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Nick Norwitz

@nicknorwitz

Aug 23

Statins Slash GLP-1 Levels - Human Controlled Trial
(🔗 at the end)
1/9) Usually, scientific research excites me. But the paper I just read? It both excited and annoyed me.

It explores how statins – the most profitable drug in history, with annual sales exceeding $20 billion – contribute to insulin resistance, increase diabetes risk, and significantly lower GLP-1 levels in humans.

These findings were published over a year ago – February 6th, 2024 – in @Cell_Metabolism, a highly respected scientific journal.

This should have been headline news. But not a word.

I’ll return to my commentary on the silence around these data. But first, let’s make sure you understand more than most doctors about this overlooked finding.

2/9) In the first experiment, researchers enrolled 30 patients who were starting atorvastatin (20 mg) and 10 control patients who weren’t taking statins. They followed both groups for 16 weeks.

The results?

Statin use led to significant increases in HbA1c, insulin levels, and insulin resistance (HOMA-IR). At the same time, it caused a sharp drop in GLP-1 – ~50% by the end of the four-month trial, with a continued downward trend still clearly visible.

In my opinion, just that one panel – Figure 1H from the paper – should’ve made headlines. Newspapers should’ve been shouting: “Statins cut GLP-1 levels by half! Here's what it could mean for your health.”

3/9) The researchers dug deeper to understand how statins were doing this. They discovered that statins altered the gut microbiome in a very specific way. The statin-treated patients had different levels of certain secondary bile acids – compounds made by gut bacteria. Most notably, there was a marked drop in a bile acid called ursodeoxycholic acid (UDCA).

UDCA is produced when specific gut bacteria convert a precursor bile acid, CDCA, into UDCA. In this case, the main producers of the UDCA were Clostridium species, which express an enzyme (7α-HSDH) that performs this conversion.

Statins depleted these Clostridium bacteria, reducing the microbiome’s ability to produce UDCA. That led to downstream metabolic disruptions – including insulin resistance and reduced GLP-1 production.

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Nick Norwitz

@nicknorwitz

Aug 22

1/9) In the most gentlemanly manner possible, @realDaveFeldman just released the lipid-nerd equivalent of “Here, hold my beer”on the KETO-CTA study.

Drawing from his slide deck and some new reveals, I’m going to summarize what you need to know.

First big question: Why have we been quiet and apparently disengaged on the KETO-CTA matter?

After the April 7th paper, “oddities” were noted in the Cleerly data. I can attest that Dave had flagged these well before publication (see ~3:36–5:25 in Dave’s lecture, linked at the end).

However, given his position as the study’s funder, he (and I by proxy) felt it was “inappropriate” to push for additional review analyses at that time. Furthermore, (i) there were robust and novel findings we could (and did) publish, and (ii) Dave et al. knew we’d eventually have all the raw data in hand to review and assess.

So, we published the data we had—knowing there would be more papers from this dataset, including plaque progression metrics with the pre-specified QAngio methodology (Cleerly was not the pre-specified methodology; QAngio was, it just takes longer to process).

We published the data we had with emphasis on the novel finding that: Plaque Predicts Plaque Progression, but ApoB does not.

2/9) Now, the pushback we received on this emphasized novel finding (“Plaque Predicts Plaque Progression, but ApoB does Not”) is perhaps one of the silliest arguments I’ve observed in the metabolic health space.

Critics argued that because “all of these people had high LDL and high ApoB,” there wasn’t a sufficiently “varying dosage.”

The reason this is such a—pardon my directness—stupid argument is because our cohort had the widest dosage variability of any prospective cardiac imaging study ever published.

3/9) It’s like critics were suggesting, “Well, a Bernese Mountain Dog and King Kong are both ‘big,’ so they have the same destructive capacity.”

This is not a well-thought-out argument.

The modern lipid-heart hypothesis does not include a ‘saturation’ effect; it doesn’t suppose that LDL of 190 and 574 mg/dl are similar.

