The Drug Report: June, 2012: The Trouble With Cholesterol

[Friends: I could write about DRUGS every day here for five years and never get tired of it, although most of you would be tired of me. The mandate I've placed on myself is to adopt the persona of a "generalist," so the drug-writing would do harm to the stated purpose of the blog...I'm not sure I've made a good case for my thesis yet anyway, although one of these days I'll arrive at the point...There are already quite a lot of good readable blogs on drugs out there anyway, and if you've seen one you'd like to give a shout-out to, go ahead and mention it in the comments section. - OG]

Lipitor and Other Statin Drugs, and Why I May Have an Excuse For Not Being As Smart As You Think I Oughtta Be...
...Which I'll get to shortly, but first: did you know that, despite our ability to synthesize new compounds as medicines/pharmaceuticals/DRUGS, we still derive most of our best-selling drugs from Nature? Can you imagine surgery before the opiate drugs like morphine? Well, where did we find out about opium? From poppy seeds. This will never cease to invoke wonder in me: a molecule produced by a flower was found to produce euphoria and a diminution of pain in humans. We didn't know why/how this worked (morphine synthesized in the lab circa 1803) until the latter half of the Roaring 20th century.

Indeed, a recent study from Singapore shows that about 25% of the best-selling medicines were derived from microorganisms first found in leeches, snails, bacteria, fungi, and other critters. To meander away from the topic for one sentence, what I found interesting in the study linked to here was that these researchers think they've punched a hole in the reigning idea that beneficial-to-humans substances can be found throughout the biosphere; they think there are hot pockets of classes of organisms where you can get much more bang for your buck when looking for the novel stuff, and this is likened to the way petroleum geologists have gone looking for where to drill most profitably. But yea: if you use aspirin, antibiotics, Procodin for coughs, Ventolin for asthma attacks, Lantus for diabetes, Beserol as a muscle relaxant, or Drovan for hypertension, you have, behind all these drugs, researchers studying the microorganisms produced by "wee beasts" - as the Father of Microbiology, Anton van Leeuwenhoek (say "LAY-ven-hook") - called them. But let me back up just a bit.

                                           statin-discoverer Akira Endo, at 75 in 2008

Lurking around since the 1950s at least was the idea that, the reason heart attacks were such a problem was that people make cholesterols in their liver, derived from dietary constituents, and these cholesterols do all kinds of beneficial things for us, like maintain cell walls and cellular skeletal structures. The liver made an enzyme called HMG-CoA reductase (which I include in this post to try to impress you), and this stuff did lots of good, but if there was too much of it, when it tried to return to the heart, it got stuck on arterial walls and formed fatty-like plaques. Maybe these plaques built up over time, but when they got too big they caused strokes; when they came loose they caused heart attacks. Those obstructed arteries probably played havoc in many ways. Certainly cardiologists and heart surgeons believed this: they saw evidence of it with their own eyes. (I'll spare you the pics.)

But let me back up again a bit.

                                  Anton van Leeuwenhoek, lens-grinder, curious self-
                                  experimenter extraordinaire. Read the chapter on him
                                  in de Kruif's The Microbe Hunters!

In 1971, a researcher at Sankyo Pharmaceuticals, Akira Endo - not to be confused with the Akira Endo who's a Japanese-American conductor - began to muck around with chemicals produced by fungi that grew on things like rice. He is credited with discovering statins, a class of drugs that definitely lower LDL cholesterol. Flash forward 35 years and Endo's receiving accolades and awards and the Japanese equivalent of the Nobel Prize for medicine. Those 35 years flash-forwarded and we also see that every Big Pharma company had their own statin drugs, but Pfizer's Lipitor (atorvastatin) was the blockbuster, the Thriller, the Titanic of all pharmaceutical drugs. It entered the market in 1997 and has made Pfizer $81 billion. It's probably the best-selling pharma-drug of all time. At least 20 million Unistatians are taking it in 2012, most of them over 45 years old. Pfizer's patent protection ran out last November, and it has been aggressively dealing with insurance companies by lowering its price in order to compete with the new generics market. Meanwhile, studies done by academic researchers and governmental bodies keep finding that statins are something like miracle-drugs, not only demonstrably lowering cholesterol and heart attacks and other cardiovascular morbidities, but they might inhibit Alzheimer's and, and, and...well, just all sorts of unforeseen wonderful things these statins do! But we consumers might want to start looking into these claims for ourselves. Chances are, we use statins ourselves or know someone who uses them. And let me just say this: make no mistake about it, Big Pharma largely funds just about every study you'll read on how great statins are.

