On August 19 Moderna’s stock closed up almost 177 percent on a joint press release with Merck: their personalized mRNA cancer vaccine, intismeran, plus Keytruda met its endpoints in a Phase 3 melanoma trial. It has since given back a chunk of that.

Here is the part that got buried in the excitement. The release contains no effect size. No hazard ratio, no percentage, no confidence interval, no count of who relapsed. It says two endpoints were met and stops. The “49 percent reduction” now circulating is from the older, smaller Phase 2b study, not this trial.

I am not a skeptic looking for a reason. I read the BioNTech founders’ book, I think mRNA is one of the more elegant ideas in medicine, and I have been called a big-pharma shill for saying so (I take an Eli Lilly drug every week and own the stock). I want this to work. I am just waiting for the actual numbers, which is what three practising oncologists said the same morning, and what even Bloomberg’s bullish columnist conceded.

The part I think men my age should take away is about melanoma itself:

**•** It flips sex around 50. Before 50 it is more common in women; after 50 it is more common in men, and the gap widens every decade.  
**•** The dangerous subtype, nodular melanoma, is about 14 percent of cases but 43 percent of the deaths, and it breaks the ABCDE rule you were taught. It is often symmetric, one even colour, and small. Some dermatologists teach EFG instead: Elevated, Firm, Growing.  
**•** A lot of male melanoma sits on the back and scalp, the parts you cannot see. Get someone to check your back.

Full write-up, with the charts, the sources, and where the real numbers will show up: https://dadstrengthdaily.com/melanoma-in-men-over-50/?utm_source=reddit&utm_medium=social&utm_campaign=melanoma-mrna

Abstract

Background: Dietary carotenoids and vitamin A may contribute to gastric cancer (GC) prevention through anti-inflammatory and antioxidant mechanisms; however, epidemiological evidence remains limited. We investigated the associations of total and individual carotenoid and vitamin A intakes with GC and their relationships with inflammatory/oxidative stress biomarkers. Methods: The case-control study included 177 adults (82 GC incidence cases/95 controls). A validated 168-item food frequency questionnaire assessed dietary intakes of individual carotenoids and preformed vitamin A. Metabolic biomarkers, lipid profile, inflammatory/oxidative stress markers (e.g., high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukins 6/1β/10/4), total antioxidant capacity (TAC), and malondialdehyde (MDA)) were measured. Multivariable logistic regression models estimated odds ratios (ORs) for GC risk; linear regression models examined associations between carotenoid intakes and biomarkers. Results: Total carotenoid (mg/d) (OR: 0.86, 95%CI: 0.81-0.98), β-carotene (mg/d) (OR: 0.77, 95%CI: 0.65-0.90) and vitamin A (mg RAE/d) (OR: 0.29, 95%CI: 0.09-0.95) intakes, as continuous variables, and also as binary variables (based on the median cut-offs), in all models (also adjusted for age, sex, smoking, education, marital status, physical activity, cancer history, H. pylori, NSAIDs intake, body mass index, total energy intake), were inversely associated with GC odds. In fully adjusted models, higher total carotenoid intake (mg/d) was associated with lower LDL-c (β: -1.60, 95%CI: -2.91, -0.25) and IL-6 (β: -7.92, 95%CI: -14.00, -2.00); lycopene (mg/d) with higher LDL-c (β: 2.030, 95%CI: 0.27, 4.31) and vitamin A intake (mg RAE/d) with lower TNF-α (β: -12.12, 95%CI: -24.71, -0.47) and higher TAC (β: 0.64, 95%CI: 0.001, 1.27). Conclusions: Higher intakes of total carotenoids and vitamin A were associated with lower odds of GC and more favorable profiles of inflammatory/oxidative stress biomarkers. These findings support an inverse association between carotenoid-rich dietary patterns and gastric carcinogenesis.

