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.

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.

🚨How Berberine Lowers Cholesterol: Blew My Mind! (link at the end)

1/6) I just learned how berberine lowers LDL-C/ApoB, and the *mechanism* blew my mind.

Unlike statins, it doesn’t inhibit cholesterol synthesis, or harm mitochondria, and doesn’t worsen insulin resistance.

In fact, it improves features of metabolic health, while also lowering LDL and ApoB in a totally unexpected way.

Let’s break it down...

⚠️ Warning: This is a heart-health nerd's only zone. Proceed at your own risk, especially with 4/6.
@ApoDudz @lipo_fan @realDaveFeldman @AdrianSotoMota @LDLSkeptic @AKoutnik @janellison @bschermd @tyler_smith @Hundredhealth @DrPaulMason @robbwolf @reallyoptimized 2/6) First, contrast with statins. Statins inhibit cholesterol synthesis, creating a relative “cholesterol starvation” state in liver cells. 

The liver compensates by ramping up LDL receptor expression, which pulls LDL particles out of the bloodstream.  Effective—but not without tradeoffs, which can include off-target effects in other organs:

👉Mitochondrial impairment
👉Reduced CoQ10 synthesis
👉Lower GLP-1 levels
👉Insulin resistance

I’m not saying statins don’t have a place—but their mechanism of action has real biological costs.

Microbiome Reset (Protocol)

1/6) If you’ve ever thought, “What if I just reset my microbiome?” Well, that’s what I want to help you do today.

But why even ask this question?

Let me back up—about 29 years—and share a bit of personal context.

As a newborn, I spiked a fever of 106°F. Out of caution, I was given powerful antibiotics.

Today, we better understand how critical early life is for microbiome development. Antibiotics like the ones I received can leave a lasting scar—even increasing risk for inflammatory bowel disease (IBD) later in life by ~500%.

Lo and behold, I did develop IBD—specifically, ulcerative colitis. It nearly killed me. 2/6) The truth is, our microbiomes are under constant assault—sabotaged daily by the booby traps of modern living.

From the moment you wake up and pour cereal into a bowl to the moment you collapse into bed, eyes glazed from “just one more” episode, our environments have drifted so far from nature’s blueprint that most of our microbiomes are evolutionarily unrecognizable.

So, what might a microbiome reset look like?

I just completed a month-long sardine diet.

1/5)The results were... surprising 😳
👉Body fat (7%)
👉Omega-3 levels, off the chart (literally, 25% higher than the visual scale goes and 2.7% above reference range)
👉Energy = Excellent (after some tweaks)
👉Cold Resistant. Maybe an impact of omega-3 on thermogenesis (via omega-3 derivatives, e.g. 12-HEPE) 2/5) The Rationale: Sardines are about as close to a superfood as one can get: packed with protein, omega-3, calcium, B12, CoQ10, creatine, etc.

They're like if a multivitamin had a baby with a protein supplement - but natural. So you can pretty much live off sardines

New Therapy for Alzheimer’s Prevention: An ApoE2 “Bath”

1/5) My Alzheimer's risk is 10-15x higher than average because I'm in the ~2% of the population that carries two copies of the ApoE4 gene, the dominant genetic risk factor for Alzheimer's.

Some consider this a near guarantee of developing the disease if you live long enough.

But I'm optimistic.

A study just published in Molecular Therapy demonstrates a potential "antidote" that gives me, and many others, a reason for hope. It’s not a cure. Not a silver bullet… but a glimpse of what’s coming…

In today’s letter (🔗 at the end), I break down these data and tell you what I do today to protect my ‘future me’ brain. (2/5) One core question has always been: Is ApoE4 actively "toxic," or is the problem a lack of functionality, functionality better provided by the most common “ApoE3” variant of the ApoE gene or protective ApoE2 variant.

If it's primarily a lack of functionality, the solution is simpler: add back what's missing.

That's exactly what this study tested. Researchers used a humanized mouse model carrying the ApoE4 gene to see if they could literally bathe the brain in extra ApoE2 to protect against Alzheimer’s pathology.

They developed a clever new gene therapy method to do to make this happen…

Stress Can Biologically Age Your Body and Brain. But How You Respond to Stress Matters More (🔗 in 7/7)

1/7) We often talk about stress metaphorically — "that job is aging me." But what if this is a literal biological truth?

A study published in Nature Aging provides a chilling mechanism, linking chronic psychosocial stress directly to accelerated biological aging.

The culprit? Stress is creating "zombie cells" (cellular senescence), especially in your most critical organ: your brain…

Are you surprised? And, how old do you think I am (biologically speaking)? 2/7) To test this, researchers used a robust model of chronic subordination stress in mice.

This isn't just "feeling stressed" — it's designed to simulate chronic social defeat. Think of it as the biological equivalent of a persistent bully at school or an aggressive, abusive boss with unchecked power.

Each day, the test mouse was exposed to a larger, aggressive mouse and physically subdued, creating a state of chronic, inescapable social stress.

Creatine Mini-Masterclass
💪How is Really Work?
💪How Do You Maximize Benefits?
🔗 in 8/8

1/8) Creatine is one of the most extensively studied performance-enhancing supplements in the world of exercise science and nutrition.

For examples, a recent meta-analysis of RCTs examined the effects of full-body resistance training programs, with and without creatine supplementation.
The key findings:

💪Compared to resistance training alone, creatine supplementation significantly increased lean body mass by 2.5 lbs (1.14 kg).

💪Creatine also led to reductions in body fat percentage by 0.88% and total fat mass by 1.6 lbs (0.73 kg).

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

So... what is Creatine and How Does It Work? 2/8) Creatine is a naturally occurring compound made up of three amino acids: arginine, glycine, and methionine. Your body produces it in small amounts, and you also get some from food—especially meat and fish.

Creatine is primarily stored in muscle tissue, where it plays a critical role in cellular energy metabolism. Its main function? Helping to rapidly regenerate a molecule called ATP—the primary energy currency of your cells.

How to Hack the Black Hole of Sugar Cravings

(1/7) Why does one person politely decline dessert while another feels irresistibly pulled toward it, as if by a "gustatory black hole?" 🍰

It's NOT a failure of willpower. It's metabolic wiring.

A fascinating paper just published in Nature Microbiology uncovers a precise gut-to-brain pathway that modulates our biological preference for sugar. 2/7) Before we get to the rest of the thread, a quick reminder. This is DAY 1 of the Nuance November Promotion at 👉 StayCuriousMetabolism.com

Link to this letter: staycuriousmetabolism.substack.com/p/the-metaboli…

Now, ONWARD!

Measuring Insulin Resistance: Your Potato-to-Grape Ratio?! 🥔🍇 (link at the end)

1/5) Your potato-to-grape ratio might predict your insulin resistance.

A 2025 study from @Stanford Snyder Lab (@SnyderShot) published in @NatureMedicine is challenging one-size-fits-all nutrition, and the findings on personalized blood sugar spikes are fascinating. 2/5) Researchers studied 55 individuals, giving them seven standardized 50g carb test meals (white rice, bread, potatoes, pasta, beans, berries, and grapes).

They tracked everyone's individual glycemic response to each meal using CGMs.

One striking finding?

🚨Quoting the paper: "for each individual, different meals produced the highest glycemic response."

Someone might spike most from bread, another from grapes, someone else from potatoes.

But the patterns weren't random.