Research Translation Podcast

David Newman
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Translating Medical and Health Research For All researchtranslation.substack.com

  1. 5d ago

    The Statin Hazard Hidden for Twelve Years

    In the coming episodes I’ll be explaining the AHA’s rationale for their new guidelines, which call for aggressive expansion in cholesterol testing and treatment. Obviously, that means walking through the data that form the basis for any claim that cholesterol is currently under-treated. But to understand the atmosphere the guideline writers were working in, I think it’s also important to see how the walls were closing in. New data like the 2025 study I discussed last week are increasingly challenging the rationale for primary prevention focused on cholesterol. Today’s translation is about another study in that category. Enjoy, and stay tuned. It only gets better. RT is FULLY reader-supported. Please support us by becoming a paid subscriber. I wondered if I had missed something. The American Heart Association was recommending more cholesterol testing, lower targets, and more pills, at younger ages. Maybe some major trial had been published? Perhaps a new data analysis? So I scoured the recent literature and, BOOM—found it. A huge new study from 2024, cited in the AHA guidelines, that should transform how we think about the world’s most prescribed cholesterol drugs, statins. But not in a good way. To understand the new paper we must go back to 2012, when the infamous CTT group published a review of statin data that led to a rapid increase in prescribing around the world. Analyzing 174,000 trial participants from 27 trials, the authors described a 1.1% reduction in cardiovascular events among low risk people as a benefit that “greatly exceeds any known hazards.” This was a shift. For high risk people like those with known heart disease, despite a surprisingly small impact, statin therapy had long been standard. But using the drugs in healthy people was, and is, controversial. The real possibility of adverse effects is harder to justify in someone who is healthy. The AHA nonetheless strongly recommended statins in primary prevention, and cited the CTT review as evidence. So where does the CTT data come from? The Cholesterol Treatment Trialists began as a group of Oxford researchers with multiple ties to statin manufacturers. For years the group has enjoyed exclusive access to the secret statin files: patient-level data from company trials that few people have seen. The group accesses the files only under signed privacy agreements that keep them from showing the data to others. Which brings us to the 2024 report. Just like the 2012 paper, it is a data review by the CTT group, this time focused on on statin-induced diabetes in 23 trials of 154,000 participants. The researchers found that five years of statin drugs at the lowest dose caused diabetes in roughly 0.5% of people, and at higher doses 6.5%. For healthy people these numbers represent a daunting and serious risk—and a startling confession. In their 2012 review the group mentioned only the low end of this range (0.5%), then insisted a 1.1% benefit “greatly exceeds any known hazards.” But a range up to 6.5% means that for millions of people currently on statins, their risk of the drug giving them diabetes is five to ten times higher than any chance of the it preventing a coronary event. Worse yet, even at 0.5%, diabetes is still more common than any patient-centered benefits. That’s because the paltry 1.1% benefit claimed by the CTT group was always a house of cards. A careful breakdown shows that half of it is a reduction in deaths the data never found, and stent procedures that don’t prevent heart attacks or strokes. Those aren’t benefits. The remainder of that ‘benefit’, at roughly 0.5%, is mostly ‘nonfatal MI’—as defined by each trial. These are typically minor events that have been proven not to affect longevity and, when counted as a ‘benefit’, are totally unmoored from the life-saving effect people generally take statins for. As you can see in the figure below, a diabetes range of 0.5% to 6.5% (even in highly selected trial populations) diabetes therefore easily eclipses, and then rapidly dwarfs, any real benefits of the drug. All of which raises an obvious question: How could the CTT know the diabetes risk, but not count the condition as a ‘known hazard’? Answer: By ignoring that diabetes is a human disease, with human costs. In the discussion section of its 2012 report, the group describes diabetes only as a contributor to future cardiovascular events. It never even considers the possibility that developing diabetes is itself a serious harm. To state the obvious, a diagnosis of diabetes carries a profound burden: dietary restrictions, medical visits and laboratory monitoring, drugs, and a long-term risk of serious complications. If that isn’t a ‘known hazard’, what is? But that was their 2012 review. What does the CTT group say about diabetes now that they know the risk often far exceeds any benefit? Today’s CTT website summarizes their 2024 findings this way: “Statins can cause a small increase in blood sugar levels, so people at high risk may develop diabetes sooner.” Huh??? The clear message—that people who experience statin-induced diabetes would have developed it anyway—is false. Not true. The CTT data shows that 0.5% to 6.5% of people got diabetes over and above the placebo group. That is not developing it ‘sooner’. That is developing it more. Obviously, studies have to stop tracking outcomes at some point, and on a hypothetical timeline we can always make their ridiculous argument. When a blood pressure medicine reduces deaths in a trial, we could say “Whatever! Everyone’s gonna die at some point, the drugs just pushed it back a little!” So to suggest it somehow does not count because someone’s glucose levels began near the threshold is totally disconnected from their human experience. Finally, it’s not just “people at high risk” who get diabetes from statins. Their data show it’s a side effect anyone can suffer. Nearly 40% of statin-induced diabetes in the analysis occurred in people whose pre-drug glucose levels were not even in the top quartile. The AHA’s new statin push is, fortunately, not based on this paper. In fact, it’s not based on anything new. It is rooted in an old idea getting new traction, perhaps to save the dying Lipid Hypothesis. Next week we will name and explore that old idea. But for now it is worth revisiting a different old—and equally wrong—idea, the one that underlies most current statin prescriptions: That in low risk people statin benefits exceed the harms. That is wrong—and it took the CTT group twelve years to show us the data that proves it. Get full access to Research Translation at researchtranslation.substack.com/subscribe