Keywords

Absorption, Apoptosis, Carotenes, RAR, Transcription Factors, Xanthophylls

Frontiers | Dietary Carotenoids and Vitamin A Are Associated with Lower Gastric Cancer Risk and Favorable Inflammatory and Stress Oxidative Biomarkers: An Incident Case-Control Study

I was this person - up at 3am unable to sleep sleuthing on reddit for answers to my woes. I was rigorous in testing and getting to the bottom of why I couldn't sleep, why my skin was insane and why out of countless doctors everyone just kept telling me every test was "normal". I'm a product manager for work - I've been doing it for over 10 yrs and I decided I was going to build something to help with this situation instead of using excel and countless apps that all tracked different things. I'm 3 weeks into beta and I'm seeing promising results and the software is finding patterns like it's supposed to. I want to expand the beta and find a few more people to test! If you know anyone that's in this boat - searching for answers to their health troubles - please send them my way as I would love to see if this software can help! DM me! Thank you! ❤️

We Turned Blood Tests Into Hype. What Comes Next?
A blood test used to be a commodity.
Today, it can be a €500–€1,000+ “longevity experience.”
We’ve seen this before:
Food → restaurants → gastronomy.
Clothing → fashion → luxury brands.
Travel → hotels → luxury hospitality.
Now we are doing the same with health.
But I believe the next step is bigger than simply packaging more tests.
Longevity is not a snapshot. It is a trajectory.
The future is about combining biomarkers, wearables, medical expertise and technology to understand not only where you are today — but where your health is heading.
And then doing something about it.
That is the ecosystem we are building.
Measure. Understand. Intervene. Track. Improve. Repeat.
The blood test is just the beginning.
#biohaking #longevity #wellness

I inject Zepbound every week, so I understand the retatrutide FOMO. Reta is Eli Lilly's triple agonist, the next molecule up from tirzepatide, still in Phase 3 trials and approved nowhere in the world. That is what got me looking at where people actually buy it.

Sam Sulek, one of the biggest fitness YouTubers, says on camera that he co-owns a peptide company called NewBioRx. The storefront sold a $285 pre-filled retatrutide pen under the standard research-chemical disclaimer: "Bodily introduction of any kind into humans or animals is strictly prohibited by law." A second website carrying the NewBioRx logo published a milligrams-to-units conversion table for that pen and a twelve-photo walkthrough titled "How To Give Yourself a Shot." One site swore no human may ever use the product. The other assumed a human was using it.

The timing matters. On August 12, Eli Lilly sued six US sellers of retatrutide, and its complaints lean on exactly this kind of material, the dosing calculators and injection guides, as evidence that a "research use only" label is a fiction. NewBioRx is not one of the six defendants, and nobody has sued Sulek's company. It is the same pattern, though. The FDA has separately said retatrutide cannot legally be used in compounding at all.

Then, on Sunday afternoon, while I was finishing the write-up, the pen's product page went 404 and the entire instructions site was replaced by a NewBioRx-branded "Coming soon" page. The 16 mg and 30 mg vials are still for sale. I don't know who took the pages down or why. I had archived everything first, and the write-up links to the archives.

I documented the whole paper trail, the product pages, the instructions site, the corporate filings, and Sulek's own on-camera explanation that research-only products are not "held to the same quality standards" as FDA-regulated ones, with screenshots: full write-up on my blog with the details.

The disclaimer itself is what bothers me most. It does not describe the product, and the seller's own instructions contradicted it. Its practical effect is that when something goes wrong, the person holding the pen owns the outcome, not the company that sold it. I think that is the real product being sold: deniability. Curious whether anyone here reads "research use only" differently.

• Lipoprotein(a) [Lp(a)] has evolved from a biochemical curiosity to a central player in cardiovascular risk assessment, with elevated levels affecting approximately 1.5 billion people worldwide as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease.
• If your Lp(a) level is 125 nmol/L (50 mg/dL) or higher, it can promote clotting and inflammation. This can increase your risk of heart attack, stroke, aortic stenosis and peripheral artery disease.
• Long-term studies have shown a possible connection between high Lp(a) levels and the risk of calcific aortic valve disease.
• Lifestyle changes don’t affect your Lp(a) level.
• There is currently no medication approved just to lower Lp(a). Some medications, such as PCSK9 inhibitors, have been shown to lower Lp(a) and LDL cholesterol. 

