🚨👉What if a diet that lowered your cholesterol… increased your risk of death? (link at the end)

1/12) That’s what a forgotten a double-blind, randomized controlled trial from the 1970s seemed to show.

It tested whether swapping saturated fats for unsaturated fats would improve heart health.

Results?

The group that lowered their cholesterol... died more often. And the lower their cholesterol went, the higher their risk of death.

And if you think you’ve heard this story before (including a proper assessment of the counterarguments and deeper nuances—you haven’t…) 2/12) The Minnesota Coronary Experiment was a randomized controlled trial conducted between 1968 and 1973 that enrolled 9,423 men and women across six mental hospitals and one nursing home.

The power of this approach—though ethically questionable by today’s standards—was that researchers could truly blind and control patients’ diets with remarkable accuracy

A Nuance Hidden in a Historic Statin Trial (link in 12/12)

1/12) Medicine is supposed to treat individuals, not populations averages. And yet, the imprecision remains, like an intellectual cancer.

So, let’s look back at one of the most pivotal studies in cardiovascular history: the 4S trial, an see what is reveals when we stratify but just two biomarkers: TG and HDL

(And if you think you know where this goes, you're in for at least one plot Twist... 🚭) 2/12) According to cardiologists, the 4S trial is widely regarded as the study that launched the statin era.

4S was a randomized, double-blind, placebo-controlled study that enrolled 4,444 participants established coronary heart disease.

Patients were assigned to receive either simvastatin (20–40 mg daily) or a placebo and followed for 5.4 years.

The headline findings were that the statin (simvastatin) significantly reduced overall and cardiovascular mortality.

But there’s another part of the story—

Dr @PeterAttiaMD recently published an article entitled, "Pitting facts against sensationalism regarding the role of LDL cholesterol in ASCVD"

1/9) Peter opens with a quote: “We must admit that our opponents in this argument have a marked advantage over us. They need only a few words to set forth a half-truth; whereas, in order to show that it is a half-truth, we have to resort to long and arid dissertations.” ― Frédéric Bastiat

I could not agree more.

That's the purpose of today's letter... to discuss Where's the Nuance, Really?!

Specifically, where is the nuance on Longevity, Cholesterol and ApoB?

What follows is a teaser for a 25 page, 4000 word "long and arid dissertations" -- linked in 7/9 🔗

Punchline: When talking about deceptive simple messaging and biased narratives, medicine should look in the mirror as well.

Let's begin... 2/9) Here's where I want to start: The three dumbest words in medicine are: “Lower is better.”

This refers to lowering LDL cholesterol or ApoB.

It’s medical clickbait—seductive, oversimplified, and deeply devoid of nuance.

“You are going to die young.”

1/8) The first time I heard those six words, they were jarring. I was 23.

The insult that provoked that perceived threat was a single number on a lab report: my LDL cholesterol (LDL-C).

After I started a ketogenic diet (June 1, 2019), my LDL-C more than tripled from 95 mg/dl to 321 mg/dl.

Link at the end... 2/8) The logic was straightforward:

If I allowed my LDL-C levels to remain in the stratosphere, I would inevitably develop cardiovascular disease and die of a heart attack—young.

The question is this: Does LDL—or more accurately, ApoB—kill?

It sounds like an easy question. But it isn’t.

🚨The New Dietary Guidelines Are Internally Inconsistent

1/7) Publicly, RFK Jr. says “we’re ending the war on saturated fat.” The iconic food pyramid has been flipped, with butter and beef now at the top.

But read the actual guidelines, and you’ll find the exact same restriction: saturated fat still capped at 10% of daily calories. No change.

(People may not like this thread or the linked long-form letter. But I'm not here to pander or choose political sides. I'm here to seek the clarifications I know Americans want and to 'tough love' this step in the right direction into a proper leap...)

cc @RobertKennedyJr @HHSGov 2/7) How can one recommend:
👉Cooking with butter and tallow
👉Eating full-fat dairy three times a day
👉Prioritizing red meat…

🚨Yet still limit saturated fat to 10% of calories? That’s not an opinion. The math doesn’t math?!