  2. Aug 9

    The Cholesterol Study the AHA Is Afraid to Discuss

    When I do a public-facing summary and critical appraisal of a study I typically do it verbally and free-form. No script, no notes. After years of journal clubbing and presenting lectures and talks, that’s how I feel most comfortable. I’m trying something new this week and I'd like your feedback. I write my own material, though ever since I lost the world’s best editor (my mom) I use AI for copy editing (proof reading, basically). But today I asked AI to craft an 800-word summary of the audio. For those who stick to the written word, I would love your feedback. Does this work for you? How you feel about it? You can also read the transcript (click above) to see if reading that is better or worse than the AI summary below. It’s an experiment. I’m open to any input. Thank youuu! RT is fully reader-supported. Please consider becoming a paid subscriber! In March 2025, the New England Journal of Medicine published the most definitive study in history on cardiovascular risk factors: “Global Effect of Cardiovascular Risk Factors on Lifetime Estimates.” The Global Cardiovascular Risk Consortium assembled individual-level data from 2.1 million people in 133 prospective cohorts across 39 countries and six continents. These were the world’s best cardiovascular databases: large, carefully conducted studies in which participants were interviewed, examined, tested, and followed over many years—sometimes for decades. The researchers examined five classic cardiovascular risk factors at age 50: smoking, diabetes, hypertension, abnormal body weight, and elevated cholesterol. They then estimated how each factor was associated with years of life and years lived free from cardiovascular disease. Having all five factors was devastating. Compared with people who had none, women with all five lost 13 years free from cardiovascular disease and 15 years of life. Men lost 11 cardiovascular-disease-free years and 12 years of life. The individual findings confirmed what the best prior data had suggested. Smoking and diabetes were the worst factors, each associated with approximately five or six years of life lost. Hypertension was associated with roughly two years lost. Abnormal body weight had little association at the conventional cutoff, although extreme obesity was associated with shorter life. Then there was cholesterol. The researchers defined elevated cholesterol as non-HDL of at least 130 mg/dL—the guideline-based definition used by the American Heart Association. By that definition, elevated cholesterol was not associated with more cardiovascular disease or an earlier death. It was associated with the opposite: approximately an additional year of life and an additional year free from cardiovascular disease. Only when cholesterol reached the highest one or two percent of the regional distribution—roughly an LDL >190—did it become associated with shorter life and more cardiovascular disease. In other words, the study found risk only at extremely high levels that overlap with the familial-hypercholesterolemia range. For ordinary people labeled as having ‘high cholesterol’ because their LDL is 150 or 160, the standard threshold did not identify increased risk. It identified longer life and less heart disease. The study also examined what happened when a risk factor present between ages 50 and 55 disappeared between ages 55 and 60. Eliminating hypertension and stopping smoking were both associated with additional years of life. But moving from high to normal cholesterol produced no benefit. Again, the result ran in the opposite direction: 0.2 years of life lost for women and 0.3 for men, although the differences were not statistically significant. This was observational research, not a randomized trial, so it cannot prove cause and effect. I am not saying that people should deliberately raise their cholesterol to live longer. But even in observational data, the lack of association is a powerful finding. This central finding is unavoidable. In the largest and most rigorous cardiovascular-risk data set ever assembled, elevated cholesterol according to the AHA’s standard definition was not a risk factor for heart disease or death. Smoking, diabetes, and hypertension were confirmed. Cholesterol was not. That finding strikes at the foundation of the Lipid Hypothesis—the governing theory of modern cardiology, which says cholesterol causes heart disease and that lowering cholesterol will therefore prevent disease and extend life. The Lipid Hypothesis and this study cannot both be true. If elevated cholesterol is not a risk factor, it cannot be the primary cause of heart disease. Yet the American Heart Association’s new cholesterol guideline doubles down. It expands cholesterol testing and treatment while never citing, discussing, or even acknowledging this study. A guideline devoted to cholesterol completely ignores the largest and best study ever published on cholesterol as a cardiovascular risk factor. And the cardiology community is not discussing it. I recently spoke with a brilliant, trained lipidologist who had never heard of the paper. When he read it, he was aghast. The weird silence is why this study matters. Read it. Bring it to your doctor. Discuss it with your friends. Challenge it if you can. But the world’s most important data on cardiovascular risk cannot simply be ignored because it threatens cardiology’s governing theory. Get full access to Research Translation at researchtranslation.substack.com/subscribe