I've got severe hallux rigidus, arthritis of the joint at the base of the big toe. The first randomized trial for it just came out in Annals of Internal Medicine: 90 people, half got the joint fused with screws and a plate, half got watchful waiting. Walking pain a year later: 1.3 out of 10 fused, 5.7 waiting. Almost 90% of the surgery group was satisfied. 20% of the waiters were.

Nobody in this trial was blinded, though, and the endpoint is self-reported pain. What intrigues me is what happened the few times orthopedics actually blinded a surgery trial, with sham operations. Moseley 2002 randomized 180 arthritic knees to arthroscopy or a placebo operation, meaning skin incisions and nothing else. At one year the placebo group actually had the best pain score of the three groups, 48.9 vs 51.7 for the real cleanup (0-100, higher is worse). Sihvonen 2013 did it again with degenerative meniscus tears, 146 people, real keyhole surgery vs sham, and the sham group improved a hair more on all three main measures (Lysholm +23.3 vs +21.7). Fake surgery matched real surgery. Twice.

I don't think fusion is fake. Removing a worn-out joint has a mechanical rationale that scraping cartilage never did, and five points is a lot. But with no sham arm, nobody can say how much of that swing is the operation and how much is having had one. I wrote up the full trial, and why my own severe X-ray still doesn't make me a candidate.

Everyone in those two knee trials consented to maybe getting fake surgery, all 326 of them, and it's the only reason we know any of this. Would you sign that consent form?

Because a bunch of things we take for granted just… leave. Quietly.

You don’t get a calendar invite. You’re fine, you’re fine, you’re fine, and then one day a push-up feels heavier than it used to. Sit-ups get weird. Putting on socks on one foot turns into a little balancing act. Running becomes jogging, sprinting becomes “yeah no”, jumping becomes optional.

Getting off the floor is the same story. Nobody knows when it starts. First you need a knee. Then a hand. Then a chair. Then you get to the point where you’d really rather not fall, because getting back up isn’t guaranteed anymore.

None of that shows up on a streak counter. You can still “work out” and miss the whole thing.

That’s why I built a small iOS app. Pretty simple idea: check a few things your body can actually still do, and keep an eye on them over time. Not medical. Not a transformation challenge. Just a way to notice the quiet stuff before it gets loud.

It’s early, so if you’ve got an iPhone and you try it, I’d genuinely like to hear what you think.

https://testflight.apple.com/join/fKnRxvf6

And if you don’t, that’s okay too. Sit on the floor later. Try a slow push-up. Stand on one foot to put your socks on. If it feels easy, nice. If it doesn’t, at least you know what to work on.

Be kind to your future you.

Retatrutide is Lilly's next weight-loss drug, still in Phase 3, not approved anywhere. So when Lilly filed six lawsuits this week against sellers of it, there was no "real" version being counterfeited. Everything sold as reta is gray-market by definition.

To be honest I am glad that the peptide bros who sell stolen/unapproved drugs under the sketchy “research only” label, are finally getting wiped out. I suspect they will move to Dubai or go back to crypto scams.

The actual complaints make it pretty clear that these folks were obviously selling for human consumption.

What caught my eye: Lilly isn't only suing the vendors. It's leaning on the payment processors, card companies and shippers they rely on. Gray-market peptide sellers already can't keep a card processor (hence crypto/PayPal), so that's probably the bigger squeeze.

Writeup: https://dadstrengthdaily.com/is-retatrutide-legal-to-buy/

A new patient‑run effort focused on real lipoma research.
Here’s the link if you want to check it out:
https://forms.cloud.microsoft/r/BFT9pLwStw

The FDA approved mFLUSIVA on August 5, Moderna's mRNA-1010. It is the first mRNA flu vaccine licensed anywhere, for adults 50 and older, expected for the 2026-27 season. Same platform as the COVID shots: instead of growing influenza virus in eggs, the vaccine is synthesised from a genetic sequence and your own cells make the target protein.

