Oftentimes people become so fixed in their thinking – and in their belief that everyone else thinks the same way – that they unwittingly raise the curtain and expose the wizard of their flawed thinking, showing it for what it really is. Statinators have done just that in an article in the current issue of the Journal of the American College of Cardiology (JACC).
The study, Effects of High-Dose Modified-Release Nicotinic Acid on Atherosclerosis and Vascular Function, compares the increase in carotid artery plaque over a 12-month period in subjects taking niacin versus those taking a placebo. It turns out that those subjects taking the niacin experienced a shrinkage of their plaque whereas plaque grew larger on those taking the placebo. The revealing hitch in this study is that both groups were on statins, which means the group on statins alone was the placebo group. Therefore the data from this study shows that statins alone do not reverse the growth of plaque (at least not plaque in the carotid arteries) despite lowering LDL levels. Taking the logic a little further, the data from this study gives weight to the idea that a lowered LDL doesn’t reduce plaque growth.
There is a lot we can glean from this study and the from the authors’ commentary on it.
Let’s take a look.
Researchers randomized 71 subjects–all of whom were on statins and all of whom had low HDL-C and either a) type II diabetes with coronary artery disease or b) carotid or peripheral atherosclerosis–into two groups. The researchers did magnetic resonance imaging (MRI) studies of the carotid arteries of both groups, then started the subjects in the study group on niacin while the subjects in the other group got a placebo. Subjects in both groups continued with their statin therapy. At six months and one year later, MRI studies determined the degree of carotid atherosclerosis and whether it had increased, decreased or remained the same.
After one year, it was found that the subjects receiving the niacin along with their statin significantly reduced their carotid atherosclerosis as compared to those subjects on placebo. And remember, the placebo group of subjects were also on statins and still experienced an increase in their carotid atherosclerosis.
Almost 90 percent (63) of the 71 subjects were males with an average age of 65. As I’ve discussed previously, there is no evidence that statins provide any benefit in terms of decreased overall mortality to females of any age or to men over the age of 65 regardless of their state of health. The only group that statins has shown to provide any benefit for in terms of decreases all-cause mortality (the only statistic that really counts) is men under the age of 65 who have been diagnosed with heart disease. Even in that group, benefit is so small as to be questionable. Knowing this, we can say (assuming an equal distribution of under 65 and over 65 to get an average of 65 years old for the group as a whole) that the majority of people in this study were taking statins unnecessarily. Those males in the study who were under 65 and who had been diagnosed with heart disease were really the only ones who (according to all published research) may have received long-term benefit from the statin therapy. This aside has nothing to do with study or its outcome, it’s simply my commentary on the widespread overuse of statins. So back to the study…
The authors reported on changes in blood values, blood pressure and body weight between the groups:
In the NA-treated [niacin-treated] group, mean HDL-C increased by 23% and LDL-C was reduced by 19% at 12 months. Triglycerides, apolipoprotein B, and lipoprotein(a) were significantly decreased by NA compared with placebo. CRP was decreased by NA compared with placebo (p = 0.03 at 6 months, p = 0.1 at 12 months). Adiponectin was significantly increased at both 6 and at 12 months (p < 0.01). From the safety perspective, minor transient elevations were noted in creatine kinase and liver enzymes, but no significant, sustained elevations (>3× the upper limit of normal for 2 weeks) were observed in any subjects. Fasting glucose did not change significantly, but glycated hemoglobin showed a small increase in the NA group versus placebo (p = 0.02 at 6 months, p = 0.07 at 12 months). Blood pressure and body mass index did not change significantly in either group.
As any of you who have taken niacin will understand, about 10 percent of the subjects dropped out because they couldn’t tolerate the flushing, itching and GI side effects of the niacin. (Some people have had good luck with taking niacin as inositol hexanicotinate, marketed as ‘No-flush Niacin’ though the tolerance for this form isn’t perfect either.)
