Fifty-five years ago, a Japanese biochemist by the name of Akira Endo isolated a compound from a mold growing on rice in a Kyoto grain shop. It would go on to prevent more heart attacks than almost any other discovery in medicine.
But in 1966, all that lay in the future. Akira Endo had just arrived in New York City.
He'd grown up on a farm in northern Japan, fascinated by mushrooms and mold from childhood. As a student, he'd read the biography of Alexander Fleming — the man who discovered penicillin in a mold — and decided that he, too, wanted to make something useful from fungi.
But it was New York that changed everything.
"I was quite surprised at the large number of elderly and overweight people," Endo later wrote, "as well as the rather rich dietary habits of Americans compared to the Japanese." And then there were the ambulances. He saw them constantly — rushing elderly patients to hospital after heart attacks. Heart disease on a scale he had simply never seen in rural Japan [1].
Years later, he'd write: "If I had not stayed and studied in New York, I would never have discovered statins" [2].
Table of Contents
- The Discovery
- The Side Effect Myth
- Start With Diet
- The Case for Low-Dose Statins
- Add Ezetimibe — Don't Just Escalate
- References
At the time, the crucial role of cholesterol in heart disease was becoming clear, and it prompted a fateful question. "Stimulated by the mounting evidence that high blood cholesterol causes heart attacks, Endo chose to search for an inhibitor of cholesterol synthesis" [3]. He wondered if a mold might harbor a chemical capable of disrupting the body's ability to make it.
He spent the next several years screening 3,800 strains of mold. What he found would become the best-selling drug class in history.
And here's what he couldn't have predicted: sixty years later, millions of people who could be helped would avoid taking the drug he discovered — not because it doesn't work, but because they'd been told it was dangerous.
The Discovery
Endo returned to Japan from New York with a hypothesis and a method. He knew that the rate-limiting step in the liver's production of excess cholesterol is controlled by a single enzyme — HMG-CoA reductase. Block that enzyme, and you block most of the cholesterol that ends up in the bloodstream [2].
His bet was that somewhere in the fungal kingdom, a mold had already evolved a compound to do exactly that. Fungi and bacteria compete constantly, and some fungi produce chemicals that block biological pathways in their rivals. Endo wondered whether one of those compounds might also shut down cholesterol production.
He started screening at Sankyo Pharmaceuticals in Tokyo. Early on, he found a compound that looked like it might work — citrinin, which strongly inhibited cholesterol synthesis. Then toxicity tests came back. It destroyed the kidneys. He discarded it and started again [4].
Another year of painstaking research passed. And then, in 1973, from a blue-green mold growing on a sample of rice collected at a grain shop in Kyoto — he found it. A compound he named compactin, later called mevastatin [1]. It inhibited HMG-CoA reductase with striking potency. In early tests, it lowered cholesterol dramatically [5].
It looked like exactly what he'd been searching for.
But Sankyo Pharmaceuticals shelved Endo's discovery. High doses in dogs had produced lymphomas. The doses were extreme — far beyond anything a human patient would take — but the company wasn't willing to take the risk [1].
Another company saw the immense potential. Roy Vagelos, President of Merck Research Laboratories, reached out to Sankyo Pharmaceuticals. He signed a confidentiality agreement and obtained samples of compactin along with a trove of experimental data [6].
Soon, Merck researchers had found a related compound — lovastatin — from a different fungus entirely. Merck undertook clinical trials. In 1987, the FDA approved lovastatin as the first commercially available statin [1].
Lipitor — atorvastatin — followed. It became one of the best-selling drugs in pharmaceutical history, with lifetime sales exceeding 150 billion dollars [1]. And the great news is that these drugs are now off-patent and incredibly cheap today.
Despite his contribution, Endo never received royalties [7]. After leaving Sankyo Pharmaceuticals, he independently isolated the same compound Merck would commercialise as lovastatin — he named it monacolin K and filed patents in 30 countries in February 1979. Merck filed shortly after. But Merck's version is the one in every pharmacy in the world [8].