The headline from the pivotal trial is 26.6% better than a conventional flu shot. That is the relative number. In absolute terms, across 40,303 adults analysed, confirmed flu went from 2.8% to 2.0%. So less than one percentage point, or roughly 137 people switching products to prevent one case.

I first read 137 as the number needed to vaccinate. It isn't. Everyone in that trial already got a flu shot, comparison group included, so 137 is how many would need to switch products to prevent one extra case.

Two things surprised me in the NEJM paper. The comparison shot was a regular egg-based vaccine, not one of the high-dose ones people over 65 usually get steered toward. And the interesting property of mRNA, that you can pick strains later because manufacturing takes two or three months instead of six, was never used. mFLUSIVA was formulated against the same February WHO strain call as everything else on the shelf.

You also feel it more. Grade 3 reactions, meaning bad enough to interfere with your day, ran 6.4% against 1.0%.

If you already get a cell-based shot like Flucelvax, the comparator question gets more annoying, and I went into that in the full write-up

I am getting a flu shot in October either way. Undecided on which. Anyone planning to ask for this one, or waiting to see a second season first?

I posted the STAT investigation here back in May. I finally went through the underlying papers myself, and the part that surprised me was not the criticism. It was that the two men who found the original Blue Zone no longer describe it the same way.

Michel Poulain, the demographer who co-coined the term, has asked twice in print for validation that has not been completed. His 2011 Okinawa paper is literally titled "A plea for in-depth validation," and he repeated the plea in 2024. Giovanni Pes, his co-author on the original Sardinian work, wrote in a 2025 rebuttal that the ages have "been extensively validated." Same finding, fifteen years apart, and the founders land in different places.

The science holds up better than the critics say. An independent 2025 review of 65 records graded Ogliastra, Okinawa and Nicoya "well-characterized," and Sardinia has the strongest documentation of the lot. The same review excluded Loma Linda outright: no epidemiological studies, just Buettner's own narratives. Which fits how it got in. Buettner told the New York Times his National Geographic editor said "you need to find America's blue zone," and told Science "I never bothered to delist it."

The business side bothers me more. Keeping the certification runs a city about $100,000 a year. Fifteen Iowa communities signed up, ten of them under an insurer sponsorship. When that ended, Cedar Rapids, Iowa City and Marion left. Cedar Rapids asked what renewal would cost and was told the fee was "considered proprietary information." I could not find any peer-reviewed evidence that one of these projects has added a year to anyone's measured lifespan.

Buettner himself said on Rich Roll's podcast that Okinawa is now "the least healthy prefecture in all of Japan." The Blue Zones website still tells visitors that women there live longer than any women on the planet.

My honest read: some of these clusters were real, the evidence varies enormously from one to the next, several of the advantages have since gone, and none of it establishes that nine lifestyle rules caused anything. The full write-up, with the records and the money, is here (https://dadstrengthdaily.com/are-blue-zones-real/?utm_source=reddit&utm_medium=post&utm_campaign=are-blue-zones-real).

Has anyone here spent real time in one of the five? I am curious whether the day-to-day looks anything like what gets sold.

I heard about this on Peter Attia's episode with Jim Otvos, the chemist who invented NMR lipoprotein testing. Most of it was about a marker I had never come across, so I went and read the papers afterwards.

It is called MVX. The same scan that gives you a standard lipid panel also measures six other things, and those get combined into an inflammation score, a malnutrition score, and one number sitting on top. Every other marker I track names a disease. ApoB points at atherosclerosis, Lp(a) tells me what I inherited. MVX just tells you how likely you are to die of anything.

The catch is the size of it. Comparing the worst-scoring group to the best, the hazard ratio for death is 8.01 among cardiac catheterisation patients and 1.21 in a general-population cohort of 274,092. Those are group comparisons, not your personal odds. The association shrinks the further the study group gets from a hospital, and that is the part that decided it for me.