    The Cholesterol Study the AHA Is Afraid to Discuss

  3. Aug 4

    The Cholesterol Charade: How Statins Debunked the Lipid Hypothesis

    I originally posted this in 2024 and there have been major, relevant study publications since then. I hate seeing my material out of date, so I’ve added the findings into this new updated version, and tried to polish things. It’s a big piece to take in, more like a chapter than my bite-size weekly, so be prepared. Also, apologies if it’s a repeat for you, I’ll be back with new material next week. Enjoy! At his 1933 presidential inauguration Franklin Delano Roosevelt was a picture of fortitude. Americans, he thundered, had nothing to fear but fear itself. And he proved it, leading a crippled and wary nation to victory in history’s deadliest war. But during a 12-year presidency, increasingly flea-bitten by a failing heart, FDR and his doctors should have been afraid. In the early twentieth century high blood pressure, or hypertension, was seen as a clever trick of nature. Increasing the heart’s force and tightening blood vessels, the theory went, were evolutionary workarounds to push blood through stiff, aging arteries. Lowering a person’s blood pressure, it was thought, could leave blood trickling like water in an outsized drainpipe. Vessels needed high pressure to force oxygen and nutrients through capillary walls into hungry tissues. Today’s term for most high blood pressure, ‘essential’ hypertension is a vestige of this flawed thinking. High BP, we now know, is not essential. It’s bad. In 1932, during Roosevelt’s first presidential campaign, his blood pressure was 140/100. The 50-year old statesman was in excellent health and his physicians were delighted. But five years later in 1937, Roosevelt’s health had begun to fail and Surgeon General Ross T. McIntire recorded FDR’s pressure at 162/98. Then, in 1940 it was 178/88, and a year later 188/105. Dr. McIntire, a believer in essential hypertension, called this “normal for a man of his age.” In March 1944 after years of conspicuously declining vigor and a blood pressure at 200/108, Roosevelt saw one of America’s first heart specialists, Howard Bruenn. From Bruenn’s notes: “He appeared to be very tired and his face was very gray. Moving caused considerable breathlessness.” Bruenn also described FDR as “in good humor, a testament to the president’s disposition and stoicism.” The cardiologist correctly surmised high blood pressure was the problem, and diagnosed FDR with hypertensive cardiac failure. But he prescribed reduced salt and digitalis, a drug that increases cardiac force. While the president’s lungs cleared slightly, improving his fatigue and shortness of breath, his blood pressure rose to 226/118. Bruenn then began FDR on a trial of phenobarbital, a powerful soporific used today only as a last resort for uncontrollable seizures and general anesthesia. This did little for his blood pressure, but he was certainly sleeping well. Through the fall of 1944 despite increasing his medicines, Bruenn routinely noted pressures up to 240/130. Then, in late November, 260/150. By January 1945 at his fourth, much quieter inauguration FDR was a feeble man. Drawn and short of breath with a bluish hue, his blood pressure was 280/130. His heart was enlarged and inefficient, his lungs full of the backwash from a failing pump. At the Yalta Conference in February Winston Churchill’s physician, Lord Charles Moran, was aghast. “The Americans here cannot bring themselves to believe that he is finished” Moran said, then predicted FDR had two months to live. Two months later, on April 12th at his Little White House in Warm Springs, Georgia, the 64-year old president clutched his head, lost consciousness, and died from a massive cerebral hemorrhage. The stroke was caused by a decade of runaway hypertension. Bruenn, a dedicated and respected clinician, was at the president’s side throughout. He recorded blood pressures “well over 300.” Research Translation is 100% reader-supported. Become a paid subscriber, please, so I can keep it going. Framingham FDR’s death sent shivers down the spine of American medicine and spawned a movement. In 1948 President Harry S. Truman signed into law the National Heart Act, which did not equivocate: “The Nation’s health is seriously threatened by diseases of the heart and circulation, including high blood pressure.” The law created the National Heart Institute, soon to be the most funded National Institute of Health. Recognizing the chicken-egg questions that plague heart disease, the Institute generated an ambitious project aiming to enroll and follow more than five thousand healthy American men and women. The Framingham Heart Study, unprecedented in scope, would become the most important research of the 20th century—for better and for worse. Originally conceived as a trial comparing treatments, experts realized there were none to compare. With not one pill, tincture, or procedure ever proven to cure or even improve heart disease, they had no control group. There were abundant theories (like essential hypertension) but no data. The plan therefore shifted from treatment to observation. The ‘trial’ became a cohort study observing a group for decades, while patiently recording blood pressure, lifestyle, cholesterol, and other characteristics. The goal was to find the predictors and seeds of heart disease. For participants, the researchers chose Framingham, Massachusetts, a blue-collar community a short drive from Harvard, the project’s nerve center. Despite how mundane the research sounds compared to today’s high speed, high tech, profit-driven palette, the Framingham Study was revolutionary. Before it, research was focused almost exclusively on illness. New antibiotics fought infection, insulin treated diabetes, and surgery could cure or mitigate common emergencies. The Framingham Heart Study was different, moving upriver to prevent disease—pulling people out before the rapids. It was risky, expensive, and long-term, bucking norms. In a culture of staunch traditionalism the Framingham researchers were epidemiological activists, charting a new path for public health. And it worked. The researchers soon identified characteristics that emerged, intuitively and statistically, as powerful harbingers. In a famous 1961 paper the investigators dubbed these ‘factors of risk’, coining a term for the ages. Some of the most powerful risk factors were immutable: age, sex, and family history. ‘Heart disease’ is a misnomer since the condition is foremost an affliction of blood vessels. Just as skin wrinkles, vessels age. The loss of elasticity in artery walls makes them vulnerable to nicks and tears. These blemishes become the building blocks of arterial plaque and fibrosis, the sine qua non of heart disease. Thus the chance of heart problems increases with age and often hews closely to family history. And for reasons that are foggy even today, men have twice the risk as women. But some risk factors held promise as targets. The most powerful was a habit. Regardless of age or sex, smoking cigarettes was associated with two to eight times the risk of heart attacks, strokes, and death. There was also a strong dose-response relationship: the more cigarettes, the more heart problems. Diabetes, a condition with its own path to blood vessel damage, also doubled the chance of heart attack or stroke. The condition was less common in the 1950s but when present it was no less ominous. Next up was FDR’s demon, hypertension. At almost the same levels as smoking and diabetes, high blood pressure was a strong predictor of disease and death. And like smoking, higher pressure meant greater risk. FDR’s blood pressure, the research showed, was a time bomb. Randomized trials soon followed, showing blood pressure control prevented heart attacks, strokes, and deaths. Antihypertensive treatment, which continues to extend and improve the lives of hundreds of millions, is a direct outgrowth of the Framingham project. But to the surprise of many, at the lowest rung on the ladder was cholesterol. In the early publications cholesterol was mathematically linkable to heart attacks and deaths, but compared to sex, age, smoking, diabetes, and blood pressure, the association was tenuous at best. And it waned with time. As the study wore on, a clear picture took shape for smoking, diabetes, and hypertension. But not for cholesterol. In the study’s 1993 final report on cholesterol, a paper with more than three decades of data, the investigators were forced to concede cholesterol had no association with mortality. After early reports in which cholesterol seemed to be a risk factor (albeit the weakest) this conclusion was a stunning reversal. There simply was no statistical relationship between early death and elevated cholesterol. When broken down into narrow age ranges, the youngest men in the study, particularly those in their thirties and forties, saw a weakly elevated risk for mortality with very high cholesterol (>300 total). But between ages 50 and 70, when most major heart problems occur, the two were unrelated. Then, beyond age 70 low cholesterol became a risk factor for death. The researchers strongly cautioned against lowering cholesterol in people over 65. Of the four big, modifiable risk factors touted in the early stages of the data—smoking, hypertension, diabetes, and cholesterol—three had stood the test of time, but one did not. Incredibly, however, in a presumptuous and ill-fated leap, ten years before the final Framingham report the American Heart Association and the NIH began collaborating to develop a consensus on cholesterol. Conferences were held and papers published extolling the Lipid Hypothesis, a theory asserting cholesterol is the primary cause of heart disease, and lowering cholesterol prevents it. This, the experts declared—before the data were in—was proven “beyond a reasonable doubt.” The Cholesterol Zeitgeist It is ironic that cholesterol, always the weake