Just one more back-up and then I'll keep it in drive from here on out?

Some Personal Stuff: About My Blood and Genes
Around 1997 I went in for a physical. I'm a lithe, ectomorphic dude. I'm omnivorous, but not a major meat-eater. I love eggs, but only have them once every two weeks or so. I exercise a lot, because I enjoy the mental states I get in when I'm hiking or riding my bike around town, and I love the endorphin buzz if I've exercised vigorously enough. But my blood tests showed too-high LDL (the "bad" cholesterol that could shorten lives). My doctor said he was surprised because of my lean body mass and asked about my parents. Well, my mom died of a massive heart attack in her sleep at age 53, but she had smoked cigarettes heavily from an early age. My dad? He's got a bit of a belly but he's in pretty good shape and yes, he's on cholesterol-lowering drugs. My doc thought I probably had a genetic predisposition to high cholesterol, and offered to write a prescription for Lipitor, which I balked at. He said I could try to lower my levels on my own through diet and exercise for six months, come back for a blood test, and if it's still high, I really ought to go on a statin. I said let's do that.

So I practically went vegan (not quite) and exercised with an added reason in mind, went back six months later: practically no change in LDL levels. So, I went on Lipitor.

Let me say this: I have never noticed any untoward effects of 10mg of Lipitor before bed. And when I went back four months later for a blood test, a few days later my doc called and said he'd never seen such a quick and dramatic lowering of cholesterol levels, especially the LDL baddies. So, as I understood it, I had moved into a mode of medical thought that was about preventing a disease before it has a chance to occur. This made sense to me, and seemed "progressive."

                                  Did mushroom spores arrive here from space? What 
                                  are some of them trying to tell us? Are you a mycophile,
                                  a mycophobe, or more neutral?

Among Us: Fungus
Lipitor hit the top of the charts, investors in Pfizer were euphoric. Later research showed all the other competing statins from the other companies were just as good (Crestor, et.al), but Lipitor's advertising was stellar. And all these billions from something derived from fungus from red yeast rice...something like that. In contemporary taxonomy of living things, Fungi has its own Kingdom all to itself. They reproduce via almost-invisible spores that fly through the air. Mycologists (AKA mushroom experts) are always fun to listen to; I've never heard a mycologist who was a dull speaker, and Paul Stamets (watch the gorgeous 150-second video in the lower right hand corner, "Fantastic Fungi: The Spirit of Good"!) and Terence McKenna (who was largely self-taught) are/were totally spellbinding in their own way. Every mycophile I've known was eccentric and very intelligent. There's something about fungus I can't put my finger on...I learned from both Stamets and McKenna that some people tend to be paranoid about the creepy images and powers of mushrooms and other varieties of fungus. These people are called mycophobes. The very straight east coast banker R. Gordon Wasson, an American, was a mycophobe, until his Russian wife Valentina - a mycophile - showed him how wonderful fungi were. Wasson later tracked down the mushroom that Mexican shamans said allowed humans to contact the gods. When he wrote an article about it for Life in the late 1950s, it caused a big stir among Beatniks and artists and other intellectual ne'er do-wells. As well it should've.

Yep: fungus can be tasty. It can create compounds with strong effects on humans, including alcohol, antibiotics, and hallucinogens. And it can lower cholesterol and save lives...according to the cardiologist model. But there are dissenters...Let's give 'em a hearing.

The Statin Contrarians
Largely shouted-out by the Big-Pharma-backed studies, this small but concerned group of medical researchers (possibly the most notable being Beatrice Golomb of UC San Diego) have been raising questions about what they think may be the vastly over-prescribed statin public, the manipulation of data by Big Pharma, the longterm side effects, whether statin use leads to Lou Gehrig's Disease and other neuromuscular diseases, and dementia, depression, and impulsive behavior. Furthermore, there may be a serious question that if statins have serious and more widespread side-effects, would we ever even find out, with the way the FDA tracks this stuff? Florida doctor Mark Goldstein even linked the massive use of statins to the 2008 world economic meltdown. I don't know how serious he was, but the impulsive behavior he saw in some of his patients who used statins made him think of the banking crash. In Tom Jacobs' article, "Cholesterol Contrarians Question the Cult of Statins," a 2009 piece for Pacific-Standard (then Miller-McCune), he concludes with these two rather paranoia-inducing (for me) paragraphs:

"So here's where we stand: A hugely profitable, largely self-regulated industry is aggressively promoting a line of newly developed products it assures us are safe and beneficial, when in fact they contain a significant element of risk. Much of the media takes the companies' claims at face value, leaving millions of people ignorant of the fact they are unwittingly participating in a huge, high-stakes gamble.

