glp1guide

This is a fantastic idea and could do a lot of real good. Any plans to get your hands on a distribution agreement for small molecule or peptide oral formulations?

I write a GLP1 newsletter and would love to learn more about what you’re building and how you see the landscape.

Reta looks like it will make it out by early next year but I personally think they’ll squeeze in to end of this year — there will likely never be a undersupply of GLP1s again and I wonder if the customization loopholes will hold (Lilly will certainly fight Reta compounders harder than they have others), interested to hear your thoughts and chat.

I keep track of GLP1s and write a lot about them (looking for negative side effects, research results, etc) and it is amazing how potent retatrutide is. It’s not simply a matter of “more agonists, more better” but it looks like Eli Lilly has really cracked it.

There is a large enthusiast community of the body building variety (who are usually first) who are already performing a bit of an unscheduled human trial and I have to say the results are amazing. We have both injectable retatrutide and pill form retatrutide to look forward to (pill form is unannounced but I have a hunch!).

> I'd love to see more research around this.

Looks like we posted around the same time, but see:

https://news.ycombinator.com/item?id=46945756

No one knows of course, but it's looking likely -- anecdotal data is piling up.

That said, there are some that have reported it also lessens desire for things they want to desire.

Did a writeup on this back in summer '25:

https://glp1guide.substack.com/p/glp1s-vs-addiction-a-quick-...

Paywalled so direct links to notable papers through the years below:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8517504

https://pmc.ncbi.nlm.nih.gov/articles/PMC8820218

https://pubmed.ncbi.nlm.nih.gov/36031011

https://pmc.ncbi.nlm.nih.gov/articles/PMC10684505

https://pubmed.ncbi.nlm.nih.gov/39764175

https://pubmed.ncbi.nlm.nih.gov/39032839/

https://www.science.org/content/article/obesity-drug-cuts-op... https://www.statnews.com/2024/02/17/opioid-cravings-glp1-wei... (The science.org article is paywalled IIRC)

https://pubmed.ncbi.nlm.nih.gov/39535805/

https://pubmed.ncbi.nlm.nih.gov/39937469/

Addiction comes up in anecdata all the time so I've written about it a few times but these papers are a good place to start to find more rigorous data points.

Eli Lilly has taken to calling GLP1s "anti-hedonics" as well

Just stating the obvious -- losing weight (and likely lowering HbA1c/having other benefits) for 18 months is probably infinitely better than never losing weight at all.

> Of the 308 who benefited from tirzepatide, 254 (82 percent) regained at least 25 percent of the weight they had lost on the drug by week 88. Further, 177 (57 percent) regained at least 50 percent, and 74 (24 percent) regained at least 75 percent. Generally, the more weight people regained, the more their cardiovascular and metabolic health improvements reversed.

So weight loss was actually maintained for most people -- the hard part is finding a healthy daily lifestyle which can maintain the drastic effects of GLP1s.

This information isn't new -- weight regain has been studied before and I've written about it before:

https://glp1.guide/content/do-people-regain-all-the-weight-l...

The missing piece to this article is just how bad the alternative is -- never having the cardiovascular and metabolic benefits is clearly not the best strategy (and if simply changing patterns was so easy, people would have done it already).

GLP1s don't work for everyone but they're pretty close to miraculous in effect given the balance of positive and negative side effects. Making GLP1s cheaper & more tolerable then figuring out how to actually deal with the complex web of how to keep the weight off sustainably for most people seems like the right way forward here, not avoiding potentially life-saving medication because you may not be able to get off of it as fast as you want (if you can afford it).

BTW, there is already generic Liraglutide, and legal workarounds for getting compounded Semaglutide that already mean no one pays the $1000 that was in the zeitgeist a while ago. Even Lilly Direct and similar outfits from Novo sell for $500/month, with the $150/month pricing coming soon[0].

[0]: https://glp1guide.substack.com/p/negotiations-are-underway-f...

Like others have mentioned, liraglutide already exists as a generic! It's not as good as Semaglutide or Tirzepatide, but.

Also, a lot of people are still getting compounded GLP1, to the chagrin of Eli Lilly and Novo Nordisk.

Separately, 2026 is about to completely change the pricing of this stuff, not even taking into account the Trump administration's recent efforts. The price of injected GLP1 is going to implode due to patents lapsing in Canada and other places -- and for the pill forms that come out soon it looks like the Trump administration is keen on keeping prices for that low as well.

At this point most experts lean more heavily on the effect of GLP1s in the brain rather than delayed gastric emptying -- it's more of a brain drug than anything else which is why it works so well.

Basically, the gastro-intestinal side effects are the biggest issue, along with CVS (not the store) and possibly eye problems.