  4. Jul 28

    The Failure of Cardiology's Plumbing Theory

    “Sandy,” I called over my shoulder. “Back in two!” I pressed the metal square on the ER’s back wall and strode into the hall toward the lounge, where lunch awaited. Behind me I heard a grunt. A well-dressed man lay face down, a pool of blood spreading from his midsection. He wore a hospital bracelet. Sticking my foot between the closing doors, I called back into the ER. “Sandy, check that—crash cart to the hall, Code Blue!” The man, I soon learned, had just undergone coronary angiography, ordered by his cardiologist to investigate the cause of a fainting spell. Good news? They found no blockages. Bad news? His femoral artery, punctured for the procedure, reopened on the way out. Once we controlled the bleeding and stabilized him, I asked his cardiologist about the angiography, since fainting spells are virtually never caused by coronary occlusions. “You never know,” he said. “Sometimes we find something we can open up!” RT is 100% reader-supported. Become a paid subscriber so I can keep it going, please! For more than half a century, cardiology has been organized around a simple, intuitive story: Coronary arteries get blocked, blood flow drops, heart muscle starves, people get sick and die. Fix the blockage, restore flow, save a life. Easy peasy! Plumbing problem, plumbing solution. And it has shaped an industry, from angiograms to stents to bypass surgery. But the story is mostly a fairytale, other than one specific scenario. That scenario is the acute, large-vessel blockage—in other words, a big old-fashioned heart attack. When a fresh clot suddenly blocks an artery, opening the artery can save lives. It is one of the great triumphs of modern medicine, and it is real. Almost everywhere else, however, the plumbing theory has failed. For decades, coronary stents were deployed with confidence and satisfaction. Tight lesion? Open it. Abnormal stress? Stent it. The assumption—better flow equals better outcomes—was seldom questioned. Then, trials tested the assumption. Trial after trial showed the same thing: For people not actively in the throes of a heart attack, stenting doesn’t extend lives. Or prevent future heart attacks. Or strokes. And while it seemed to reduce symptoms like chest pain, even that turned out to be wrong. When stenting was compared to fake stenting (artery secretly not opened, no stent placed) the improvement in symptoms was exactly the same. Incredibly, despite this evidence, most of the 1.2 million stents placed annually in the U.S. are still done for non-heart attack cases. Equally disturbing, coronary artery bypass grafting surgery (CABG), the grafting of clean vessels from other parts of the body to bypass clogged heart arteries, is the world’s most common major heart operation, with about 400,000 annually in the U.S. But despite an air of heroism and fancy gizmos—saws! operating rooms! bypass machines!—this procedure, too, is on shaky ground. There are a handful of controlled trials from the 1970s-1990s and most found no mortality benefit. This was despite comparing bypass to nonsurgical treatments that were much less effective than those routinely used today. In more recent data, three of four major trials again found no mortality benefit. Which just means the justification for the great majority of bypass surgeries rests not on proof, but on an abiding faith in the plumbing theory. In reality, coronary disease is not primarily a problem of pipes slowly closing. It is a diffuse, partly inflammatory, biologically active process. Heart attacks, the great danger of coronary disease, occur not due to gradual closure but due to plaque rupture. This sudden, as-yet unpredictable event occurs not in lesions that are tight, but in lesions that are unstable. Which is why the great majority of heart attacks arise from arteries that were never clogged enough to stent. This also explains why therapies that do work for heart disease, like blood pressure control and smoking cessation and diet, don’t fit the plumbing metaphor. They don’t fix pipes. They quiet inflammation and stabilize plaques. They change the ecosystem, not the tunnel. Which brings us back to the man bleeding in the hallway. The angiogram nearly took his life. More than one person in fifty having the procedure suffers a major complication—including kidney injury, stroke, heart attack, or death. In the United States, that means more than 10,000 people each year severely harmed, permanently disabled, or killed. So why was he in the cath lab to begin with, undertaking all that risk? Getting a coronary angiogram for a fainting spell is like getting a CAT scan of the foot for a headache. But to a cardiology brain hijacked by the notion of plumbing and roto-rooters, every problem looks like a pipe that needs checking. The plumbing model flatters our visual instincts, rewards intervention, and turns complicated biology into a target that can be dilated, bypassed, and billed. Most of all, it feels like doing something. “Sometimes,” the cardiologist said, “we find something we can open up!” That sentence contains the entire plumbing theory. But finding something we can open is not the same as finding something we should. Get full access to Research Translation at researchtranslation.substack.com/subscribe

