I've been taking Lipitor for 29 years.
This is my friend, Joe.
Joe Bagnoli.
I'm 59 years old.
I live in St.
Paul, Minnesota.
Joe and I have been friends since college.
I would describe him as constitutionally happy.
He's gregarious.
He's a thoughtful person with a lovely wife, Barbara, and three amazing kids.
Oh, and he's a very successful lawyer in the Twin Cities.
He'd want me to say all of that.
But for my purposes today, the reason we're talking is because, as he said, he's been taking Lipitor or atorvastatin, as the generic version of the drug is known, for a very long time.
Literally for the first time in my life, I got this doctor and he's like oh, you're Tom Bagnoli's son.
He's like, well, we got to work you up a little bit.
And I said, okay, great.
He works me up and he comes in and he says, well, your cholesterol is a little high.
And I said, well, how's that?
I had no idea what cholesterol was.
I'm in really good shape.
I'm not overweight.
I had just run a marathon.
And I said, how is this possible?
And he said, well, you know, sometimes it's hereditary.
I said, I can't believe this.
And then he said, well, what'd you eat last night?
And I said, well, I had cheese tortellini and butter and garlic sauce.
And I said, I might have had a root beer with that.
And he said, well, how often do you do that?
And I said, well, I like cheese tortellini and butter and garlic sauce.
That's a very great meal.
I said, I probably have that two to three times a week.
And he said, well, what do you have for lunch?
And I said, well, you know, often a hamburger, some fries, a Coke.
He said, diet?
No.
I said, no, I hate diet Coke.
I might have, you know, a Rice Krispie bar.
Or a candy bar or something a little sweet?
He said, your diet's horrible.
And I said, yeah, but I look great.
I'm in great shape right now.
I'm fortunate.
I metabolize pretty well.
I'm relatively thin.
And he goes, no, no, no, no, no.
It's terrible.
But I'll give you a drug.
It should control it.
But you got to take it every single day.
I said, all right, I will do that.
And he said, try to eat a little bit better.
Well, at the time, I sort of thought, well, I'm on the drug.
I'm bulletproof.
Why do I need to really change?
I changed a little bit.
I don't eat the tortellini with the butter sauce every now and then I do, but not often.
Then a year and a half to two years later, it wasn't close in time.
It was when I was at 330.
They gave me the speech.
330 was the level of LDL cholesterol in Joe's blood.
We'll explain more about that later, but for now, just know that 330, it's considered really high.
Many doctors will prescribe statins for a score of anything over 150 or 200.
You have a major problem and you have to change your ways and be cognizant of this.
Try to keep your weight down.
Try to keep your intake.
Basically, they said, even though you're not morbidly obese, you can be thin and still have high cholesterol.
My issues are clearly hereditary.
To be as high as I am without other difficulty, but it means I have to try to watch it as much as I can.
I can't say I'm perfect with taking the.
They then went from.
I think I was at 10 milligrams but I had never been rechecked.
I just was taking the 10 milligrams or whatever it was.
I'm at 40 milligrams of atorvastatin, which is a relatively high dose now.
And that has cut my numbers down to, I want to say somewhere between 150 to 180.
So much more reasonable.
Much more, much, much more reasonable.
I haven't had any in the last, whatever, 20 some odd years.
I haven't had any muscle issues.
I haven't had anything like that.
So it's been relatively straightforward.
And how often do you get your cholesterol checked?
Your lipid panel.
I get my lipid panel checked.
It's about once a year.
Do you need anything more?
Have I given you enough here?
Yeah, yeah.
No, this is fantastic.
The whole episode is going to open with Joe's diet.
She's totally in a Rice Krispie bar.
That's pretty much it.
I love that.
It was a lot of salt.
With a lot of salt.
It's something.
It's high living.
I'm Thomas Goetz, and this is Drug Story.
Today's drug story is about atorvastatin or, as it's also known Lipitor, the brand name of the drug atorvastatin.
Today, atorvastatin is the most prescribed drug in the United States.
Number one, more Americans take atorvastatin than any other prescription drug.
For a time, it was the most profitable drug in history.
We're talking many billions of dollars of pure profit for the drug maker Pfizer.
Joe's experience with atorvastatin is common for a lot of Americans, a lot of people across the globe.
They feel fine, they feel healthy, but the level of cholesterol in their blood is high, meaning that it's a sign that you may be at risk of heart disease.
And so they are prescribed a drug like atorvastatin.
It works really well to lower the level of cholesterol in the blood.
And by extension, the hope is to reduce their risk of heart disease.
And just a technical note here there are actually two kinds of cholesterol in our blood LDL cholesterol and HDL cholesterol.
I'm not even going to get into what LDL and HDL stand for, And oftentimes these levels are reported as total cholesterol, which combines both LDL and HDL, which is confusing because LDL is considered bad and HDL is considered good.
So when we talk about cholesterol scores and high cholesterol and whatnot, we're always talking LDL, the bad kind.
But here's the thing.
Nobody really dies of high cholesterol.
The consensus in medicine is that a high cholesterol level raises your chance of heart disease, most specifically atherosclerosis.
That means clogged arteries, clogged with plaque, and you guessed it, clogged with cholesterol.
And atherosclerosis itself is really a risk factor for another bad thing, which is coronary heart disease.
That is the leading cause of death in the United States today.
It can also lead to a stroke, which is basically a heart attack in the brain.
Stroke is the fifth most common cause of death in the US today.
So that's what this drug, atorvastatin, is really trying to do.
It's trying to reduce the chance of something else bad happening later down the line.