Those subjects who were able to tolerate it had niacin (nicotinic acid) added to their statin dose and experienced a slight decrease in carotid plaque volume. Meanwhile those on statins alone had their plaque volume increase. Below is a representative MRI showing the difference:
To the untrained eye, these kinds of studies are difficult to read. Even to the trained eye, they can be misread, so there have been computer programs designed to calculate the plaque area so that it can be quantified. You can see the results graphically below:
Before we all start thinking the combination of statins and niacin (nicotinic acid in the graph) is the second coming as far as atherosclerosis treatment is concerned, let’s be aware of a couple of facts. First, these differences in plaque volume don’t really mean squat in terms of blood vessel functionality. As the authors stated:
Neither aortic distensibility nor flow-mediated dilation of the brachial artery was significantly altered by [niacin] treatment.
The terms “aortic distensibility” and “brachial artery dilation” are measures of arterial function, and neither changed. Also, as you can see from the MRI above, the differences in plaque size don’t seriously compromise the open area in the artery through which blood flows.
The fact that none of these indicators of functionality changed and the plaque shrinkage didn’t make a measurable dent in the blood-carrying capacity of the arteries means that none of these subjects really got any short term benefit from the therapy in terms of true risk reduction. Maybe subjects who were worse would have, but we don’t know. And maybe if the therapy continued for the long term, really remarkable changes between the two groups would begin to become manifest. But we don’t know that for sure, either.
What I found the most interesting about this study is what it didn’t say. Or, I guess, a better way to put it is what it said, but probably didn’t intend to say.
If you were to ask any statinator worth his/her salt what it would take to really significantly reduce the risk for heart disease, he/she would tell you to try to get LDL-cholesterol levels below 100 mg/dl. If you then asked, “Well, what about if we got those levels to 80 mg/dl, what then?” You would be no doubt told that the risk for heart disease would then be minimal.
Well, the subjects on placebo – those on the statin alone – in this study had their LDL-cholesterol levels below 100 mg/dl. In fact, at baseline their LDLs averaged 84 mg/dl and fell to 80 at six months and one year. Yet their plaque continued to grow.
We can conclude from this study that reducing LDL to these low levels doesn’t stop plaque growth. We might also conclude that LDL levels may not have a whole lot to do with heart disease. We can’t really make that conclusion definitively from this data, but it sure adds strength to that hypothesis.
In an JACC editorial (available by subscription only) about this study, the author begins thus:
Despite the substantial clinical benefit offered by potent low-density lipoprotein (LDL)-reducing therapeutics such as statins, a majority of patients will still experience major cardiovascular events.
Hmmm. Let’s tease out all the information loaded into this one sentence.
Despite “substantial clinical benefit” provided by statins means the substantial treatment of lab values, i.e., LDL-cholesterol lowering. Statins lower LDL-C; no one denies that. But to what end? The last half of the sentence tells us: A “majority of patients will still experience major cardiovascular events.” If what you’re trying to do is reduce LDL levels, sounds like statins are the drug of choice. But if what you’re trying to do is reduce heart disease, maybe not.
We know for certain that statins reduce LDL, so the sentence also tells us that LDL may not have squat to do with heart disease, since significantly lowering it obviously doesn’t accomplish a lot.
Now, here’s how the authors of the paper started out in their introduction:
Atherosclerosis is a systemic condition in which coronary, carotid, and peripheral arterial disease frequently coexist. In patients with atherosclerotic disease, low-density lipoprotein cholesterol (LDL-C) reduction with [statins] has consistently shown reduction in major cardiovascular events and mortality. However, treatment of LDL-C with statins prevents only a minority of cardiovascular events.
Another few sentences filled with interesting truths. What the authors say about statins reducing “major cardiovascular events and mortality” is true as long as the word ‘mortality’ is associated with ‘cardiovascular.‘ In those who take them, statins do indeed reduce the incidence of cardiovascular events and deaths due to cardiovascular events. What isn’t said in this sentence is that the decrease in cardiovascular deaths the statins prevent is more than made up for by deaths from other disorders that statins likely cause. As far as your risk for death is concerned, taking statins is a zero-sum game: you don’t die from heart disease but you do die from something else within the same period. What you want to do is not to die. Or at least not for a long time. You want to decrease your all-cause mortality, i.e., deaths from all causes, not simply switch from one form of death to another.
Also in the above paragraph, the authors – statinators to a man (or woman), I’m sure – state that treatment with statins “prevents only a minority of cardiovascular events.” From this last sentence, we can once again draw the conclusion that – at least in the minds of true believers of the lipid hypothesis – lowering LDL doesn’t do diddly to reduce heart disease. Yet they all continue to try to treat it by lowering LDL.