"Sound familiar? Statins may not have caused the financial meltdown, but the parallels between the two stories are positively heart-stopping."

In early 2012, the FDA issued new warnings for statins, mentioning possible increased risk of Type 2 Diabetes, and...I forget what the other thing was...oh yea: memory loss. (Can one monitor one's own side effects, always? With the 5% of the population that experience muscle fatigue and muscle pain with statin use, this seems easy. But note how often you or your friends blame their temporary inability to recall a name or a word in conversation. If you're over 40 and you have smart friends, they will darkly joke about early-onset dementia or Alzheimer's. The very significant segment of the over-45 population on statins that are reporting memory problems? Do we know this is caused by the drug and not that they're...aging? HERE is a horror story. But statistically, this is in fact rare, and the cost-benefit of using statins still seems to be in the statins' favor. I said "seems.")

A Gene Thing To Note
Researchers at Oxford found a "rogue" gene  (SLC01B1, just to keep you thinking I'm smart) that may account for 60% of the reasons why some people experience nasty-to-life-threatening side effects from statin use, especially neuromuscular disorders. If you have one copy of the gene, you're four times more likely to experience a nasty side effect; if you have two copies? 16 times more likely! And what's really a bit disconcerting: 25% of the population carries one or two copies of this gene, a number so high I think another reporter's use of the term "rogue" was misleading. This, I confess, I found more than a tad creepy.

Thinking For Ourselves
The statin contrarians say the public has been conditioned to be "cholesterol-phobic." They say that what heart specialists see should be balanced with what neurologists and other doctors see with regards to statin use. There's a very vocal crowd that seems mycophobic; they have argued that statins are a "mycotoxin" that obstruct the mevalonite pathway and, well, let me just give you the shrill title of a book I found: How Statin Drugs Really Lower Cholesterol and Kill You One Cell At A Time, by Yoseph and Yoseph. At the risk of sounding flippant, this reminded me of the plot from the old Twilight Zone episode, "To Serve Man." My gawd! The book To Serve Man? It's...it's...a cookbook!!!

[But then again, maybe the Yosephs are Cassandras and we statin users are guinea pigs in one of the worst biomedical disasters in the entire Pan-Galactic Archives? For now, I'm still swallowing my statin after brushing my teeth. You gather your information, sift, weigh the pros and cons, call 'em as you sees 'em, take responsibility for your decisions, think for yourself. Are you sure you want to be eating that Thing you had for lunch?]

But I have studied enough statistics to not be scared off statins for now. As you can see by yet another too-long blogspew, I keep up on this stuff. But before I leave you (as if anyone is still reading by now!), I want to add something that, for some reason, has generally gone unsaid in this statin side-effects brouhaha.

The Possible Role of Co-Enzyme Q-10
My favorite Media Doctor has always been Dr. Andrew Weil. I really like his books. He was at Harvard studying medicine when Timothy Leary was experimenting with psilocybin (a fungus!), and was writing for the Harvard Crimson. He seemed to want in on the experiments, but couldn't get in. He found that other undergraduates were in on the research, a violation of Harvard's code of ethics, so Weil blew the whistle on Leary, Metzner, Alpert (Ram Dass), and eventually the psychedelic psychologists were kicked out of Harvard, or dropped out, or asked to leave. Weil had since then come to rather amiable terms with Leary (before Leary's death in 1996), but Ram Dass seems to have never forgiven him. (According to Don Lattin's The Harvard Psychedelic Club.) Anyway, I digress...because apparently I can't help myself. ("Impulsive behavior" driven by statins? No, I think I started digressing in writing around age 7...)

I went to see what Weil thought about statins, and he seemed to stress the use of the dietary supplement Co-Enzyme Q-10. (Hereafter CoQ10) So I read up on CoQ10. Very interesting. But I didn't start buying supplements of it.