That's why people take it.
The whole idea is to minimize one risk factor in a chain of risks that, without treatment, could lead to a heart attack or a stroke and death.
In today's episode of Drug Story, we're going to examine that chain of risk.
We'll make our way from one link to another.
You get the metaphor.
One end of this chain starts at where many of us are today undiagnosed, going about our lives but with certain potentials or probabilities to reach the other end.
A heart attack, a stroke, dead.
That's the other end of the chain.
But along the way, across all these links, it's all about the numbers.
A statistical estimation of how likely we are to move from one link to the next link.
Our age, our blood pressure, our cholesterol score Each of these things can increase or decrease our risk for heart disease, but it's always a game of probability and prediction.
This is the best guess that medical science has for predicting your specific individual risk for something worse happening.
So today we're going to dig into those risks and the idea of using drugs to reduce that risk.
We'll see how, over the years, the number of people taking atorvastatin and other statins has increased to a staggering 35 of Americans over the age of 40.
That's one out of three people.
But even as these drugs became so common, they have also become one of the biggest controversies in modern medicine, one that still is not settled.
And our story starts with the death of an American president.
That's coming up next.
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Welcome back to Drug Story.
Each episode of Drug Story has three parts, the diagnosis, the prescription, and side effects.
This is part one, the diagnosis, where we look at the disease behind the drug and how that disease emerged in modern days.
We'll start back in March 1944, when the tide of World War II was turning.
The Allies had successfully bombed Berlin and planning for the D-Day invasion was roaring ahead.
President Franklin Roosevelt, though, was unwell.
In truth, he had been in poor health for more than a year, with what his staff called good days and bad days.
The presidency, after all, was a demanding job, especially in wartime.
And in 1944, FDR was campaigning for an unprecedented fourth term in the White House.
In a physical exam, he was diagnosed with an enlarged heart, high blood pressure, bronchitis and congestive heart failure.
Congestive heart failure is a term that I never thought about much.
I knew it was bad, but what it means obviously, when you think about that word congestive well, it's that the heart gets congested, just like your nose.
But a congested heart is a lot more dangerous.
With the heart, it means that it isn't pumping blood into the body like it needs to.
And you can't blow your heart like you can your nose.
Anyway, so they knew FDR was unwell.
But the fact was, in 1944, they just didn't have much they could do for him in terms of medicine.
He was prescribed codeine for rest and digitalis, an old drug that helps increase the heart rate and improve blood flow.
He was told to rest, no exercise, and to try to smoke and drink a little less if he could manage.
Doctors kept watching him, kept measuring his blood pressure which, at 200 over 100, was much higher than normal.
Normal blood pressure we know today is about 120 over 80.
So his was really high.
That November FDR was re-elected to that fourth term and he was inaugurated in February 1945 at the age of 63.
But he was still very, very sick.
The public didn't know he was sick.
His health status was considered a matter of national security, and so they did everything they could to make him appear healthy and vigorous.
But his family knew.
His ticker situation, they called it.
And so FDR stayed on, leading the nation on.
And then, on April 12th, 1945, Roosevelt complained of a terrible headache.
In a few hours, he would be dead of a massive stroke.
Less than a month later, the Allies would defeat Germany, leading to victory in Europe.
Today it seems remarkable that FDR's doctor could have been so blasé about his health and so unprepared to help him.
The care and the treatment seem almost primitive to our eyes.
In truth though, medicine simply didn't know much about high blood pressure, or heart disease or stroke.
There just wasn't much science knew about these conditions.
They had his numbers, those daily blood pressure reports, but they didn't really understand what those numbers meant in terms of risk.
They couldn't connect FDR's status to any science about the causes or consequences of heart disease or stroke.
And in any case, there wasn't a lot they could have done for him anyway.
In 1945 there were no heart transplants, no coronary bypass surgeries and there were basically no drugs to treat his symptoms or to reduce his risk.
But Roosevelt's death would change all of that.
The fact that the President of the United States died of something so common and yet so poorly understood.
Well, it shook things up.
In 1948, Harry Truman FDR's successor, he signed the National Heart Act into law, officially creating the National Heart Institute as part of the illustrious National Institutes of Health.
The first order of business was a new research project, unprecedented in its scope and ambition.
This was a grand scientific experiment to put an entire city under the microscope, to observe the citizens of this city for two decades, to measure them and observe them in the hopes that they could reveal the causes of heart disease.
The idea was that if medicine could better understand what caused heart disease, medicine might be better equipped to help those like FDR who had symptoms before a heart attack or stroke.
Or better yet.
Maybe the experiment could reveal how to prevent heart disease in the first place, before symptoms of disease even occur.
The city they chose was Framingham, Massachusetts.
Framingham is about 20 miles outside of Boston.
And in 1950, it had a population of about 30,000 people.
If you've ever been to Framingham, and I've been there, well, there's not a lot to see.
It's too far away from Boston to be a suburb, but close enough to be an exurb, one of those sprawling cities with miles of tan beige shopping centers without windows.
Piece of trivia for you.
The Shopper's World Mall, which opened in Framingham in 1951, was the first mall east of the Mississippi.
Back then, the largest employer in town was General Motors, which had opened a plant just a few years before.
There are not six, not seven, but 10 Dunkin' Donuts in town today.
It's a pretty ordinary East Coast excerpt, which is what made it pretty much perfect.
They chose Framingham not just because it was close to Harvard Medical School, where many of the researchers worked.
It was also a very middle-class city.
And importantly, a lot of doctors lived in town, because the Framingham study was going to require a lot of visits to the doctor.