Full Breakdown: staycuriousmetabolism.substack.com/p/the-new-diet…

1/10) No word yet from 'Dr' Johnson. So, I've decided to use this as a springboard to deeper learning.

Quick review: in a recent Twitter exchange between @chamath and @bryan_johnson, Bryan proclaimed: “Definitely do not stop statins.”

Today, we deconstruct common logical missteps that could lead to this misguided medical mandate.

A 🔗 to the full letter is at the end.

This won't be shallow reaction content, but an opportunity to dive deep... 2/10) Main Point #1: Causality is Overrated

Just because a molecule or biomarker plays a causal role in a disease process does not mean it is sufficient to cause disease.

More importantly, it does not mean intervention is the prudent path.

The presence of a “causal” variable does not ensure disease nor is the treatment benign.

Can TUDCA Really Slow Atherosclerosis? 🫀

1/6) The bile acid and supplement, TUDCA, has the potential to reduce atherosclerosis.

And it appears to do so not by lowering cholesterol, but by reducing inflammation inside arteries. (Red = fatty deposits in arteries)...🔗 in 6/6 2/6) In atherosclerosis, macrophages in the artery wall take up too much oxidized LDL.

This can trigger *ER stress* and activate inflammation, pushing the macrophages into *foam cells* that are a cause and hallmark of atherosclerosis.

5 Things to Know About Cholesterol-Lowering Drugs 🧵

1/6) Statins are the go-to prescription — but with baggage.
They can:
👉Deplete GLP-1
👉Cause insulin resistance
👉Trigger muscle pain/damage and potentially muscle loss

These risks aren’t often mentioned, but they should be part of a real cost-benefit analysis.

🔗 to the letter at the end, including all hyperlinked references

2/6) Lp(a) and Drug Effects
👉PCSK9 inhibitors = tend to lower Lp(a)
👉Statins = tend to raise Lp(a)
This often-overlooked detail could matter a lot depending on your individual risk profile.

Creatine Explained: How One Molecule Boosts Muscle and Brain Health 💪🧠🧵

1/11) Creatine is one of the most extensively studied performance-enhancing supplements in the world of exercise science and nutrition.

And yet, despite its popularity, few people truly understand how it works or what its full range of effects might be.

So, let’s break down what you need to know about creatine.
💪Muscle Hypertrophy Mechanisms
💪Brain Health
💪Protocols 2/11) There are several mechanisms through which it can support muscle growth (a.k.a. hypertrophy):

First, Satellite Cell Activation

When muscle fibers grow, they require additional nuclei to manage the increased protein production.

Unlike most cells, which contain only one nucleus, muscle cells are multinucleated. These extra nuclei come from satellite cells—a type of muscle stem cell.

Combined with resistance training, creatine stimulates satellite cell activity, which helps supply growing muscle fibers with the extra nuclei they need to expand.

In simpler terms: creatine makes it easier for your muscles to grow by helping recruit and integrate new cellular “command centers” (nuclei) into the muscle fibers.

Never get Alzheimer’s Disease: The NAD+ Breakthrough

1/9) This graph hints at a potential breakthrough in Alzheimer’s disease.

It shows that NAD+, a key energy carrier in the brain, is depleted in Alzheimer’s—but preserved in cognitively healthy brains.

Restoring it may not just protect memory—it might reverse dementia. 2/9) What is NAD+? NAD+ is an essential energy carrying molecule in the brain.

Most major energy metabolism pathways (carb burning via glycolysis, fat burning via beta oxidation, TCA/Kreb cycle, mitochondrial metabolism) rely on NAD.

When NAD drops, the brain fails.

Escape the Black Hole of Sugar Cravings

1/4) Why can some people say no to dessert, while others feel pulled toward sugar like it's a black hole?

It's NOT a failure of willpower.

🦷But before we start, tell me: do you have a sweet tooth? What's your dietary Achilles' heel? 2/4) Human data show that levels of a nutrient sensor, FFAR4, are reduced in diabetes, are negatively associated with fasting blood sugar, and are even linked to metabolic health in mendelian randomization studies.

