever become anything more than a valuable supplement to nuclear.

"4) Give people the incentives, and the time, to walk or bike to work"

Will you settle for taking the bus? It's what I do.


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19. Anonymous on June 2, 2011 2:03 PM writes...

A high level flaw replete in the field is the unsophisticated use of blood biomarkers as an endpoint. We know how to fractionate the lipoprotein particle sizes, we know how to measure whether the lipoproteins are in their proper functional forms, we can image plaque size (IVUS) and composition (intravascular NIRS),... etc., and yet we don't use these very much in development plans. I guess cIMT is in there, but that's a joke. A good dental cleaning reduces cIMT, and a slight fever will increase it. And it still takes thousands of patients and several years (so why not do a few more and wait for events?). For CV, it's either the easy way out with the standard lipid panel (which the FDA is not going to accept anymore) or a giant 10k+ patient events trial (the unreasonable direction the FDA is pushing everyone) and nothing in between.

Predictions for the next Wonder Drug Factory to exit cardiovascular?

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20. Tony Justin on June 24, 2011 5:04 PM writes...

Comment 16 is the classic "blame the patient" suggestion. As a cardiologist, I am often confronted by interns and residents whose first inclination is to blame the patient for whatever illness they have contracted. In the case of diabetes, hypertension and atherosclerosis: it is the patient's fault for overeating and that is the entire reason for their illness. Apparently, their family history and genetic milieu has nothing to do with their illness.

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21. Ed Terry on December 26, 2012 2:11 PM writes...

The study compared statin+niacin against statin only. Too bad it didn't add a niacin only group. although any subject taking niacin will know it. I also wonder about the adherence to niacin, since most people do quit taking it due to the flushing effect, which is also mediated by serotonin release from platelets.

The flushing effect does lessen considerably with continuous use. I've taken immediate release niacin for 9 years and I no longer have any flushing, except for my ears. I've also experienced a reduction in my coronary calcium score.

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