Endo left Sankyo Pharmaceuticals in 1978, became a professor, and spent his later years watching the industry built on his discovery make billions for everyone except him. Joseph Wu, president of the American Heart Association, called it "the second-most important discovery of the century after penicillin" [9]. Michael Brown and Joseph Goldstein — who won the Nobel Prize for their own work on cholesterol — put it even more directly: "The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo" [10].
Fleming got a Nobel Prize for his penicillin discovery. Endo didn't. He died on June 5, 2024, aged 90 [11].
Today, statins are prescribed to more than 200 million people worldwide [2]. They are one of the most studied interventions in the history of medicine. And the evidence for them is, frankly, overwhelming.
But a shadow has fallen over that legacy. And it's worth taking seriously.
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Get Your Personalized Health PlanThe Side Effect Myth
In 1991, a Danish physician named Uffe Ravnskov published a book called The Cholesterol Myths, arguing that the link between cholesterol and heart disease was a fraud, and that statins were unnecessary at best, harmful at worst. He went on to lead an organisation called THINCS — The International Network of Cholesterol Skeptics [12]. The movement he started has been refuted in journal after journal. But it has never died. It moved online — into Facebook groups, into YouTube comment sections, into your aunt's WhatsApp.
Search "statin side effects" online, and you will find a very confident internet telling you that statins cause debilitating muscle damage, destroy your memory, tank hormone levels such as testosterone, and give you diabetes. People share stories. Doctors get pushback. Patients quietly stop taking their medication.
And here's the thing: some of those concerns have a grain of truth. But most of what circulates online is badly distorted. And the gap between the fear and the evidence matters — because people are stopping a medication that could prevent their heart attack.
Let's go through the actual data, starting with muscle symptoms.
Muscle aches — what doctors call myalgia — are the most commonly reported side effect of statins. In unblinded observational studies — where patients know they're on a statin — rates of 10% or higher are commonly reported. The PRIMO survey, for instance, found muscular symptoms in 10.5% of patients on high-dose statins [13].
This sounds alarming. But here's the critical thing: when you look at blinded, placebo-controlled trials — trials where neither the patient nor the doctor knows whether they're taking a statin or a sugar pill — the picture is completely different. A meta-analysis of blinded statin trials including more than 80,000 participants found no meaningful excess of muscle symptoms in the statin group versus placebo [14].
How is that possible? A trial called SAMSON — the Self-Assessment Method for Statin Side-effects Or Nocebo — gave us the answer. It enrolled 60 patients who had already stopped taking statins because of intolerable side effects. For twelve months, they alternated between one-month periods of atorvastatin, matched placebo, and no tablets at all — in random order, fully blinded. Each day, they rated their symptoms on a smartphone app [15].
The result: symptom scores were nearly identical on the statin and the placebo. Both were significantly higher than the no-tablet periods. The researchers calculated a "nocebo ratio" of 0.90 — meaning 90% of the symptom burden these patients experienced on statins was also triggered by the placebo. When I first read this number, I had to read it twice. Ninety percent. Not most of it — almost all of it [15].
The symptoms are real. The patients aren't imagining anything. Aches and pains are common as we get older. But the cause is very rarely from the statin — it's the act of taking a tablet they believe might harm them. When patients in SAMSON were shown their own symptom charts at the end of the trial, half of them restarted statins they had previously abandoned [15].
True pharmacological muscle injury from statins does exist. Serious myopathy — measurable muscle breakdown with elevated blood enzymes — occurs in about 1 in 10,000 patients per year. Rhabdomyolysis, the most severe form, is rarer still [16]. These are real, and they're worth knowing about. But they are not what most people stopping statins are experiencing.
But worries are also raised about how statins impact the brain.