How Lp(a) Really Causes Heart Disease

1/9) New study finds that high Lp(a) increases the risk of death from CVD by as much as 230%.

Since Lp(a) is thought to be genetically determined, some people think if you have high Lp(a), you’re screwed.

🚨But I don’t think so...

2/9) The researchers studied 1,027 patients with advanced coronary artery disease who were undergoing cardiac surgery.

The conventional view is that Lp(a) and related molecules promote atherosclerosis by physically sticking to the artery wall, infiltrating it, and essentially “seeding” plaque.

But there’s more to the story…

1/6) A study published in Atherosclerosis found that 37% of individuals with “optimal” LDL (<70 mg/dL) still had measurable atherosclerosis.

That’s not a trivial number—but it does require nuance.

The first objection is familiar: a single LDL measurement may not reflect lifetime exposure.

Maybe these people lowered LDL later in life after years of higher levels?

But all participants were untreated—no lipid-lowering medications.

That makes it more likely that most had lifelong low LDL. Yet 37% still had atherosclerosis on CAC or carotid ultrasound.

🔗 Link to details at the end
PMID: 29751286 2/6) To be fair, this was modestly lower than the overall prevalence in the cohort (49%).

But a 12% relative difference, while not nothing, is a surprisingly small payoff compared to improving factors like blood sugar control or insulin sensitivity.

The punchline: across two diverse, untreated cohorts, having “optimal” LDL did not prevent atherosclerosis.

Not even close.

Can Nattokinase Reverse Atherosclerosis? 🫀❤️‍🔥
(link in 6/6)

1/6) When it comes to cardiovascular health, few supplements have sparked as much public interest — or confusion — as #nattokinase.

This enzyme, derived from Japanese fermented soybeans, has achieved near-legendary status for its potential to improve, or even reverse, atherosclerosis.

But the hype surrounding nattokinase is often matched by a lack of understanding — both about how it works and whether it actually works. 2/6) Let’s start with some human data.

In one study, 29,000 participants were followed for 16 years.

People in the highest quartile of nattō consumption, compared with those in the lowest quartile, had a 25% lower risk of dying from cardiovascular disease (HR = 0.75), after adjusting for covariates.

How a $1 Trillion Drug Got it Wrong

1/6) Today’s video on statins (linked below) dives into several key studies you need to understand, along with some provocative demonstrations that will definitely stick in your brain.

But in this short thread, let’s quickly review a few major takeaways... 2/6) Take Away 1: Across the board—whether you're looking at the 4S trial or more recent datasets involving cardiac imaging—a consistent pattern emerges:

People with good metabolic health and/or a zero-calcium score may see minimal benefit from statin therapy or LDL reduction.

Now, of course, there are nuances.

But broadly speaking, if your coronary artery calcium (CAC) score is zero, there's little to no reduction in cardiovascular events from lowering LDL.

Have High Lp(a)? You Need to See Today's Video covering a new 2025 study on Lp(a) and waist-to-hip ratio

1/5) Here's a quick breakdown...

The goal of this new study was to determine whether a measure of adiposity—waist-to-hip ratio—modifies the relationship between Lp(a) and cardiovascular disease risk. 2/5) To explore this, researchers analyzed data from 4,652 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), following them over a median of 17.4 years.

The study stratified individuals based on Lp(a) levels defined as >50 mg/dL and investigated how this risk interacted with waist-to-hip ratio as a marker of central adiposity and visceral fat

*Lp(a) (nmol/L) = Lp(a) (mg/dL) x 2.15

New Study: Person Study Finds Statin Use Associated Decline in Muscle Mass

1/6) A colleague of mine—a medical doctor—texted me recently: “I’m stopping my statin.”

The new paper referenced concludes: “Continuous statin use is associated with a decline in muscle function and mass over time (25% decline in grip strength and 73% decline in appendicular lean mass compared to never-­ users).”