Framingham was an observational experiment, meaning they would take a large sample of the city's population more than 5000 people, equally divided between the men and the women and send them to the doctor for tests and to measure various vital signs, and then have them come back six months later for more tests and measurements.
This went on for years.
The idea was to see if they could connect any of the measurements with what happened to people later in terms of diagnoses of disease or causes of death.
They wanted to connect the dots, basically, between causes and effect.
A few of these kinds of studies had been done before in Scotland and Minnesota, but there had never been a study with so many people 20 of the total population of the town over such a long time period, with a focus specifically on heart disease.
What started to emerge within just a few years actually, much earlier than they expected was this idea of risk.
There were a handful of specific factors that were strong predictors, strong risk factors of heart disease.
That's where we got all of our classic ideas about heart disease risk was from the Framingham study.
This is Dr. Rita Redberg.
We're going to learn a lot from her in this episode.
I'm a professor of medicine and a cardiologist at the University of California, San Francisco.
And they identified a handful of factors, right?
Right off the bat.
I think they measured a lot of things, but then they narrowed it down to a handful of factors.
Age is the big one.
All right.
Which is not modifiable.
But the older you get, the higher your risk of all diseases pretty much, and certainly heart disease.
Age sex cholesterol levels and they, I believe, use total cholesterol and HDL blood pressure.
They use systolic blood pressure.
Smoking status.
These five measures age sex, blood pressure, cholesterol level and smoking status.
They emerged quite early as strong associations with heart disease.
If one of them was high, or if you were a smoker, it was more likely that you would develop heart disease.
And if you had two or three or four or even five risk factors at once well, your risk of heart disease later was much, much higher.
The breakthrough was not just that there was a strong predictive value here.
It was also that these things could be measured quite precisely and pretty easily.
Age and smoking status.
Well, not so hard, but blood pressure could be measured with just a cuff on the arm, and cholesterol level just required a small amount of blood and a simple lab test.
Taken together, these risk factors offered a very powerful, very new way of understanding heart disease and maybe a new way of treating it or even preventing it.
Framingham was initially conceived as a 20-year study, but it's still going on to this day, nearly 80 years later.
They're now on the third generation of subjects, meaning the children and grandchildren of the initial participants are going to the doctor and getting their tests.
Data that is revealing all sorts of things about the genetics of heart disease.
They've also expanded the study, which was originally mostly white people.
Now it includes black and Asian and Hispanic members of the Framingham community.
That ensures that any racial variations in disease and risk are captured.
And as the study has grown, so has the sophistication of the analysis.
Those five risk factors have been refined into a fancy statistical algorithm that doctors use to calculate something called your Framingham Risk Score.
It's basically a calculator and it predicts an individual's risk of coronary heart disease over the next 10 years.
In other words, it's a statistical prediction of your health, letting you see into the future.
And if it predicts something bad, hopefully there's enough time to do something to lower your risk and improve your odds.
It seems pretty obvious today, but back in the 1950s and 60s the idea of prevention, stopping disease, before it happened, that was a whole new paradigm for medicine.
The risk scores are not meant to be used for people that have symptoms.
They're used essentially for screening.
And screening means you're looking for a disease in an asymptomatic population, because identifying that disease early is going to lead to improved outcomes for that person.
Right.
That's a basic theory of preventive medicine, right?
Of screening.
That's right.
And so that's the idea in identifying what the risk factors are is that we could then lower risk factors, either on an individual level or on a population level, and that would lower the rate of, in this case, heart disease.
Of course, back then in those early days of Framingham and during the boom of post-war America, there was only so much you could do to lower your risk, in part because so much of everyday life in those days of plenty was actually raising your risk.
The boom in post-war America was unprecedented in human history.
An explosion of economic prosperity and abundance were the bounty of modern life.
Ample food, an affordable home with a car in the garage, booze and cigarettes aplenty that could be enjoyed by all, or so it seemed.
For those who could afford that bounty and those who indulged in that bounty.
It turned out that this new American lifestyle created a lot of hidden risk.
For the first time in civilization, everyday life was just not all that good for you.
Food was cheap, but not very healthy.
Lots of meatloaf and very few salads.
The suburbs were expanding, which meant more driving and less walking.
For downright satisfaction, there's just nothing quite like Valley Forge beer.
Alcohol consumption in the U.S. doubled between 1940 and 1970.
So inhale, feel that light extra mildness in the smoke of a Cavalier.
And so much smoking.
40% of Americans smoked at least a pack of cigarettes a day.
And exercise?
Exercise, it wasn't really something people did outside of team sports in school.
So what we have is a general ganging up of all sorts of factors, including excessive food intake, decreased exercise, increased stress.
If one is constantly in a hurry and pushed by an executive job.
All of that adds up to just one thing that modern man in the United States is in grave danger from obesity.
My dad died at age 51.
He had a coronary when he was 46, and his second coronary failed within five minutes when he was 51.
My mother just passed away recently.
She was 62.
The doctor who most recently examined me, Dr Kenneth Cooper, indicated that the only reason in his opinion I had not already had a coronary was because I did not smoke, because I'd do everything else wrong.
Thanks to Framingham medicine, started to understand that this lifestyle was not healthy and, in fact, that it was very good at creating heart disease.
The most obvious risk was smoking.
In 1964, the US Surgeon General issued a report on smoking and disease, declaring that cigarette smoking was hugely risky, not just for lung cancer but for heart disease.
Of course, the tobacco companies.
They spent decades and millions of dollars, probably billions, really trying to confuse the argument.
But it was clear that quitting smoking was the single best change someone could make for their health.