    The Failure of Cardiology's Plumbing Theory

  5. Jul 20

    Is Your Doctor A Cholesterol Bully?

    A friend of mine has a cholesterol of 258. Recently, when his new doctor saw this for the first time, she flipped. In addition to scolding him for not being on drugs, visibly shaken, she threatened to send him to the ER. For what, exactly, I cannot say. Emergency cholesterol-ectomy? Waterboarding? I found the story amazing, and emblematic of our cholesterol obsession, in which the molecule matters far more than the human. Later that evening NBC’s national news hammered the point home, gushing about a “gamechanger” new cholesterol pill, a “breakthrough,” “more effective than statins.” Let us clarify what they mean by effective. The new drug is enlicitide, approved by the FDA last week. I wrote about it in February when the first major trial results were published. Like other PCSK9 drugs, it lowered cholesterol dramatically—more ‘effectively’ than statins. But incredibly, it did not even pretend to reduce heart problems or deaths. It simply lowered cholesterol. Yay? This is objectively deranged, and perfectly highlights just how massive the chasm has become between the conventional wisdom on cholesterol and biological reality. So, before we go any further, let’s ground ourselves in a few basic, irrefutable facts. First, according to the American Heart Association, ‘elevated cholesterol’ means an LDL of 130 or higher (my friend’s is 160). And it may be useful to know that elevated cholesterol is not a risk factor for heart disease or death. Ya heard? Last year the biggest, best ever study of cardiac risk showed that calling cholesterol a risk factor is, and has always been, a mistake. With over 2 million participants in dozens of countries, some followed for nearly 50 years, the study found that an LDL >130 is associated with LIVING LONGER and FEWER HEART PROBLEMS. Facts. See figure below, and note that when the bars extend to the right of the vertical line, it means more CV disease (panel A) and higher mortality (panel B). Which is true for all of the risk factors EXCEPT FOR CHOLESTEROL, whose bars fall left of the lines. In contrast, high blood pressure, diabetes, obesity, and smoking were confirmed as true, and often powerful, risk factors, particularly diabetes and smoking. I am not making this up. Check my work. Though yes, I concede: The AHA, medical establishment, and mass media have all pretended not to notice the study (or any of its many progenitors). Importantly, a true understanding of these numbers requires nuance. In reality, about 1% of the population has familial hypercholesterolemia, with LDL levels routinely over 200. Particularly above 300, there is a meaningful association with heart disease and death. But including these people in the calculations pulls the overall average higher. Therefore it is true that for some people with LDL >130 (mostly way higher) cholesterol is a genuine risk factor. But incredibly, that also means the risk of ‘elevated cholesterol’ for people like my friend is even farther to the left—even more protective—than the study’s numbers suggest. All of which helps explain a finding that often shocks people: A careful reading of the data shows that, other than for people with known heart and vascular disease, lowering cholesterol does not extend lives and comes with very real dangers. Indeed, cholesterol reduction has been famously unsafe with some drugs. The fibrate and trapib medications, for instance, both reduced cholesterol—but increased deaths. Even statins, which are comparatively safe, can have serious and life-affecting dangers. This is why even the AHA, the world’s most cholesterol-obsessed group, only recommends lowering cholesterol when the baseline risk of a heart problem is high enough (specifically, 7.5%) that it outpaces the risks of the drug. When my friend and I did what his doctor should have, checked his risk on the AHA calculator, it was 4%. Plugging this into the RT statin checker, which personalizes benefits and harms, we saw that he is far more likely to be harmed than helped by statins. Even using the AHA’s happiest (read: b******t) numbers, statins are 4 to 15 times more likely to give him diabetes or painful muscle damage than to help him. And no matter how we slice the data, the drugs will not extend his life. But his doctor never checked. She simply saw an ‘elevated’ cholesterol—in a thin, athletic, otherwise healthy person—and lost her s**t. So whether it’s threatening healthy people with the ER, or news anchors gushing over a drug that lowers a number but doesn't extend a life, this is how modern medicine thinks about cholesterol. Molecules matter more than humans. Until that changes, the real breakthrough will never come from a new pill. It will only come from being informed, and using that information to stand up to cholesterol bullies. Get full access to Research Translation at researchtranslation.substack.com/subscribe