Ironically, in making this argument, our critics were strengthening the case against the lipid-heart hypothesis more than we ever have.

So, I repeat, “stupid argument.” Honestly, my assessment is that “high = high” became a thoughtless meme among critics that propagated because the mass meme assault distributed responsibility for critical thinking on the matter.

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Nick Norwitz

@nicknorwitz

Aug 16

Can this Little-Known Hormone Can Rejuvenate Your Heart? (🔗 at the end)

1/9) We tend to think of heart aging as inevitable — a slow, steady decline baked into the passage of time. But emerging research suggests that a fat-derived hormone might hold the key to reversing age-related decline in cardiac function. Not with drugs or supplements, but with a simple intervention you can access today. And I’m going to prove it to you.

Perhaps you’ve heard of brown fat—a type of fat tissue that is specialized to produce heat, i.e., “thermogenesis.” It protects against the cold and is often discussed in nutrition, metabolism, and biohacker circles because of its impressive ability to burn calories.

But that simplistic view of brown fat has led many to overlook its more important role: brown fat is an endocrine organ, secreting hormones that alter metabolism and physiology in meaningful ways.

One class of hormones that’s particularly interesting are the oxylipins—metabolites of polyunsaturated fats like omega-3 and omega-6.

2/9) One specific oxylipin that’s gaining attention is 12,13-diHOME, a derivative of the Omega-6 fat linoleic acid.

In a nutshell, a new study in Nature Communications found that 12,13-diHOME levels decrease with age in both humans and animals, alongside a decline in brown fat activity. This decline is associated with decreased cardiovascular function, as 12,13-diHOME acts on the heart to keep it functioning optimally.

But transplanting brown fat from young animals into old animals or directly treating old animals with 12,13-diHOME restores youthful cardiovascular function. This suggests that this special lipid could serve as an anti-aging hormone.

3/9) And here’s the kicker: there are already things you can do to boost it without pills or injections. I promise, we’re getting to that. But first, let’s look at more data.

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Nick Norwitz

@nicknorwitz

Aug 14

Intermittent Fasting Reprograms the Alzheimer’s Brain (🔗 at the end)

1/5) Emerging research suggests that intermittent fasting — also known as time-restricted feeding (TRF) — may slow the progression of Alzheimer’s disease by altering the rhythmic expression of genes in the brain.
That might sound like an extraordinary claim — maybe even too good to be true. But consider this: Alzheimer’s disease is already closely linked to circadian disruptions — including difficulty falling asleep, staying asleep, and excessive daytime drowsiness.

What’s more, poor sleep impairs the brain’s ability to clear metabolic waste, contributing to the buildup of misfolded proteins associated with Alzheimer’s and other neurodegenerative diseases.

This sets the stage for a vicious cycle: Alzheimer's pathology disrupts the circadian rhythm, which then worsens the disease.

2/5) Now, let’s turn to the study that inspired this newsletter, published in @Cell_Metabolism. Researchers used a mouse model of Alzheimer’s disease. While not a perfect analog for sporadic human Alzheimer’s, these models offer key advantages:
👉The disease progresses rapidly enough to study in real time
👉Interventions can be tightly controlled
👉And crucially, brain tissue can be harvested for molecular analysis

First, researchers observed that the Alzheimer’s mice—like humans with the disease—exhibited altered and fragmented sleep that worsened with age. This led to decreased total sleep time and disrupted patterns of activity across daily cycles. Interestingly, TRF improved these disrupted patterns, restoring them to the level seen in control mice without Alzheimer’s.

Perhaps this isn’t surprising, as food can be a very strong zeitgeber (circadian cue). However, that’s only a superficial understanding. Let’s look under the hood—i.e., under the skull.