A cognitive effects warning was added to statin labels by the FDA in 2012 and is still widely cited online [17]. But the FDA warning was based on case reports, and a meta-analysis of 25 trials found no association at all [18].
Worries over cognitive health and statins stem from the fact that the brain is rich in cholesterol, and it's essential for the brain's function. Some theorized that statins might starve the brain of cholesterol. But here's why the worry is misplaced. Every cell in the body can produce its own cholesterol [19]. Medications that reduce the cholesterol concentrations in our bloodstream do not cause our cells to lack the cholesterol they need for optimal function.
In fact, there's compelling evidence that statins actually lower dementia risk. A massive analysis of 55 observational studies including over 7 million participants published last year found statin use was associated with a 14% lower dementia risk [20].
What about diabetes?
This one is real. Statin use is associated with a modest increase in the risk of new-onset type 2 diabetes — a meta-analysis of 13 statin trials found a 9% increased risk overall [21]. But context matters enormously here. For the patients who benefit most from statins — those at elevated cardiovascular risk — the reduction in heart attacks and strokes substantially outweighs the diabetes risk in virtually every analysis that's been done. You're trading a small increase in diabetes risk for a large reduction in the risk of dying from a heart attack [21]. Which is why all type 2 diabetic patients are advised to start a statin if they aren't already on one.
The bottom line on side effects: the fear is understandable, but it's badly out of proportion to the evidence. The biggest risk for most people isn't taking a statin. It's stopping one — or never starting — because of something they read online.
There's a footnote to this that I find quietly moving. Even Akira Endo — the man who discovered statins — was initially reluctant to take one himself. For years, he tried to manage his cholesterol with exercise alone. Eventually, he admitted it wasn't working. "I am now taking a statin," he wrote [22]. Even the discoverer had to reckon with the question every patient faces: what else can I do, and when is a drug the right move?
Start With Diet
So what else can you do? Apart from medications, diet is the most powerful lever most of us can pull when it comes to cholesterol levels. But can you get a benefit from diet alone that's actually comparable to a medication?
That's exactly what researcher David Jenkins wanted to know. Jenkins was a nutrition scientist at St. Michael's Hospital in Toronto, and he had an intriguing idea: what if you combined all the foods with known cholesterol-lowering properties into a single dietary pattern? Not just one or two foods. All of them, together [23].
He called it a dietary portfolio. Like a financial portfolio, each component contributes a piece of the return, and the effects add up.
In 2003, Jenkins published a randomized controlled trial in JAMA. Forty-six adults with high LDL cholesterol were assigned to one of three arms for one month: a standard low-fat control diet, that same diet plus lovastatin 20 mg — a first-generation statin — or the dietary portfolio [23].
The results?
The control diet lowered LDL by 8%. With the control diet plus statin, it fell by 31%. So how did the dietary portfolio compare? It lowered LDL by 29% [23]. Nearly identical to the drug.
Now — I want to give you the full picture here, because this number deserves context.
This was a metabolically controlled trial. Food was provided. Participants weren't shopping for it or fitting it into a busy week. In a follow-up study, when Jenkins followed participants for a year under real-world, free-living conditions, the LDL reduction dropped to around 13–14%. Still meaningful — but not 29% [24].
For most of my patients, I advise them to follow the Mediterranean diet, which emphasizes olive oil, fish, nuts, vegetables, legumes, and whole grains. But as Jenkins' real-world trial showed, the LDL-cholesterol lowering that we can achieve through diet alone has a ceiling. And for most people at meaningful cardiovascular risk, it leaves a significant gap.
That's where medication comes in. The question isn't diet or drugs. Both are critical and a drug is never a replacement for a healthy diet and regular exercise.
And this is where Endo's discovery becomes not just historically interesting, but personally relevant. Because the question of what statin dose we need turns out to be just as important as whether we take one at all.
The Case for Low-Dose Statins
Here's what I actually do.