And Framingham showed that lowering sodium levels in the blood would also reduce blood pressure.
And that lower blood pressure reduced the risk of heart disease.
But that meant dietary changes.
Asking people to eat less salt, which was hard to do in those days, maybe harder than today even.
But then, a breakthrough.
In 1957, the first drug was discovered that actually lowered blood pressure.
This was chlorothiazide, which was called Dioril by Merck, the drug company that developed it.
Most drugs, as you're probably catching on, most drugs have two names the chemical or generic name and the brand name, the name that's given by the drug maker when it's under patent.
Once it's off patent, you can buy the drug from anyone in a generic version.
Chlorothiazide is a diuretic, which means that it increases urine production in the kidneys and, along the way, excretes electrolytes such as sodium, potassium and chloride.
Basically, the drug makes you pee out salt, and that reduces blood pressure, which lowers the strain on the heart and that reduces the risk of heart disease.
This was a huge breakthrough.
At the time, cardiologists talked about the era BC, that is, before chlorothiazide, and the era AD, after diuryl, the brand name of chlorothiazide.
This raised hopes that there might be other drugs that could be used to reduce other risk factors.
These days, there are many kinds of drugs used to lower blood pressure.
Calcium channel blockers and beta blockers and ACE inhibitors, including lisinopril, which is the most popular blood pressure drug today.
But lowering cholesterol?
In the 1960s.
The only way to do that was lifestyle changes, mostly those two big ones diet and exercise.
And right around then, a young Japanese chemist visited New York.
And that visit would change everything.
More on that in part two, after this word from Lipitor, which is not one of our sponsors, by the way.
Here's one of the first ads for Lipitor, a TV commercial from 1999.
Problem?
Doctor said my cholesterol is still too high.
Lipitor, the number one prescribed medication for lowering cholesterol.
In clinical studies, Lipitor with diet was proven to lower bad cholesterol 39 to 60 percent.
Total cholesterol 29 to 45 percent.
Triglycerides 19 to 37 percent.
He said over 4 million people have started taking Lipitor to lower their cholesterol.
Lipitor is not for everyone, including people with liver disease or possible liver problems, women who are nursing pregnant or may become pregnant.
There'll be blood tests to check for liver problems.
Tell your doctor about muscle pain or weakness, as these may be signs of serious side effects.
We take Lipitor once a day.
Ask your doctor or pharmacist for more information on Lipitor and call 1-888-LIPITOR.
Well...
Lipitor did it.
My cholesterol's way down.
Lipitor, the lower numbers you're looking for.
Welcome back to Drug Story.
This is part two, the prescription, where we learn about how atorvastatin, aka Lipitor, was discovered.
In 1966, Akiro Endo arrived in Manhattan.
Endo was the son of farmers.
He had just received his PhD in chemistry in Japan.
He was in New York on a two-year fellowship.
Endo was interested in the emerging field of enzymes, and Manhattan was the place to be.
Some of the world's leading chemistry researchers, including Nobel Prize winners.
They had laboratories in New York City at the time.
But it was what Endo saw outside the lab that got him thinking.
In New York, I was surprised at the large number of elderly people and overweight people.
As well as the rather rich dietary habits of Americans compared to Japanese.
I was also surprised to see that many American people suffer from heart attacks.
That was a speech by Endo delivered by a translator years later.
When Endo returned to Japan, he took a job with Sankyo Research Laboratories, where he was allowed to choose his own project.
He chose heart disease and cholesterol in particular.
Endo was inspired by the classic story of penicillin, the first antibiotic.
Alexander Fleming famously discovered penicillin in London in 1928 by accident.
He observed a strange mold in a petri dish.
That mold stopped bacteria from growing, and it worked in our bodies too.
Perhaps, Endo thought, something in mold could break down cholesterol too.
Endo's team went across Japan in search of strange molds.
In a grain shop in Kyoto, in a bag of old rice, they found a blue-green mold.
This mold was like the ones that contaminate fruits, like oranges or lemons.
If you've ever left an orange on the counter too long, you know just the type of mold that Endo started with.
So they got to work.
They isolated different cultures from this mold to see if any compounds might break down cholesterol.
They started in petri dishes, and when they had something promising, they did testing in animals.
After five years of trials and failures, they finally had something promising, a substance they called mevastatin, which would reliably reduce the levels of cholesterol in animals and then, in a series of one-person experiments, in human beings as well.
This was, it turns out, the first statin drug.
But if you've never heard of mevastatin, well, that's because it never saw the light of day.
There seemed to be too many animals dying in the experiments, so the company shut down Endo's research.
By then though, other companies had heard about Endo's work, and they had begun their own experiments.
In their studies their own drugs which were very similar to mevastatin.
They seemed safe at a lower dose and very effective.
First among these companies was Merck, which in 1986 submitted its statin drug lovastatin, to the FDA for approval.
The Food and Drug Administration today approved a new anti-cholesterol drug.
It's called lovastatin.
The FDA said it is the first of several new drugs that clinical trials show as highly effective in reducing cholesterol levels.
As happens in the drug business, other pharmaceutical companies kept working on other molecules that might have similar or even better results.
These are often called Me Too drugs.
I should say the term has nothing to do with the Me Too movement, by the way.
They're called Me Too drugs because these new medicines often are no better than the original drug.
But they're developed and sold because another pharma company wants their own bite at the apple.
After lovastatin, there was pravastatin, and then simvastatin and then, in 1997 atorvastatin, which was developed by Warner Lambert and sold under the brand name Lipitor.