Then I read a wonderful book of interviews by David Jay Brown called Mavericks of Medicine: Conversations on the Frontiers of Medical Research. Durk Pearson and Sandy Shaw got on the topic of statins, mitochondria, the politics of biomedical studies, etc. I will throw this out there for the general edification of anyone reading this: food for thought, grounds for your own research!

In the Realm of Conspiracy Theory
Pearson says (I'm reading from page 112) that statins indeed do block the synthesis of mevalonate, which is used to make cholesterol. "However, mevalonate is also used to make a substance called Co-Enyme Q-10, which is part of the the single electron transfer chain controlling chemistry in the mitochondria." Pearson suggests a supplementation of CoQ10 higher than I already use (I'm a convert!), and gives good reasons why. He also says our ability to synthesize our own CoQ10 degrades as we age, or our mitochondria age. Pearson says you won't find this info in the Physician's Desk Reference, so even doctors don't know we should be supplementing with Co-Q10, much less the massive statin-using public. The FDA has been unresponsive to researchers and other doctors who have raised this issue. Why? Here's a nice little conspiracy theory, ladies and germs:

Pearson/Shaw (they're always together and, as Brown says, finish each others' sentences) say that Merck Pharmaceuticals has a patent on any statin plus CoQ10 since around 1990. They're not making it because it's really hard and expensive to get FDA approval of a combination drug, so they're sitting on this info. Yea, but why? If statins can be so debilitating, why not go ahead and try to get FDA approval anyway? Because by the time researchers knew about the drawbacks of statins they were already approved and making boffo dinero for Big Pharma. Coming out with the drawback data would have delayed the gravy train, gravy ironically elevating cholesterol levels to the point where your aorta congeals into a hockey puck, but there I go digressing again...On with the conspiracy theory:

Rather than pull the statins, then go through the long clinical trials of statins plus CoQ10, the Industry kept mum, lest the money-flow float out the window. And if the Public knew about the liabilities, they'd sue, sue, sue. The law among Big Pharma was like the law of the Mafia: omerta. Or: keep your mouth shut! Shaw/Pearson liken this to RJ Reynolds, the tobacco company, who did develop cigarettes that were safer, but didn't release them, because doing so would be an admission you'd already been poisoning the community. The FDA wouldn't let them say their new cigarettes were "less carcinogenic."

Here's Ray Kurzweil, from Brown's book:

"Co-Enzyme Q-10 is important. It never ceases to amaze me that physicians do not tell their patients to take CoQ10 when they prescribe statin drugs. This is because it's well-known that statin drugs deplete the body of CoQ10, and a lot of the side effects such as muscle weakness that people suffer from statin drugs [...] [CoQ10] is involved in energy generation within the mitochondria of each cell. Disruption of the mitochondria is an important part of the aging process and this supplement will help slow that down. CoEnzyme Q-10 has a number of protective effects including lowering blood pressure, helping to control free radical damage, and protecting the heart." (pp.242-243)

Here's a line from Nassim Nicholas Taleb's book of aphorisms, Bed of Procrustes: "Pharmaceutical companies are better at inventing diseases that match existing drugs, rather than inventing drugs to match existing diseases."

And with that ominous observation, I take full responsibility for...what I can take responsibility for...and  urge the Reader to look under rocks and see what squirms there, no matter how unpleasant. Because, whether the Truth shall set us free or not, trying to find more "truth" is bound to make our lives far more interesting than jelling out in front of the TV, no?

At any rate, if you think, after reading me, I'm sort of a dim-bulb, I have my excuse: I was only trying to save my own life!

Some Books and Articles Consulted, From Memory:
Happy Accidents: good on the discovery of statins and other drugs, very readable and delightful!
Scientists Greater Than Einstein: a modern version of the medical researcher/doctor as Hero - a chapter devoted to the heroic life-saving efforts of Akira Endo - in the mold of Paul de Kruif's classic The Microbe Hunters and Sinclair Lewis's fictional offshoot of that book, Arrowsmith, which was heavily influenced by de Kruif.

"Drug To Cut Cholesterol Tests Better Than Statin" (there may be much better drugs for controlling cholesterol coming down the pipes, but this one has to be injected.)

"American's Cholesterol Levels Shrink, Even as Their Waistlines Expand." (ties in with my obesity blogs?)

"Statins Cause Fatigue In Some People" (and yet, nothing on CoQ10)

"Lipitor Patent Ends; generic available: What Now?"