Let’s discuss. (links in 5/6 and 6/6) 2/6) We’ll break this up by discussing the cross-sectional (single time point) and longitudinal (over time) results.

Cross-sectional analysis: In the fully adjusted model, adjusting for age, sex, education, smoking, BMI, activity score, diet quality score, high blood pressure, diabetes, and so on, statin use was associated with lower grip strength and lower appendicular lean mass.

Sardines Accidentally Supercharged my Metabolism?(link in 8/8)

1/8) Now, I want to follow-up on one of the strangest findings from the Sardine Diet Experiment...

I became cold-resistant.

Taking off my shirt on an icy Boston winter day felt almost like a cool, soothing summer breeze.

It felt weird. It was unexpected. But it also makes sense... Let's discuss...

https://x.com/nicknorwitz/status/1988943850044366975

2/8) As a quick recap, I recently did a self-experiment that can be summarized in just two words: Sardine Diet. After a couple weeks on this extremely high omega-3 diet, I became conspicuously cold-resistant.

This was weird.

And I wanted to understand what might be happening. So, I dug into the literature.

The Best form of Omega-3 Matters (🔗 in 8/8)

(1/8) Alzheimer’s disease is personal for me. In my early 20s, I discovered I carry the ApoE4/4 genotype—placing me at the highest genetic risk. I was terrified. But over time, that fear shifted to a realization:
👉A genetic predisposition is a vulnerability, not a destiny.
👉 Our choices shape our health trajectory more than our genes ever could.

Today, I want to share a piece of that puzzle: The Omega-3 Paradox.

👉The Signal: Data clearly shows eating fatty fish lowers Alzheimer’s rates and boosts cognitive longevity.
👉The Failure: Yet, large clinical trials using Omega-3 supplements often fail to protect the brain.
👉The Question: Why?

One answer lies in a specific delivery mechanism most people—and many researchers—overlook.

Here is the science of getting Omega-3s into the brain. 🧵👇 (2/8) So, why do supplements often miss the mark? The answer is likely the form in which the Omega-3s are packaged.

When you eat seafood, you ingest Omega-3s in diverse forms, including phospholipids. However, most supplements on the shelf provide them in other forms, like triglycerides.

The Form Matters…

How Metabolic Disease Feeds Emotional Eating 🧠🍩
(link at the end)

1/8) A brand new study (Dec 10, 2025) reveals how poor metabolic health can drive emotional eating.

Why this is important: There’s a known link between metabolic disease (obesity, diabetes, etc.) and mental health conditions (eating disorders, anxiety, depression).

But the causal relationships remain murky.

In uncovering the “how” we lay the groundwork for innovative solutions.

cc @Metabolic_Mind @janellison @TuitNutrition @ChrisPalmerMD @MitoPsychoBio @WilliamFurness @drjenunwin 2/8) The researchers behind the experiments took interest in ImP, which is known to be elevated in patients with metabolic conditions like diabetes (below)—and is linked to cardiometabolic disease.

*ImP levels are elevated in humans with type 2 diabetes (red) vs healthy controls (blue).

When The “Cholesterol Drop” Misses the Mark
(Links in 6/7 and 7/7)

1/7) Can we assume that how much LDL drops tells us how much cardiovascular risk is reduced?

A new meta-analysis in the European Heart Journal says, “No.”

In fact, it suggests the link between LDL-C reduction and actual cardiovascular outcomes is incredibly weak.

So, have we built a multi-billion-dollar industry on the assumption that hot chocolate equals real illness?

Let’s unpack that…

cc @realDaveFeldman @AdrianSotoMota @ApoDudz @DrEricRodgers @LDLSkeptic @AKoutnik @janellison @bschermd 2/7) This was an umbrella review of meta-analyses of randomized controlled trials.

In total, the review included 20 RCTs comprising 194,686 participants, with a median follow-up of 4.85 years.

So, what did they find?

In this study, the r² for LDL-C on major adverse cardiovascular events ranged from 0 to 0.1.

In other words, this calls into serious question whether LDL-C can be used as a surrogate for clinical outcomes in statin trials.