Warner Lambert was so skeptical of its own drug that it signed a deal with Pfizer to co-market the drug.
And Pfizer ended up gobbling up the whole company a few years later.
By the time Lipitor appeared, each of these previous statins was bringing in at least 1 billion in annual revenue.
They were all blockbuster drugs.
At first, atorvastatin was considered just another Me Too drug, no different than the other statins.
Then research started to show that it actually worked better at reducing cholesterol than other statins.
What's more, people taking atorvastatin instead of pravastatin had slightly lower rates of cardiac events heart attacks.
So doctors tended to prescribe Lipitor more often than the other drugs.
Soon, it was the number one most prescribed statin.
Pharma insiders started calling it turbostatin.
But it wasn't just the science that made atorvastatin such a hit.
The drug turned out to have perfect timing.
1997 when atorvastatin hit the market.
That was the same year that the FDA changed its rules to allow drug makers to advertise directly to consumers.
It's hard to believe these days, with drug ads all over TV, but before this time FDA rules only allowed drug companies to advertise to doctors, to prescribers, usually in academic journals, sponsoring conferences or something like that.
But then the FDA changed the rules and allowed what's called direct-to-consumer advertising.
Now drug companies could go directly to potential patients and preach the benefits of their drug in newspapers or even TV commercials.
That first year, drug companies spent over 2 billion in this kind of marketing, compared to 0 the year before.
Now Paxil, the only medication proven effective for social anxiety disorder, offers new hope.
Introducing Propecia.
Vioxx is here, a prescription medicine for the most common type of arthritis pain.
These ads were incredibly effective.
One estimate suggested that pharma companies made $22 for every $1 spent on marketing in 1998.
With that kind of return on investment, why not turn on the faucet full blast?
And so they did.
You might have heard a lot about Zenecal.
There's a unique weapon in the Battle of the Bulge.
It's called Zenecal.
When your allergies are a nightmare, prescription Zyrtec goes to work.
Pfizer's marketing department was especially savvy about its campaign for Lipitor.
First they started a campaign called Know Your Numbers, which promoted the idea that people should know their cholesterol score as an easy way to prevent heart disease.
Do you want to be healthier?
Start by knowing these four numbers.
Know your numbers.
What numbers do you need to know?
It's important to know your numbers.
Connect with your healthcare team to know your numbers and plan for a healthier you.
And they wallpapered these ads all over TV, not just on network news, which tended to have older viewers, but also during hit medical TV dramas like ER.
And they deployed armies of salespeople to visit doctors' offices across the country.
Army's is no exaggeration.
Pfizer had more than 7,000 salespeople on its staff.
I think it's very clear now that epidemiologic evidence demonstrates a very strong linear relationship between the level of LDL cholesterol in the blood and the incidence of both cardiovascular morbidity and mortality.
This is from a video that Pfizer sent to doctor's offices to explain why Lipitor was such a no-brainer.
We have obviously made great progress in the battle against cardiovascular disease in this country, but we still have a long way to go.
It seems like there's a bottomless pit of patients with hypercholesterolemia out there.
And the best drug to treat this bottomless pit of patients was, of course, Lipitor.
A bottomless pit of patients.
That's a lovely image, isn't it?
And Pfizer was also super smart about pricing.
Instead of charging the highest price for Lipitor, which would make sense.
It works the best, so why not charge the most?
Instead though, they priced it just below the other statins, making Lipitor that much easier to prescribe.
The genius here was that Pfizer didn't treat Lipitor like a prescription drug.
As one Wall Street analyst noted, the marketing campaign turned Lipitor into something like a consumer product, like Nike's or Gatorade or Apple.
They made people want Lipitor for very human reasons.
And boy, did people want it.
Lipitor was soon the most profitable drug in history, generating over 13 billion in revenue at one point.
From the time it was released in 1997 until 2011, when the patent expired and the drug went generic, Lipitor brought in more than 125 billion.
Now remember.
The reason there was so much enthusiasm for atorvastatin and the other statins is that they really did reduce people's cholesterol numbers quite dramatically.
And that, in turn, meant fewer people were dying of heart disease in later years.
Statins seemed like miracle drugs with basically no downsides.
One British doctor even suggested only half in jest, that we start putting statins in the drinking water so as to reach the most people possible.
This doctor's name was Dr. Reckless.
No joke.
It turns out, though, that putting it in the water may not have even been necessary.
By 2008, 22 of American adults over age 40, that's over 30 million people.
They were taking a statin drug.
Atorvastatin was now the most prescribed drug in history, ever.
Which raises one question.
What happens when you put tens of millions of people on a drug for the rest of their lives?
Before we answer that, here's a commercial from Pfizer for Lipitor.
This one generated some significant controversy.
We'll explain why after the break.
Dr. Robert Jarvik, inventor of the artificial heart.
High cholesterol can lead to heart disease.
When diet and exercise aren't enough, adding Lipitor lowers bad cholesterol 39 to 60%.
And Lipitor is clinically proven to reduce your risk of heart attack and your risk of stroke if you have several common risk factors for heart disease.
The more we learn about Lipitor, the more impressed I am.
Lipitor is not for everyone, including people with liver problems and women who are nursing pregnant or may become pregnant.
You need simple blood tests to check for liver problems.
Tell your doctor if you're taking other medications or if you have any muscle pain or weakness.
They may be a sign of a rare but serious side effect.
Lipitor is one of many treatment options to consider with your doctor.
Could you be doing more with Lipitor?
Ask your doctor.
This is part three, side effects, where we discuss the costs and consequences of putting millions of people on a drug to prevent a disease they don't yet have.