  6. Jul 14

    Tamiflu, and the Fatal Mistake of Doing Something

    As a long time critic of Tamiflu and its brethren, I have often heard defenders make the following last ditch plea to justify its use: “What about people in the ICU with the flu?? Without it they could die!.” The unspoken insanity behind this claim is a powerful, almost gravity-like bias in medical culture: the urge to intervene. At the bedside of a critically ill patient, doing something simply feels better. But in medicine there is no free lunch. Sometimes, doing something is a grave mistake. At a conference last month, researchers presented unpublished results from the first ever trial of Tamiflu for people critically ill due to influenza. Despite the absence of trial data, major guidelines (CDC, WHO, IDSA) have for years strongly recommended the drug in such patients. But Tamiflu in the ICU, we learned, has been a decades-long massacre. The trial was abruptly halted when a safety committee saw, after enrolling 652 people, that Tamiflu increased deaths by more than 40%. Based on these preliminary data, it appears that guideline-based ICU care has probably killed hundreds of thousands of people. To grasp the absurdity of ever having used Tamiflu in the ICU, we first have to look at how poorly the drug performs in the best of circumstances. As the Cochrane group famously found after a years-long battle to unearth the drug makers’ hidden data, Tamiflu was a bad drug to begin with. When the data were in, Tamiflu and its class didn’t reduce hospitalizations, or pneumonias, or critical illness—the marketing claims that led governments to stockpile the drug, and millions of doctors to prescribe it. The sole ‘benefit’ found in trials was a symptom reduction of less than one day (out of seven)—but even that was available only when the drug was started in the first 48 hours of illness. This is why Tamiflu’s only FDA approved use in treating flu is for “uncomplicated illness with symptoms no more than 2 days.” That should make its use very rare, since most people don’t seek medical care for a flu-like illness unless it becomes severe, or long-lasting. Which means only the hypochondriac who panics at every tickle in their throat can reap the awesome one-day reward. And only if they have easy access to their (poor) doctor. Unfortunately for the hypochondriac, even that dubious benefit is basically erased by side effects like nausea and vomiting. Therefore in the exquisitely rare, very best case scenario, Tamiflu means trading a few hours of sniffles for a day of hugging the toilet. Extending this silliness to the ICU was always nonsense. If it barely works for mild outpatients in a strict 48-hour window, why on earth would it save the life of someone on a ventilator who is virtually always days or weeks into their illness? And should we really toss yet another chemical into their body, then cross our fingers? It was an insane proposition from the start. So how did guideline writers justify it? With observational studies. The most famous, most cited paper is a review combining many observational studies. It is also a twisted, misleading, and smug spin job that was funded—shocker—by Roche, the maker of Tamiflu. But guideline committees fell for it. Even more shocking? Seven of the 18 IDSA guideline committee members disclosed financial ties to the makers of either Tamiflu, or drugs in its class. For a quick primer on how observational studies misrepresented Tamiflu, see the Paxlovid version of this eerily similar story. In short, they’re hopelessly contaminated by biases, most prominently the healthy user bias. Which means observational studies don’t show people getting healthier because of the drug, they show people getting the drug because they’re healthier. This is because in the real world the decision to give a drug is not random, therefore people who receive it are fundamentally different from those who don’t, in ways a spreadsheet can never fully capture. Observational studies of drug effectiveness are designed to find a difference and almost always do—one that favors the drug. This is why using observational data to craft recommendations is a reliable path to both bad care, and ignominious reversal—because most drugs don’t work for most conditions, but most observational studies will find they do. Crucially, the critics of Tamiflu are not visionaries. We have simply done an honest reading of the evidence, using elementary scientific principles, common sense, and the discipline to resist a bias to ‘do something’. To the IDSA and others who agitated for Tamiflu in the ICU, let this be a lesson: We should have waited to see randomized trial data before unleashing a drug on our sickest and most vulnerable. Instead, we let a bias to ‘do something’ override the fundamentals of evidence, and of science. The cost of that mistake is a body count we are just beginning to comprehend. Get full access to Research Translation at researchtranslation.substack.com/subscribe

    Tamiflu, and the Fatal Mistake of Doing Something

  7. Jul 7

    Is Moderate Alcohol Consumption Dangerous?