3/5) Gene Expression: Under the Hood of the Brain

Remarkably, Alzheimer’s disease altered the circadian rhythms of a massive suite of genes in the hippocampus, a key memory region of the brain and one of the most severely affected areas in Alzheimer’s disease. Many of these genes were involved in key pathways known to play a role in neurodegeneration, like protein folding. Impressively, TRF helped restore these rhythmic patterns closer to normal.

Take a look at the heatmap graph below. It might seem intimidating at first, but I’ll walk you through it:

The yellow–purple color scheme represents relative gene expression, with yellow indicating higher expression and purple indicating lower expression. Each row represents a different gene. The blue, orange, green, and red bars at the top categorize the columns by genotype and feeding pattern: Blue: Control mice. Orange: Alzheimer’s mice. Red: Ad libitum feeding. Green: Time-restricted feeding (TRF)

So: The blue–red overlap = control mice fed ad libitum. The orange–red overlap = Alzheimer’s mice fed ad libitum. The orange–green overlap = Alzheimer’s mice fed TRF (18:6 schedule)

What you’ll notice is that the overall yellow–purple pattern is largely inverted between control and Alzheimer’s mice under ad libitum feeding. However, this pattern is clearly restored toward normal in Alzheimer’s mice on the TRF regimen.

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Nick Norwitz

@nicknorwitz

Aug 13

1/7) I keep getting pinged about a rather viral reel by @drmarkhyman on Instagram from his interview with @hubermanlab on Seed Oils and the Minnesota Coronary Experiment. I’ve gotten a few questions, so I thought I’d break it down quickly.

Mark was referring was Ramsden et al., 2016 in the BMJ, which presented 'new' data from Minnesota Coronary Experiment — a multi-center, double-blinded, randomized controlled trial conducted between 1968 and 1973...

2/7) The intervention was a corn oil diet versus a control diet relatively higher in saturated fat.

The corn oil diet included 13.2% of calories from linoleic acid (a 280% increase in linoleic acid and a 51% reduction in saturated fat from the baseline diet)

The control diet, which had 4.7% of calories from linoleic acid.

3/7) Cholesterol decreased substantially in the intervention group by 13.8% (−31.2 mg/dL); however, the survival curve suggested a trend toward higher all-cause mortality in the intervention (high–linoleic acid) group, as well as a dose-response relationship between greater cholesterol lowering and higher probability of death. Recall, this was a randomized controlled trial.

Additionally, focusing only on cardiovascular health, the intervention group also fared worse. Interestingly, they had an autopsy cohort. In this autopsy cohort, 41% (31/76) of participants in the intervention group had at least one myocardial infarct, whereas only 22% (16/73) of participants in the higher saturated fat, lower linoleic acid control group did.

They also conducted a meta-analysis of randomized trials as part of this publication that similarly found little support for the traditional diet–heart hypothesis.

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Nick Norwitz

@nicknorwitz

Aug 12

The Hard Truth: Viagra Could Prevent Alzheimer’s Disease (🔗 in 5/5)

1/5) The talk of the town this last week has been the Nature paper showing that Lithium may help prevent Alzheimer’s disease. But what if another common (bedroom) compound could reduce Alzheimer’s risk by 69%? …

Viagra might prevent Alzheimer’s disease. And yes, I am serious. The paper I want to talk about was published in @NatureAging. The researchers began with an exploratory analysis, looking for predicted molecular interactions between existing drugs and pathways involved in Alzheimer’s disease.

Viagra (Sildenafil) stood up — darn it! — I meant, stood out.

2/5) Now, if Viagra truly reduces the risk of Alzheimer’s, we should expect to see that effect in large population datasets. And we do. The researchers performed multiple analyses on over 7 million individuals enrolled in Medicare Advantage insurance plans and found that Viagra use was associated with a 69% reduced risk of Alzheimer’s disease compared to non-users.

3/5) To reduce the chances of confounding variables, they also compared Viagra against other commonly prescribed medications — including diltiazem, glimepiride, losartan, and metformin. Every time, Viagra use was associated with a reduced Alzheimer’s risk compared to the comparison drug group.

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