And just to state the obvious, Prevention is great.
Prevention is ideal.
Prevention is what we should strive for in medicine and public health.
And if it takes a drug to achieve that, then that's great.
That's okay.
Of course, that's assuming that the drug works as promised and that it's only being taken by people who really, truly need to take it right.
But let's not get ahead of ourselves.
Back to that ad we just heard.
Let me talk about the Lipitor ad there with Dr. Jarvik.
Mr. Jarvik, he's not a licensed doctor, right?
No, but it's my understanding he does have an MD degree.
Correct.
So he would be appropriately referred to as Dr Jarvik, although it is also my understanding, he has never been licensed.
This is testimony from a 2008 congressional hearing into direct-to-consumer drug advertising.
You're hearing Bart Stupak.
He was a Democratic congressman for Michigan.
He's questioning Dr. Nancy Nielsen, the president of the American Medical Association.
And they're talking about that Lipitor ad.
He's not licensed to write a prescription for Lipitor, is he?
That's correct.
But once he graduated from medical school, he is doctor.
Okay.
Is he a cardiologist?
It is my understanding that he is not.
No, he is certainly an expert in matters involving the heart, as we all know.
In terms of the device,
Is he a cardiac surgeon?
No, sir.
As you can tell, there were a lot of things wrong with that ad for Lipitor.
First, let's explain who this Dr. Jarvik was.
Dr Robert Jarvik was the inventor of an artificial heart, which was first transplanted into a human subject in 1982.
This was a huge story in the 1980s because this was the first successful transplant or, as it turned out, sort of successful of an artificial heart into a human being.
This first patient, his name was Barney Clark.
He died just four months after the transplant.
But four months was still four months, longer than pretty much anybody had survived without an actual human heart ever.
And so this idea of an artificial heart earned headlines around the world.
Dr Robert Jarvik was known far and wide as a futuristic adventure of medical miracles which starts to explain why Pfizer hired him to tout Lipitor.
He was a well-known expert on hearts.
And if he vouched for Lipitor, a heart medication, that must mean something.
But, as the congressional hearing made clear, not only did the ad suggest that Dr Jarvik was a cardiologist, which he wasn't, he wasn't even a practicing doctor.
And the ad failed to mention that Pfizer had paid Dr Jarvik more than 13 million to appear in the ad and to read their script about how great Lipitor was.
That was a violation of the FDA rules.
Pfizer ended up pulling those commercials just a few months later.
But the controversy with the Jarvik ads serves as an example of just how aggressively Pfizer was pushing this drug and just how far the marketing for Lipitor was getting ahead of the science.
Even though the ads with Dr Jarvik caused a lot of frenzy congressional hearings, nightly news reports, big stories in the New York Times and so on there was another, much more quiet controversy brewing, but one that would have even more impact on who was taking atorvastatin.
This was all about where to draw the line for who should take the drug.
This was about what's called the clinical guidelines.
To understand this controversy we need to go back to Framingham, which established years ago that high cholesterol was a significant risk for heart disease.
But what exactly did high mean?
In those early years, they drew the line at a cholesterol score of 260 or above.
If your level was above that number, you had a significantly higher risk of heart disease in the future.
Below that score, and your risk was considered normal.
But with the arrival of statins, the leading organizations for cardiology and health came out with specific recommendations for when patients should consider taking statins or when doctors should prescribe them.
Those recommendations are known as clinical guidelines.
And the idea is that cardiologists and other doctors would follow the guidelines in how they care for their patients.
For the first statins.
The guidelines suggested that doctors consider writing a prescription at even lower levels, about 200.
By the time Lipitor first came out in 1997, the guidelines had dropped to suggest a cutoff of 160, meaning that someone with a cholesterol score of 160 or higher was considered at significant risk and worthy of a prescription for a statin.
For those with two or more risk factors, say they smoked and had high blood pressure and had elevated cholesterol the cutoff was even lower 130.
That's why Pfizer was running commercials saying you know it's important to ask about your numbers.
But here's the thing about risk.
Everyone, in theory, is at some sort of risk for heart disease, even if it's a teeny tiny risk like less than 1.
The question is where to draw the line.
What was a significant enough risk to justify the treatment?
The cost, the chance of side effects, and so on.
If atorvastatin was indeed a miracle drug, if it truly helped people from falling into that bottomless pit of hypercholesterolemia, then it would make sense.
Or it could make sense, one could argue that maybe even more people should take the drug.
As Dr. Reckless said, maybe it should go into the drinking water.
But even if you didn't want to put statins in the water, it could be argued that the guidelines should change.
And so the NIH created something called the National Cholesterol Education Program.
This was an official committee of experts responsible for looking at all available data, all the available science, and making a recommendation for where to draw that line.
In 2001, the committee recommended lowering the cutoffs to include more people.
A lot more.
According to the new recommendations, 36 million Americans...
That's 23 million more people who are now eligible for statins than according to the old guidelines.
And in 2004, the guidelines shifted again.
And in 2013, with a total of 56 million people now candidates for statins.
For the first time in a decade, there are new guidelines to lower the risk of heart attacks and strokes.
Two leading heart organizations issued the recommendations, which could lead to a big change in the number of Americans who use statin drugs to lower cholesterol.
It turned out many of the committee members making recommendations had gotten funding from Pfizer and other drug makers.
But the reports often failed to disclose these relationships.
What's more, many of the studies used to make the recommendations were conducted and paid for by the drug companies.
That controversy didn't stop doctors from writing prescriptions, though.
