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Statins
The birth of statin medications goes back to the 1985 Nobel Prize for Medicine which was shared by Michael Brown and Joseph Goldstein for their research. This would be the beginning of an overwhelming war on cholesterol. At this point in time the link between cholesterol and heart disease was growing stronger by the day. Today we know that reality is a little more complicated, but the “bad” cholesterol misinformation was spread so far and wide that it would set off a pharmaceutical arms race. Prior to statins the only cholesterol lowering medications available were nicotinic acid (niacin), clofibrate an early precursor to fenofibrate which is still used today and cholestyramine a resin which binds cholesterol in the gut preventing its reabsorption. Cholestyramine was the most effective but also had GI side effects that many patients could not tolerate. So, it is easy to see how the medical establishment would look at something that reduces cholesterol as a panacea for heart disease.
Although Mevacor (Lovastatin) developed by Merck gets the title of the first approved statin the story begins in Japan at a drug company called Sankyo. The first experimental statin known as compactin was developed to inhibit cholesterol synthesis and it did a fantastic job in vitro. Unfortunately, in animal testing the therapeutic effect would disappear in a few hours as rats were able to increase the enzyme it blocked tenfold quickly overwhelming the cholesterol reduction. Normally a failure of this magnitude would result in the drug being scrapped completely but to Sankyo’s credit they would spend two years identifying why it did not work in rats and conducting further studies in hens, dogs, and monkeys where it would prove effective. Compactin would go as far as phase 2 trials in humans where it was effective in lowering cholesterol. Development would be stopped due to two issues; the first were crystalline microstructures discovered in the liver of rats who received high doses, toxicologists were concerned that these were toxic metabolites. After nine months of study researchers were able to identify these microstructures as cholesterol which was not toxic. The second would come when dogs that were given extremely high doses would develop lymphomas. The doses that caused it were nowhere near what was being used in human patients, but two strikes were enough to stop the development in its tracks and even halted a competitors drug lovastatin for fear of lymphomas. Merck would later decide that the positive human trials of compactin warranted further research and development was restarted and they would submit their new drug application in 1986 with approval coming the following year.
There was great hope with these new medicines that cardiovascular disease would become a relic of the past, unfortunately that did not occur despite statins becoming the best-selling drugs in history. Statins like all therapies are just a tool and its optimum efficacy occurs with proper rational use. What constitutes rational use has changed over time; at one point not treating an elevated LDL with a statin was considered medical malpractice. LDL was treated hyper aggressively and with such widespread use case reports of adverse events would slowly start building the argument that we may be causing more problems than we are solving by overprescribing.
Toxicity from statins can range from muscle weakness and fatigue all the way up to life-threatening rhabdomyolysis. Myopathy is the largest patient complaint with statins and results in poor adherence and thus more heart attacks in those patients who may truly need it. As we approach three decades of statin therapy, what causes its most common side effect is still debated. Mitochondrial dysfunction has long been suspected as the reason behind these side effects and recent animal studies have highlighted a potential mechanism of action.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338935/
Researchers here administered rosuvastatin to rats with varying dietary cholesterol. Proving the devil is in the dose; 400 milligrams of rosuvastatin combined with a high cholesterol diet resulted in the death of every single rat by the sixth day. Damage to the mitochondria’s structure and function was in the words of the researchers “not compatible with life“.
While that sounds bad these are whopping doses compared to what is used therapeutically for humans, it certainly proves that the medication is not without potential harm.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8927716/
This in vitro study is the first to show the connection between atorvastatin and ferroptosis, an iron mediated form of cell death. Atorvastatin was shown to induce muscle injury in both skeletal and cardiac muscle by suppressing the Nrf2-xCT/GPx4 pathway this induces ferroptosis which results in excessive lipid peroxidation and increases oxidative stress. Ferroptosis is currently being studied for its role in Parkinson’s and Alzheimer’s. Recent research has also identified this as a potential pathway for the neurological damage post covid infection. Interestingly the only statin that does induce ferroptosis is atorvastatin, which was also the most popular one.
Jacob Hyatt Pharm D.
Father of three, Husband, Pharmacist, Realtor, Landlord, Independent Health, and Medicine Reporter
https://substack.com/discover/pharmacoconuts
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Further reading and references
https://pubmed.ncbi.nlm.nih.gov/35411172/
https://pubmed.ncbi.nlm.nih.gov/35411172/#&gid=article-figures&pid=figure-2-uid-1
https://pubmed.ncbi.nlm.nih.gov/32726602/
https://pubmed.ncbi.nlm.nih.gov/30545434/
https://www.nobelprize.org/prizes/medicine/1985/summary/
Published in Healthcare
I have at least one Sankyo stereo cassette deck in my collection.