I take a low-dose statin because you get most of the lipid-lowering effect at the low doses [25]. The additional benefits diminish sharply as you push the doses higher.
And crucially, the side effect risk does not follow the same curve. Muscle risk scales disproportionately with higher doses. In the Heart Protection Study, the incidence of myopathy/rhabdomyolysis with simvastatin 40 mg was less than 0.1%. With simvastatin 80 mg, however, the SEARCH trial showed the risk shot up to roughly 0.9% — compared to just 0.02% on simvastatin 20 mg [26].
Now, does the LDL-cholesterol reduction actually translate to fewer heart attacks and deaths? This is where the evidence is genuinely remarkable. Scientists with the European Atherosclerosis Society pulled together the data from hundreds of studies, and they saw a clear pattern. Reducing LDL-cholesterol levels reduces the risk of heart disease. And the longer our levels are lower, the greater the risk reduction [27].
I aim to get my LDL-c below 55 mg/dL because of the PESA study. It showed plaque could start building up in the arteries even at an LDL-cholesterol level of 60 mg/dL [28].
A brand-new study adds additional weight to the merits of this aggressive target. It compared outcomes in patients with heart disease using two different treatment targets. In one group, they aimed to get LDL-cholesterol below 70 mg/dL. In the other, they pushed much lower — to 55 mg/dL. After 3 years, the group at the lower target had 33% fewer heart attacks, strokes, and other serious heart-related incidents [29].
In light of data like this, there's been an important shift. Just this spring, the American College of Cardiology and the American Heart Association published their first major dyslipidemia guideline since 2018 — and the targets got lower.
The new guidelines recommend an LDL goal of below 55 mg/dL for patients with established cardiovascular disease who are at very high risk — that means patients with multiple prior cardiovascular events, or one event plus risk factors like diabetes, smoking, or hypertension. And for those at high risk but not meeting the very-high-risk threshold, the goal is below 70 mg/dL [25].
The guideline committee's overarching philosophy is "lower for longer." As Dr. Roger S. Blumenthal, the chair of the committee put it, "We know that lower LDL cholesterol levels are better…We also know that bringing elevated lipids…down in young adults supports optimal heart and vascular health throughout a person's life" [30].
For most patients at high risk levels, hitting a target below 55 mg/dL on diet alone — or even on low-dose statin alone — isn't realistic. Many cardiologists would still recommend pushing the statin dose higher. But that old reflex is, I'd argue, the wrong move.
Add Ezetimibe — Don't Just Escalate
Here's where I think the evidence has shifted in a way that most patients — and honestly, a lot of clinicians — haven't fully caught up with.
Remember, you get diminishing returns on LDL reduction from statin dose increases, along with rising side effect risk. There's a smarter approach: add a second drug that works through a completely different mechanism.
That drug is ezetimibe.
Statins work by telling your liver not to produce as much excess cholesterol. Ezetimibe works by telling the gut to not absorb as much cholesterol [31].
Because these medications work on two different pathways, they work extremely well together to lower LDL-cholesterol levels.
The clinical evidence backs this up clearly. A recent meta-analysis compared the effectiveness of traditional, high-intensity statins to a combination of a moderate-intensity statin and ezetimibe. The combination yielded greater LDL-cholesterol reductions. And more patients hit their target levels [32].
Practically speaking, ezetimibe is off-patent and cheap. It's taken once daily, well-tolerated, and can be added to any statin. The combination is precisely the tool the evidence supports for reaching the recommended targets while keeping the side effect burden manageable.
In 1966, Akira Endo watched ambulances rushing through New York to pick up people having heart attacks. Sixty years later, millions of those ambulance trips never happen — because of what he found in a mold growing on rice in Kyoto. He never got the Nobel. He never got rich. But by the end of his life, the discovery he made was preventing more heart attacks than almost any other in medicine.
What Is Your Cardiovascular Risk?
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Get Your Personalized Health PlanReferences
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