And the number of people actually taking statins, well, it is just staggering.
Today, more than 90 million Americans report taking a statin drug.
That's one in four people.
We're studying one in two people over the age of 40.
That is a lot of people taking a lot of drugs.
Which raises a pretty basic question.
What is the benefit?
If so many people are taking these drugs, how many people are benefiting in terms of lives saved or heart attacks avoided?
After all, these people are just at risk of a heart attack down the line.
They aren't certain to get it.
And it turns out that there's a way to calculate this.
It's called the number needed to treat, or NNT.
And it's one of the most controversial things about statins.
Here's UCSF cardiologist Rita Redberg again.
So the number needed to treat is an important concept, because how many patients or let's call them people, because these are not, they don't have an illness.
So how many people would have to take a medication in order for one person to have a benefit from it?
And the fallacy is that most people think that by taking a medication, for example statin, they will be protected from a heart attack.
Now, in theory, the perfect number needed to treat would be one.
Everyone who takes a drug derives a benefit.
But few drugs work like that.
Taking ibuprofen for a fever has an NNT of four, meaning it works for one in four people.
Antidepressants have an NNT of about five.
Steroids have an NNT of one for meningitis.
These are all considered totally worth it.
But the NNT for statins is nothing like those drugs.
For a hundred people that take statins for five years.
One or two people will not have a heart attack that might have had one if they didn't take statin.
So that means 98 or 99 people have absolutely no benefit.
At an NNT of 100, the case for statins isn't so clear.
Or rather, the case for so many people taking statins isn't clear.
Under older guidelines, when fewer people took the drugs, the NNT was much lower, about 40%.
There might be more people benefiting, but there are also a lot more people not benefiting.
As the guidance has gotten more broad, more and more people are taking the drug who would actually never have had a heart attack in the first place.
And there's another thing that happens when millions of people take these drugs.
You start to see side effects happen to more and more people.
At first, statins were thought to have few, if any, serious side effects.
The original studies, the ones that the drug companies ran to convince the FDA that statins were safe and effective.
Well, those studies reported that less than 2 of people stopped taking their drugs because of side effects.
And the most common side effect was muscle pain and sometimes muscle weakness.
So if 2 of people suffered and stopped but 98 kept taking it and millions of people lowered their risk of heart disease well, that's what science calls the risk-benefit ratio.
And those numbers persuaded a lot of people that these drugs are a huge win for medicine.
So let's dig on both of these, the risk and the benefit.
First, let's deal with the risks, the side effects.
Before the FDA approves a drug, it requires drug companies to do many rounds of clinical experiments, partly to measure benefit on patients, but also to evaluate safety and side effects, which is technically called adverse events.
These are very rigorous, very expensive experiments.
They usually involve several thousand patients and they take several years to set up and run and calculate the results.
If all goes well, these studies show clear benefits, few side effects, and the drug is approved.
Boom, you're in business.
And once a drug is approved, the drug company has very little incentive to spend more money to do more studies.
The drug, after all, has already passed the burden of evidence.
It's been approved by the FDA.
The benefits outweigh the risks.
Let's focus on the benefits.
But as millions of people start taking the drug in the real world, another kind of data emerges.
This is observational data, when you observe what is happening.
And what they found in the observational studies was that a lot more people were complaining about muscle pain than suggested by those original clinical studies, the ones paid for by the drug companies.
And a lot more people chose to stop taking statins because of how it made them feel.
In fact, about 10 of patients prescribed statins stopped their medication due to subjective complaints, most often due to muscle symptoms.
Now, 10% of 40 million people is 4 million.
10% of 90 million people is 9 million.
That is a lot of people who are reporting side effects so bad that they have to stop taking their medication.
That's five times as many people as in the clinical trials before FDA approval.
And so what about the other side of the risk-benefit ratio, the benefit?
In the case of atorvastatin, the benefit meant people who avoid suffering a heart attack or other traumatic event or, even better, those who avoid death altogether because of the drug.
These were very specific outcomes, and they could be measured.
The original clinical studies for atorvastatin, again paid for by the drug company.
They indeed showed lower cholesterol scores and significantly fewer heart attacks and strokes among those taking atorvastatin over tens of thousands of subjects.
And so the drug was approved.
But other studies, the ones not paid for by the drug companies, they revealed some inconsistencies.
Some studies showed statin saved a lot of lives and some couldn't find much evidence that they were working as intended at all.
And this made some researchers skeptical about these miracle drugs.
Rita Redberg was among those skeptics, and she was actually in the position to do something about it, because it just so happened that she was the editor-in-chief of one of the most important academic journals about internal medicine in the world.
It's called JAMA Internal Medicine.
JAMA is short for Journal of the American Medical Association.
So when I took over as editor-in-chief in 2009, I was then in charge of deciding what articles we would publish in JAMA Internal Medicine.
One of the articles we published, maybe in the first year after I took over, was a study which was actually a review of all of the trials on statins and cardiovascular events in high-risk patients.
So the idea was that this Kaush Ray was the first author.
He did a lot of work to collect all of the data, took people that had increased risk factors by framing him risk score and then compiled all of the results to see whether there was a benefit on cardiovascular ransom mortality.
And what he found, putting all the data together, was that actually statins, there was not a benefit on mortality.
This study appeared in 2010.
It combined data from many studies with more than 65,000 patients in total.
And this time the researchers made sure to distinguish between people who already had heart disease they may have clogged arteries or even had a heart attack and those who just had a risk for it, for those who had high cholesterol scores.
A lot of the early studies included both groups, so they didn't do a good job answering the question.