I’m glad researchers are looking at niacin as a supplement to be used in the treatment of heart disease. As I’ll discuss below, they have ulterior motives in doing so, which is why they combined niacin with a statin instead of having an arm of the study with niacin alone. About 12 or 13 years ago MD and I found ourselves FAB (flat-a**ed broke) after sending three children through expensive private universities. We had just written and published Protein Power, but it hadn’t started to sell, and we didn’t know if it ever would. Our agent approached MD (who can write like the wind) about being the ghostwriter for one of the major university family medical guides (I can’t tell you which one, but it’s one of the Harvard-, Johns Hopkins-, Mayo Clinic-type of giant family medical guides than many of you may have in your homes) for a nice chunk of change. She didn’t want to do it, and I didn’t want her to do it, but we decided that she should because it would probably make Protein Power a success. Why did we decide this? Because that’s how fate works. We reasoned that if we didn’t take the deal, Protein Power would die on the vine, and we would be wishing that we had taken it. If we took it and Protein Power took off, then we would be wishing that we hadn’t taken the ghost writing deal and could buy our way out. We took it, Protein Power took off (thank God), and MD bought out of her contract after having written about four fifths of the book.
During this awful project, I did a lot of the research and MD did all the writing. Plus MD did all the teleconferences with the major university honchos whose names are actually on the book. After each of these conferences she would run for the wine, because these guys (all were guys) were so detached from reality that it was impossible to deal with them. They were so hidebound in their mainstream way of thinking that no amount of reasoning could dissuade them. Which is why MD didn’t want her name anywhere on the book. She didn’t want to be associated with such idiocy when she had had years of hands-on clinical practice teaching her that most of what these people – who probably hadn’t treated patients in years, if ever – believed was bunk.
Where this dreary tale is leading is that during the research for this book, we determined from all the published data out there that niacin was the only substance that had ever been shown to actually reduce all-cause mortality in cardiovascular patients. That was in the mid-to-late 1990s and now they’re just getting around to evaluating it again.
So why after all these years are they now looking at niacin in conjunction with statins in this study?
Follow the money.
Robin Choudhury, in whose lab this study was done, is on the payroll of several statin manufacturers, including Merck. The study was underwritten by Merck, the maker of Mevacor and Zocor. Okay, so why would statinators and statin manufacturers want to add what is basically a nutritional supplement to their beloved statins? A discussion in an online cardiology site tells the tale.
From heartwire (requires free registration):
The paper comes as anticipation builds for the ARBITER-HALTS 6 study results. ARBITER-HALTS 6 is an imaging study comparing changes in carotid intima-media thickness in patients treated with ezetimibe (Zetia, Merck/Schering-Plough) or extended-release niacin; market analysts are already predicting a win for niacin. As previously reported by heartwire, ARBITER-HALTS 6 was stopped early: full results will be presented Monday, November 16, 2009 at the American Heart Association meeting in Orlando, FL.
So, it appears that extended-release niacin is going to kick tail when compared heads up to Zetia, or at least that’s the way the market is betting it. And that’s usually because the market has info that the rest of us don’t. If niacin is the clear winner, the press will be all over it and many people (and their physicians) will be wanting to switch from other cholesterol-lowering drugs to niacin.
With this study in hand, Merck and the other statin manufacturers can say, “Don’t give up your statins; the science shows that statins plus niacin is the effective combo.” Just keep your statin and add some niacin. And prescription niacin, to boot, so it all stays in the Big Pharma family.
Which is why – as heartwire reported – this paper is coming out now: to beat the rush.
We’ve learned a couple of things from this study.
First, we’ve learned that we have here a randomized, double-blind, placebo-controlled study showing that statins reduce LDL but don’t stop the progression of atherosclerosis, which, after all, is why we would take them.
And we have learned from reading between the lines in this study that statinators don’t really believe their own hype. As Samuel Johnson said about second marriages, the statinator’s reliance on statins as a cure all for heart disease “is a triumph of hope over experience.” Things haven’t really changed since MD wrote the family medical guide. If you’re worried about heart disease, take some niacin, the only substance yet that has been shown to decrease all-cause mortality. And it doesn’t have to be the prescription variety.
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