    Last month the Journal of Studies on Alcohol and Drugs (‘JSAD’) published a large data review comparing mortality rates in light-to-moderate drinkers with mortality among people who don’t drink alcohol. The NY Times and others gleefully picked up the story, trumpeting the most provocative finding: Up to 1 in 25 moderate drinkers will die because of their alcohol intake. SAD! As always, the study deserves a close look. For my part, I did not know about the SAD journal, so this was a welcome chance for me to see what kind of SAD research it’s offering. It turns out the SAD paper is a review of earlier studies. No new data is offered. The researchers selected their data from earlier studies of “conditions with established causal relationships to alcohol.” Hmmm. There are only a few such causes of death that are ‘established’. For instance, deaths due to alcoholic liver failure, and fatal drunk driving accidents. Both can comfortably be attributed to alcohol. In contrast, as I’ve written before and shown extensively, on careful inspection almost every cancer that researchers have often claimed is caused by alcohol turns out to have, at best, a fatuous statistical association with alcohol. Indeed, not one of those associations can plausibly be described as causal (much less ‘established’) by any honest expert of epidemiology or research translation. This mis-attribution of cancer deaths isn’t a new problem. In 2024 the Surgeon General launched a campaign making frightening claims about the dangers of moderate alcohol intake and cancer, only to be embarrassed a few days later when a comprehensive review by the National Academy of Sciences—written by real researchers, carefully and honestly examining the data—found the opposite. Having sifted the alcohol data myself, I can confirm these findings. I can also testify to the hidden agenda driving many public health claims on alcohol: In 2009, while I was teaching a class in research translation at Columbia University, a prominent public health official asserted that “There is no level of alcohol consumption that can be considered safe.” When my students and I emailed him to ask about the claim, he basically admitted that he knew this was untrue, but hoped scaring people might reduce drunk driving. SAD? Back to the SAD study: There is a wonderful and informative figure in the paper that, to my eye, answers a question the headlines never asked: What exactly are these ‘alcohol deaths’? The figure above shows accumulating causes of death in different color bands, on a graph that plots number of deaths against alcohol consumption. First, note that most deaths ‘caused by alcohol’ in men are due to injuries. Hmmm. How might we understand this finding in the context of the evening drink that most headline readers are now second-guessing? For instance, did my father’s longstanding tradition of an evening martini put him at risk of a tragic refrigerator incident? If so, I never saw any close calls. On the other hand, I suppose I can understand how, for people who find high speed driving and forestry irresistible after their martini, moderate drinking may represent a serious threat. Fortunately, my father doesn’t have that problem. After ‘injuries’, the next most important cause of death due to alcohol in the Figure is liver cirrhosis, for both men and women. Cirrhosis deaths rise with alcohol intake, as one would expect. But remarkably, the risk begins to appear in the Figure at one drink per week. Obviously, that suggests a problem in the data: reporting bias. These data are based on survey studies, and—shocker—people aren’t always honest about their drinking. Which seems pret-ty obvious when a study claims that a drink a week can cause fatal liver disease. Because that isn’t how liver disease works. In a recent review more narrowly focused on cirrhosis risk, alcohol consumption was not even statistically associated with cirrhosis until respondents reported at least two drinks per day. It took five drinks a day for the numbers to look consistent and causal. But do we even need studies to know that claim was bunk? The notion that a drink a week can kill someone due to liver failure doesn’t pass the whiff test. Instead, it says more about the reliability of the data than it says about alcohol. SAD! Finally, the figure makes it clear that if we remove injuries (don’t play with chainsaws) and remove liver failure (your ‘one’ drink shouldn’t be a Venti) all of the remaining risk was due to cancer. Here, once again, the problem is real—but it is relegated to severe alcoholics. I’ve been through these data over and over and I invite you to check my work. In short, esophageal and liver cancers occur more often in very heavy drinkers, but in moderate drinkers the numbers are barely different. For most other cancers the numbers are similar for moderate- and non-drinkers. There are even a few cancers (kidney, thyroid, lymphoma) mathematically less common in drinkers than non-drinkers. Which brings us to an interesting finding: Check out the red areas on the graphs. Cardiovascular deaths, the most common cause of death, were LOWER with moderate alcohol intake. HAPPY! Unfortunately, none of the associations found in the underlying studies represents a cause-and-effect relationship. Even the ones we like. There is neither an important protective effect nor a mortality risk. Whether the category is cardiovascular death or cancer, the small differences found between moderate- and non-drinkers aren’t because of drinking habits. They are because people who do and don’t drink are different to begin with: genetically, environmentally, culturally, socio-economically, geographically, and otherwise. So they have different rates of cancer. Is moderate alcohol intake a threat to your health? The NY Times wants you to think so, as do the public health experts who wrote the study. But most readers who see the headline will naturally picture damage done by alcohol itself. Yet the majority of colored territory in the figure is for injuries—drunk driving, falls, drownings, violence, and other behavioral consequences that can be associated with alcohol use. Apparently the greatest danger from moderate drinking isn’t liver failure. It’s an irresistible urge to climb ladders, operate chainsaws, and drive into trees. Meanwhile, non-injury deaths in this dataset are almost entirely due to severe alcoholism. Headlines like “1 in 25 killed by moderate drinking” sound frightening because they invite you to picture something the study never actually observed: ordinary people dying because they enjoy a glass of wine with dinner. That’s not what this paper found. Instead, it bundled alcoholism, injuries, and weak associations into one emotionally charged statistic, then attached the words ‘moderate alcohol intake’. That’s how SAD research, and SAD translation works. It isn’t built on outright fabrication. Instead, it’s built on selecting words that lead people to picture something the data never actually showed. Get full access to Research Translation at researchtranslation.substack.com/subscribe