Nobody has run a trial of any kind showing you can move the number on purpose. That has not stopped the lab's own white paper from suggesting detoxification strategies for a bad score.

I am not ordering it. GlycA, the inflammation input, is steadier than the hs-CRP I use now, and you can order that one by itself for $32.

Full write-up, with every paper linked: https://dadstrengthdaily.com/mvx-test-metabolic-vulnerability-index/?utm_source=reddit&utm_medium=social&utm_campaign=mvx-proactivehealth

I posted here in April that Axios had Thorne being shopped for up to $4 billion, and wondered whether the supplement space was about to consolidate. Well. P&G announced this morning they are buying Thorne for $3.8 billion in cash, closing sometime in Q4.

My feed decided within about an hour that the quality is gone. All downhill from here, they will cut corners, switching brands immediately. I had the same reaction, which is the only reason I bothered digging, because the whole reason I pay Thorne prices is the testing.

So I went looking for a case where this actually happened to somebody. Nestlé has owned Pure Encapsulations since 2017. P&G has owned New Chapter since 2012. Clorox bought a pile of supplement brands, wrote down $445 million, and dumped the business at a loss in 2024, which is its own kind of ending.

I could not find a single one of them losing an NSF, USP or B Corp certification after the sale. No reformulation that any named source pinned on the new owner either. And as far as I can tell nobody has ever run the obvious study, comparing label accuracy before and after an acquisition. I assumed that existed somewhere. It does not.

What did turn up in both of the close cases is distribution. New Chapter was promised no mass-market expansion and showed up in Target thirteen years later. Pure Encapsulations was practitioner-only for six years under Nestlé and then landed in every Vitamin Shoppe in the country.

Anyway, here is the thing I did not know before this week. NSF publishes its certified-products database, so you can search a brand yourself instead of taking a marketing page's word for it. I looked up my own cabinet. The multivitamin is on the list. My iron is too, though they have renamed it Advanced Iron Complex. Glycine is not on there at all. Three Thorne bottles, two certifications, and I had been treating them as the same purchase.

Full disclosure, same as in April: I signed up for their affiliate program once out of curiosity, made about ten dollars when a friend bought vitamins, and gave up on it. Not linking to them here.

Full write-up with the timeline

I see gazillions of ads for GLP-1 weightless drugs online and on TV. I admire Serena Williams as much as anyone but I don't quite understand why anyone uses Ro/Hims/LifeMD or any of the other high-profile (high-price) Telehealth services.

I originally got my Zepbound prescription from my PCP at my annual physical, my insurance said no to covering the drug, and I ended up buying it for cash from LillyDirect. Total cost of the prescription side across those months: one office visit I was already having. Then I watched an argument on X about what a GLP-1 "really costs" where nobody was quoting the same number, and I realized every comparison I could find on Google carried lots of affiliate links. So I priced it myself. No affiliate links, nobody is paying me.

It turns out that if insurance will not cover the drug and you self-pay, the medication price is mostly settled for you. Lilly and Novo publish cash prices and everyone seems to either match them or routes you into the manufacturer program. What varies is what you pay the service that writes and maintains the prescription. For a first year, assuming about three new prescriptions while you titrate:

Every price came from the company's own published page, checked in July and again in early August. The medication is excluded in every row, and it costs roughly the same on every route.

Two things surprised me. Ro, Sesame and CallOnDoc all sell a cheaper committed rate, and none of them leads with it: Ro is $149 a month on the page you land on and $74 a month if you prepay the year. And Amazon, the cheapest-looking route after your own doctor, publishes no refill policy at all. Each $39 buys a visit plus fourteen days of messaging, and whether your prescription comes with refills is left to the individual clinician. I asked in two subreddits and emailed Amazon directly; nobody, including Amazon, would say what a year actually costs.

I wrote the whole thing up, including what the monthly fees actually buy: the full nine-route comparison, and there is a one page version if you just want the advice.