Three decades in and fear Statins!
Let’s fear all medications!
By the way, if they stop cardiovascular events, the risks might be outweighed by the benefits.
But hey, trade offs are so conservative.
Just because water can cause potential harm at whopping doses (drowning), that doesn’t mean that water isn’t good for you.
Agree with Dr. B here. I think. Long time heart doc said you don’t need them even though high cholestoral numbers given your genes. OK, fine with me. My doc friend never had PSA tests and died six months after he was diagnosed with prostate cancer. His doc partner said take the statins and get the numbers down. So I did. And it worked. No complaints for side effects. And get the PSA checked every 3 months.
What causes high serum cholesterol?
Does high cholesterol cause atherosclerosis?
Does reducing dietary cholesterol in any way reduce serum cholesterol levels?
And does high cholesterol mainly result from from consuming high cholesterol foods, or is it mainly produced by the body apart from diet?
Does the body produce high cholesterol incidentally and for no good reason, or does it result of damage to vascular endothelium?
Several Ricochetti have reached out to me privately about this post, asking for comments. Including one of you who remembers hearing me speak on this topic at a medical conference in Dallas some years ago – pretty cool! I used to give around 50 speeches a year on this topic, all over the country. In the question / answer sessions I’ve heard every possible perspective on this topic, always learning from my audience.
Anyway, I really try to avoid commenting on medical topics online. As a doctor, that could be interpreted as medical advice, which it would not be. And which Jacob’s article is clearly not intended to be, either.
Jacob didn’t mention the benefits of statins, either because the data is so overwhelmingly positive that he didn’t feel the need to point out the obvious, or because that wasn’t the point of the article.
He mentioned the dangers of giving enormous doses of statins to animals (so don’t do that). And he mentioned that some people have muscle aches on statins sometimes. We think. Although we’re not sure why.
It’s a complex topic, of course, and Jacob was not trying to explain the risks and benefits of these drugs. That would be a book, not a Ricochet post. He probably has better things to do.
And I’ll probably avoid that as well. Maybe someday I’ll cover some basics in this realm. But I probably should keep my nose out of it on this forum.
My cardiologist prescribed a statin drug for me. I took it. It made me stupid. Bad side effect. I now refuse to take statins.
Cholesterol is essential health. Our bodies manufacture it. The brain depends on it. Although high cholesterol levels, particularly the so-called bad cholesterol, may be associated with heart disease and arterial plaque, I have yet to find anything definitively proving that cholesterol causes it or causes arterial plaque. Coexistence does not logically equal cause and effect.
We know that inflammation is always a negative thing inside the body. One cardiology surgeon that I have read says that in 100% of the bypass cases he has had there has been arterial inflammation. I have read nothing to suggest that cholesterol causes arterial inflammation.
My views have been influenced by the following two books, surprisingly having the same name:
The Great Cholesterol Con by Dr. Malcolm Kendrick.
The Great Cholesterol Con by Anthony Colpa.
These books analyze scientific studies that supposedly support the benefits of attacking cholesterol as if it were the cause of heart disease and find them wanting. However, there do seem to be benefits to statins for those who have survived a heart attack.
If anyone has scientific references that refute the analyses discussed in these books, I welcome the opportunity to have my mind changed. I really don’t want to die of a heart attack. Or anything else, for that matter, however inevitable!
Good heavens no.
Most inflammation is your body’s effort to heal something. Like when a twisted ankle is hot and swollen and sore. That’s obviously an inflammatory process. It is also healing.
Some inflammation can be bad, too, of course.
We don’t know how to tell the difference yet.
@drbastiat Point well taken. Perhaps it is more accurate to say that inflammation is a marker that something is wrong.
It seems to me what is important is that the drug/procedures/therapy/supplement/food eliminates the inflammation by fixing whatever it is that was causing the inflammation.
It took decades of experimentation and research to reach the point we are at today in understanding cholesterol. Sadly, we had to go through many fads to get here, and some people stay stuck on one fad or another, just because that’s how people are. Letting go of something we read or thought and made our own is very hard to do.
After thirty happy years of gardening every day from early spring to late fall here on beautiful Cape Cod, today I am instead sitting at my computer nursing a whopping tick bite I got Sunday.