  8. Jul 2

    Alzheimer's and Amyloid, A Summary

    What you see below is not grape soda. It is urine from a human being—Purple Urinary Bag Syndrome, as it’s called, is quite something to behold. But it is brief, and happens when bacteria interact with the plastic of a urinary bag. Treating the underlying infection (typically mild, if there is one) is all that’s required. The color is a distraction. At the Royal Psychiatric Clinic in Munich, Germany, in 1906 a similar distraction was discovered by an enterprising young neurologist named Alois Alzheimer. On slides from the brain of a woman who died of early-onset dementia, Dr. Alzheimer saw plaques that looked deeply abnormal, crying out for explanation. Surely something so striking must be the cause, he thought. But that is not a question that can be answered by gestalt, as the German doctor might have said. It is a question for wissenschäft — for science. In part 1 we reviewed two autopsy studies from the 1990s, the first real scientific test of Dr. Alzheimer’s hypothesis that amyloid plaques cause dementia. His Amyloid Hypothesis failed: both found no association between amyloid burden and dementia. In Part 2 we saw landmark studies from the early 2000s that again disproved the Hypothesis. In a mouse model of Alzheimer’s the plaques appeared—but only after dementia developed. Karl Popper, the father of modern scientific reasoning, would have called these findings ‘black swans’—each one potent enough by itself to discard the Amyloid Hypothesis. Popper argued that the surest path to truth is not proving hypotheses, but trying to disprove them. His touchstone example was black swans, clear proof that “All swans are white” is a hypothesis to be discarded. Despite repeated black swans for the Amyloid Hypothesis, in 2005 amyloid devotées pressed forward with a novel vaccine for people with early Alzheimer’s. The vaccine successfully cleared amyloid from the brain—and their dementia progressed, unchecked. It was the most irrefutable black swan yet. By every standard of scientific reason, the Amyloid Hypothesis was dead. Some amyloid researchers pivoted, perhaps desperately, hoping to find invisible precursors that might salvage a role for amyloid. This also did not end well: In Part 3 we reviewed the precursor ‘star-56’, presented in a 2006 paper. Its ‘discovery’ turned out to be, arguably, the greatest fraud in the history of modern neuroscience. We also saw that while amyloid’s star fell to earth, the clinical enterprise became increasingly invested in amyloid plaques. Imaging companies engineered PET scans to visualize them, chemistry companies developed blood tests to detect them, and pharmaceutical companies created dozens of drugs to remove them. Which led to something remarkable—though eerily familiar. Instead of asking whether removing amyloid helps people, the field gradually began asking whether removing amyloid… removes amyloid. The endpoint changed. The question was no longer whether people improved, it was whether amyloid improved. In Part 4 we therefore saw industry trials designed to find differences between their drug and a placebo that people could not perceive. Amyloid was removed. People didn’t get better. Then, in Part 5, we saw the final capitulation. Medical journals called amyloid drugs ‘disease-modifying’. PET scans and blood assays that were actually for amyloid became, in the lingo of the establishment, “tests for Alzheimer’s.” Alzheimer’s Disease, in other words, became Amyloid Disease. How could this happen? History is our guide—we have seen this movie before. Doctors and scientists, like all of us, are irresistibly attracted to elegant explanations. One lesion, one pathway, one cure. This plaque causes Alzheimer’s. This cholesterol causes heart disease. This tear causes knee problems. Human biology, however, is virtually never that simple. Which is why the history of medicine is littered with visually striking pathology that rises to mythical, unimpeachable status. Doctors, industries, and systems inevitably stake careers—and commerce—on finding and fixing these culprits. Remove amyloid! Open arteries! Repair cartilage! Lower cholesterol! It then takes generations to wind down the mythology. Why does this pattern repeat, and redound? Because humans and their systems are easily captivated by stories and pictures—in other words, by gestalt. In some domains, like art, this works in our favor. But in pursuit of scientific truth it does not. The purpose of wissenschäft, of science as described by Popper, is to force us, repeatedly and sometimes painfully, to abandon the theories that fail—the path to truth. Scientific, and thus human, progress depends on finding black swans, and even welcoming them. Sadly, after more than a century of amyloid research, including hundreds of billions in grants, laboratories, scanners, blood tests, and drugs, people with Alzheimer’s suffer much as they always have. Not because science failed—because we failed to follow it. Instead of abandoning a theory that failed, we abandoned scientific method. And in doing so, we abandoned the patient. Because disease is not what appears under a microscope. Disease is what happens to people. Get full access to Research Translation at researchtranslation.substack.com/subscribe

    Alzheimer's and Amyloid, A Summary
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