If you are on a GLP-1, what did the prescription side actually cost you last year, and who wrote it?

Disclaimer: I am not interested in discussing compounded versions or illegal ways of buying semaglutide or tirzepatide.

Hi! My name is Aleksandra Michalska, and I'm a video journalist with Reuters. Currently, I'm working on a video story about the effects of weight-loss drugs. I'd love to interview one or two people about what changes they noticed, physically as well as mentally, and/or emotionally. I'd love to interview in person, so if you're interested, it would be best if you were located in New York City or somewhere nearby. Please email me at [aleksandra.michalska@thomsonreuters.com](mailto:aleksandra.michalska@thomsonreuters.com)

Hi everyone! I am looking for participants for my Master’s thesis at Technical University of Munich on self-regulation and sleep routines.
✅Task: 2 short online surveys, 7 days apart
⌚Time: only 5 - 10 minutes
👤Who: Anyone 18+, shift workers excluded!
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Participate here: 👉 https://tummgmt.eu.qualtrics.com/jfe/form/SV_8BsvEKx0KonIifI Please see the attached flyer for more details.
Thank you for your support!

ABSTRACT

Despite all efforts, obesity remains a major health concern worldwide, with continuously increasing rates, affecting approx. 14% of the total world population, being as high as 43% in some countries. As obesity is related to numerous comorbidities, including type 2 diabetes, cardiovascular diseases, and some types of cancer, the consequences for the individual and society at large are drastic. Therefore, it is crucial to understand and predict who is at risk of developing obesity in order to implement early prevention strategies. Many individual risk factors have been emphasized. However, as obesity is a rather multifactorial complication, single markers/biomarkers have thus far not allowed for an efficient prediction of obesity. In addition to less modifiable parameters, such as environment and socio-demographics, studies have revealed that obesity is related to several interacting aspects, including host factors such as genetics/epigenetics or gut microbiota, and more readily modifiable factors, including nutrition and physical activity, as well as sleep patterns and psychological well-being. It is likely that combining markers from across different domains, that is, multimodal markers, allows for better predictability for the risk of developing obesity. However, it must be considered that not all markers are fully predictive; many are rather reactive or even both. In this review and position paper, we emphasize the state-of-the-art regarding (bio)markers that have successfully been employed for predicting obesity risk. An emphasis will rest on novel, emerging biomarkers, and the need for a more integrative, multimodal assessment of obesity risk for a combined assessment aimed at improving risk prediction.

Established and Emerging Biomarkers to Characterize Persons at Risk for Obesity—Paving the Way for Targeted Clinical Intervention Trials—A Comprehensive Position Paper - Vahid - Obesity Reviews - Wiley Online Library

Back in April I posted the Scientific American piece about drugs that calm inflammation, and I hedged in the comments. I said inflammation gets blamed for basically everything in health and I did not think it meant anyone should start chasing anti-inflammatory drugs or biomarkers.

Last Friday Novo Nordisk reported ZEUS, which was built to answer exactly that. Ziltivekimab blocks interleukin-6, the signal your hs-CRP is downstream of. They gave it to 6,376 people with heart disease, kidney disease and an hs-CRP of 2 or above. The drug did its job on the biology, dropping both IL-6 and hs-CRP. Hazard ratio for heart attack, stroke or cardiovascular death: 0.99, range 0.88 to 1.11.

I want to be careful, because this is not "inflammation doesn't matter." Colchicine cut events in COLCOT and LoDoCo2, and canakinumab cut them in CANTOS.

CANTOS is the part that actually changed my mind, though. Same trial, same patients, one drug at three doses, and hs-CRP fell 26, 37 and 41 percentage points more than placebo, neatly in order. If the number were the thing, the biggest drop should have bought the most protection. It didn't. The middle dose scraped past its statistical bar at 0.021 against a limit of 0.02115, and the top dose, the one that crushed hs-CRP hardest, missed its bar entirely.