Did statins actually work for all those people who only had high numbers?
And so when this study just looked at those people, it found that there was no clear relationship between mortality and cholesterol level.
In other words, there was no clear evidence that the drugs provided a benefit.
Redberg was editor of JAMA Internal Medicine for almost 15 years.
And at that time, the journal published a lot of papers about statins.
When you go through them you get the sense that statins definitely do help reduce the risk for people who are at high risk, who have really high cholesterol scores.
But you also get the sense that there are a lot of people taking statins, taking a drug every day for the rest of their lives, who almost certainly are not going to benefit from it.
They will die, almost certainly, but probably not of heart disease.
There are a lot of other things people die of.
And there were other problems that popped up.
There is also.
I don't know if you call it a moral hazard, but for example, when I was at JAMA Internal Medicine, we published a study which was called Gluttony in the Age of Statins.
And it tracked people, statin users and non-statin users over 10 years. and compared them.
And the statin users were much more likely to become more sedentary and to gain weight than the non-statin users.
And the idea was that perhaps they thought, well, I don't need to watch my diet.
I don't need to walk because I'm taking a statin and that's going to protect me.
My friend Joe definitely falls into this camp with all his cheese tortellinis.
In 2022, right before she resigned from the journal, Dr Redberg co-authored an essay subtitled Time to Curb Our Enthusiasm Over Statins.
The paper boils down to the simple argument that the idea that statins are a panacea, a cure for everything, is highly exaggerated.
And it argues that the way the guidelines keep pulling more and more people into the net of taking statins well, maybe that's not always a good idea.
I felt very bad for all patients because I was seeing increasing numbers of patients coming in to see me every week who were really suffering and who, even frankly, under the most liberal interpretation of the guidelines, should never have been placed on statins in the first place.
Because the message that got out that was a lot easier to understand was anybody whose cholesterol had that little asterisk if it was over 200 should get a statin.
And that wasn't even what the guidelines said.
These people were suffering really unnecessarily on a medication that Suffering because of side effects.
They were suffering because of side effects.
Although even if you don't get side effects, there's not a lot of upside to taking a medication that has no benefit to you.
I mean, nobody likes to take a pill every day.
Yeah.
Today, the official organizations are once again fiddling with the guidelines.
They are trying to find a new way to set the ideal target for who should take atorvastatin and the other statins.
For once, they're actually considering tightening the standards and even suggesting that millions of people would not benefit from statins.
As many as 17 million Americans could fall out of the high-risk category and could be spared the burden of taking a daily statin.
Of course, if they're wrong, millions of people would stop taking a drug that could potentially save their lives.
One paper out last year crunched the numbers and argued that tightening the guidelines would result in 107000 more heart attacks and strokes a year in the US alone.
I realize that this episode has offered a fairly skeptical take on atorvastatin today.
I want to be clear.
There's no doubt that atorvastatin and statins in general, they have indeed prevented heart disease in many people.
And they have saved many lives, thousands of lives, likely millions of lives.
But when you talk about prevention, you're talking about risk.
And risk means odds.
Risk means probabilities.
It means predictions and forecasts and estimations and bets and best guesses.
It's all in the numbers.
And despite the billions and billions of dollars that these drugs have earned and despite the millions of dollars spent on researching them, Dr Redberg says there's only one set of numbers that is still missing.
I find it incredibly disappointing that 40 years after these drugs came on the market, we still don't have a randomized controlled trial with an all-cause mortality benefit.
And so the point is 40 years they've been out and there's still no study that actually says whether people are Living longer.
Living longer because of these drugs.
Exactly.
Or feeling better.
Right.
Or, you know, even... having less heart attacks.
But even while we wait for that research to happen and it probably never will there is one proven thing
One thing that all science says will actually work to reduce your chance of heart disease.
One miracle cure.
Here it comes.
It's important to say that I think the best way to reduce your heart disease risk is through lifestyle measures and eating a healthy diet kind of a Mediterranean style diet, with fresh foods and fruits and vegetables, and getting regular exercise and having lots of social connections and enjoy yourself is the best way to stay healthy.
And the other benefit of exercise is which is a real risk reduction measure.
I mean people that walk 30 minutes a day regularly have a 50 lower chance of a heart attack than people that don't.
There's no medicine that's going to give you that benefit.
Regular physical activity also reduces your risk of cancer.
It reduces depression.
I mean, it reduces arthritis.
There's so many benefits.
So I think, if your goal is to prevent heart attacks, we really need to be thinking about.
I could walk a little bit more, I could do a little more activity, and I'm going to try to avoid processed foods and eat fresh foods.
Diet and exercise.
Turns out that's the best medicine of all.
That's it for this drug story about atorvastatin.
Thank you for joining us.
Drug Story was created, written, and hosted by me, Thomas Goetz.
Molly Warner is our research director.
From Reasonable Volume.
Rachel Swaybe produced and sound designed this episode with assistance from Audrey Ngo.
Elise Hu was the editor.
Mark Bush is our engineer.
Drug Story was produced with support from the University of California Berkeley School of Public Health.
Special thanks to Claudia Williams and Michael Liu.
Thanks also to Joe Bagnoli, Adam Rogers, and Dr. Rita Redberg.
For an annotated list of our sources for this episode, visit drugstory.co.
Drug Story is an independent production.
There's no tech company or big media conglomerate behind us.
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There are just so many drugs.
Seriously, help us spread the word.
And next up on Drug Story, we look at Zoloft, the most prescribed antidepressant in the United States.
A drug that, it turns out, we don't even really understand how or why it works.
We'll see you next time.