Ticks are a fact of life on Cape Cod. Consequently our doctors are experts on them. Regional health issues will do that–create a truly daunting body of knowledge in that region’s medical sphere. When my daughter attended the University of Vermont and sustained a serious ACL injury in a skiing accident, her orthopedic surgeon here on Cape Cod said he would be thrilled to coordinate her therapy with the doctors and physical therapists at Fletcher Allen Hospital at the university: “They are the world’s experts on this type of injury.” For mountains of reasons. :-)
With all that I know about preventing tick bites and treating them when they do occur, I learned some new-to-me things from my wonderful ER doctor Sunday night. He asked me what happened, and I told him I had discovered it on my leg when I took my shower and I had pulled it off immediately. I said sheepishly and apologetically (I knew better than to yank it off!) that I didn’t know if I got all the parts. There’s some elaborate procedure people do to get the bugs to back out of the wound so the victim can get the whole thing. That was the main reason I was at the ER–to make sure the bug was all gone.
The doctor said, “You did exactly the right thing. We don’t wait anymore. Get as much out as you can as quickly as possible. They longer they are there, the longer they are injecting poison.”
That was a surprise! But it makes sense.
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He cleaned out the bite site, and he gave me two doxycycline tablets while I was there. That was also a surprise to me. He said for bad bites (meaning bites that look like the tick was attached for a long time), they don’t wait to find out if the patient has symptoms of Lyme disease. Then he said to call my doctor and tell her about the incident and get a Lyme test in two weeks. “But,” he said forcefully, “if you develop any symptoms–joint aches, fever, chills, neck pain, or the telltale circle around the bite–you come back here immediately. Do not call your doctor. Come straight to the ER. Ticks carry many diseases, not just Lyme. If you don’t develop symptoms but you test positive for Lyme two weeks from now, we’ll put you on a course of doxycycline.” I left the ER with six pages of very well written information on the prevention and treatment of tick bites. All of this information was prepared by Cape Cod Hospital.
It was shocking to me to see how treatment has changed in the thirty years I’ve lived on Cape Cod. When I first moved here, no one was taking Lyme disease seriously. The insurance companies refused to pay for treatment. Most of the medical profession believed it was an imagined disease. And it turns out that doxycycline is a very interesting drug. It’s an antimalarial drug, effective in the same realms of disease as Ivermectin. Apparently, doxycycline is one of the drugs they are looking at for covid-19 treatment.
As I thought about the evolution of Lyme disease prevention, diagnosis, and treatment, I realized that five or ten years from now, the coronaviruses that cause pneumonia will be understood too. Keeping people from becoming deathly ill from these viruses will fall on the ER doctors’ shoulders. At some point, the enemy more powerful than the virus will be ignorance. It is truly impossible for the average person to keep up with the minute-to-minutes advances in medicine. The public dips in and out of the information published by the press from one moment to the next, the public forms an impression of what is true or false, and they make that information their own. People get stuck at some point that becomes fixed in their mind as The Truth of the Matter. :-)
Our nation’s cardiologists are dealing with older patients who have been reading about statins for decades. That “knowledge” is what they bring to the cardiologist: “Don’t take the statins. Throw out your eggs and butter!” Just like the covid-19 battles today, these wars were fought on the front pages of the New York Times, Wall Street Journal, and New England Journal of Medicine. We readers were watching the ultimate Muhammad Ali versus Rocky Marciano battle of the century. And eggs and butter were the masks of twenty years ago. :-)
I would disagree with you on this. Hearing talk from Evidence-based researchers looking at the history. Studies done by the late 70’s were showing a lot of evidence against it and by the early to late 80’s (don’t remember when in the 80’s) pretty conclusively proved there was no correlation. Now I have not read these studies myself. However, the hypothesis was taught in medical school before any research was ever done to prove it.
So the real question is why medical schools ignored the evidence and every one taught doctors this let alone kept teaching after the studies proved it was false for decades. That is the real scandal, of not caring about evendicence-based medical care when teaching.
Have you read Douthat’s book?
No. :)
A lady that used to work with me was a life-long vegetarian and an active long-distance runner. Her cholesterol numbers were sky-high.
Taking statins makes me feel 20 years older, with muscle-aches and general lethargy. Maybe they’re good for some people, but my body tells me that something is wrong when I take them. I decided to listen to it.
We’re none of us getting off this planet alive, anyway.
I can name a few orthopedic surgeons who will (carefully) induce inflammation at the affected site to improve blood flow where post-op healing in cartilage is not proceeding well.
I deal with ticks using technology: we spray the entire property against mosquitos – and ticks die, too. It makes being outdoor far more pleasant. Even our cats, who live outdoors, never get ticks anymore.
Better living through chemistry!