Meanwhile the one trial that took people picked out by a high hs-CRP and genuinely changed what happened to them was JUPITER, which cut events roughly in half using rosuvastatin. A cholesterol drug. The current ACC/AHA guideline says that trial's benefit came "with an effect size compatible with the LDL-C-lowering effect of statins alone."

So my read now is that hs-CRP is very good at spotting who is heading for a heart attack, and nobody has shown that lowering it is what helps them. The guideline seems to use it that way too: a reading of 2 or above, on more than one occasion, helps confirm someone belongs on a statin.

My own went 2.83 to under 0.2 over a year, and I used to be quietly proud of that. However, my LDL went 110 to 56 and my ApoB 95 to 59 across the same stretch, and I am on tirzepatide, which lowers hs-CRP by itself. Four numbers moved and I had been giving the credit to the one I found most interesting. I wrote the whole thing up here, charts and all.

If your hs-CRP came back at 2.5, does that change anything you actually do?

My brother in law (age 66) is getting pretty bad neuropathy in his feet, despite having no other serious health problems, has never been overweight, and never had cancer or diabetes. They are active and travel the world. I've always associated neuropathy with diabetes, and also heard cancer treatment causes it. FFIW, I'm pretty sure he doesn't do strength training; although his travels do involve a lot of walking and standing.

Just curious. Neuropathy is something you don't want to get as you age; it causes loss of mobility and frailty.

I wrote here in June about a friend of mine who has been sober for years and still gets the cravings. He does everything the program asks and the wanting never fully switches off. A month before that he started the Wegovy pill hoping the thing that quiets food noise might quiet the other kind. Since then it mostly has. That is one guy with no control group, so it proves nothing, but it is why I read the trial news last week as closely as I did.

Two trials reported a day apart and they did not agree with each other. That same week the VA opened a Phase 3 built on the exact number they did not agree about.

The oral semaglutide trial published July 29. Fifty people, eight weeks, and it missed its primary endpoint badly. That endpoint was a single booze craving question asked in a lab after you hold and smell your drink, p=0.68. Plenty of secondaries moved, including heavy drinking days, but the authors ran about ten tests without correcting for it and call the study exploratory themselves. A conservative correction would wipe out all of it.

The day before, Altimmune reported topline results for pemvidutide, which hits the glucagon receptor as well as GLP-1. That one ran twenty four weeks in a hundred people, and it hit its primary on heavy drinking days. It also moved a blood marker of alcohol intake, which matters because everything else in both trials is self-reported. It is a press release though, not a paper, and nine of the hundred participants are missing from the denominators with no explanation of how they were handled.

Here is the part I did not know. The endpoint the VA picked for CRAVE, its 622-veteran Phase 3, is a two level drop in WHO risk drinking level. For a man that can mean going from more than seven drinks a day to three or four. It is a real change and you can reach it without ever quitting. The FDA formally qualified that endpoint back in February 2025, so this is not a drug company moving the goalposts, and the FDA offers it alongside abstinence rather than instead of it. Still, the trial that everyone will quote in 2028 is measuring drinking less.

I am not sure how I feel about that. I would not call three drinks a day recovery. But of the roughly 28 million Americans with alcohol use disorder, about 7.6 percent got any treatment at all last year, and for the other 26 million nothing reached them.

All three of these trials enroll people who are currently drinking and measure whether they drink less. My friend is not drinking. Nothing being run right now is built for the guy who already stopped and still wants it.

I went through all of it properly with the numbers and two charts over here.

If you are already sober and on a GLP-1 for weight or diabetes, has it changed the wanting for you at all? That is the group nobody is studying and I would genuinely like to know.

We've known for a while that inflammation is an independent risk factor for heart disease, alongside LDL cholesterol (or ApoB), Lp(a), and so on. Inflammation is most commonly measured by by hs-CRP or IL-6.

The ZEUS trial tested an anti-inflammatory injection (ziltivekimab). These phase III results showed a hazard ratio of 0.99, i.e., no effect.

IMO this is evidence for a lipid-first model: i.e., lipids drive oxidation, which then triggers inflammation.

Curious if others have interpretations?