That said, the negative side effects look to be incredibly rare and manageable (including via stopping treatment) -- and the positives are quite tremendous.

It's not a magic drug, but it is the first of it's kind with such a skew to the positive on side effects.

A bit late, but thanks for noting this -- I had no idea that this workaround was so well established. I don't often dive into concrete suggestions on how to obtain GLP1s because of how it could be perceived, but maybe I've underestimated how many people know how to do this right now.

Absolutely -- certainly in their biggest markets they'll be able to protect those patents.

Both companies have thus far been unable to really stop compounding pharmacies and/or gray market suppliers from replicating though, and price negotiation with the government is definitely going to happen (Trump recently announced wanting $150 GLP1s, Novo's lawsuit against medicare price negotiation failed)... I do not have much faith in their ability to protect their pricing power for very long, which unfortunate for them is probably what's best for humanity and is very well known at this point.

Not only that, there is a legitimate raft of companies lining up to make generics.

There’s one wrinkle though, legally importing prescription drugs from Canada isn’t really allowed in the US/UK AFAIK. HIMS is probably feverishly figuring out how to do that right now.

Shameless plug:

https://glp1guide.substack.com/p/another-glp1-generic-launch...

Also somewhat separately, injectable GLP1s are about to be upstaged by oral variants — orfoglipron for Eli Lilly and the Wegovy Pill for Novo.

Yeah weirdly enough they’re only taking NAION and gastroparesis cases. Do you know by any chance why that is?

The NAION link is tenuous (research was inconclusive, I have written about this before[0]) and gastroparesis is a known side effect.

This was a great chance to learn the name of the vomiting symptom though — will be looking more into “cyclic vomiting syndrome”

[0]: https://glp1.guide/content/glp1s-and-the-link-to-blinding-di...

That sounds like a terrible experience, sorry you and the wife went through that and somehow the negative side effects STILL persist. This is honestly the first case I’ve ever heard of such an adverse effect.

GLP1s are certainly not for everyone, and if she had that reaction on a starting dosage then it certainly is obvious stopping was the way to go.

That said, for the vast majority of people though, GLP1s are likely going to the key to living longer and carrying less weight (including into old age). At this point, the research is behind the drugs being useful for the vast majority of the population, and the literal millions of people taking these drugs do not seem to be running into such horrific side effects, especially ones that continue after stopping the drugs.

Would you mind sharing which GLP1 she was on? This actually sounds like something that should be more widely known. Throwing up forever is quite a crippling side effect, and since GLP1s are more recently considered primarily brain drugs, I wonder if it triggered a persistent chemical imbalance.

Do yourself a favor, and just take GLP1s instead (after talking to your health care professional). The research on the effects is plentiful, they're incredibly effective, and next year by next year you'll have very effective FDA approved (for weight loss) oral GLP1s to take.

Losing weight is almost solved at this point, I'd post links but at this point the substack I run is heavily paywalled -- the research is out there and not hard to find with a quick search.

Sorry a bit late here, but the numbers for CagriSema are actually not as good as Retatrutide's were. Unless I'm missing something:

Reta 8mg -22% body weight at 48 weeks

CagriSema -20.4% body weight at 68 weeks

CagriSema has been on my radar for a while, and it's certainly going to be exciting.

Here's a slightly better link for the curious:

https://pubmed.ncbi.nlm.nih.gov/40544433/

https://clinicaltrials.gov/study/NCT05567796

This is a valid concern but the subreddits I'm thinking about are not quite that -- no one is selling or trying to push you to some distributor, it's a lot of the bodybuilding/peptide crowd. More like walking into a classic forum thread than modern reddit. You can tell by the comments.

Interesting -- would love to hear anything more you have to share! The research numbers would suggest that Reta was top, results wise.

Any other significant differences you felt/noticed? Also, do you find Tirz to be an imiprovement over Sema?

Well for one they're flying in the face of the patent protection in place for Retatrutide -- that said the legalities around distributing prescription drugs or unknown chemical substances is murky (hence "gray" market).

Well there's no reason, except it's even more effective.

And 100%, using Retatrutide right now is illegal/not a good idea. It is super risky.

That said, anecdata from people with that risk tolerance is certainly worth looking at.

> If Eli Lily is the only producer, how is the gray market being supplied? This makes no sense...

It turns out enterprising chemists and pharmacists are capable of reverse engineering.

I don't think it's that hard to figure out how someone might do it -- imagine having to reverse engineer food you've received, given many samples. Imagine some of those samples might have "fallen off the back of a truck".

> That being said, I'm waiting for oral GLP1 agonists. Injections are a hassle and gray market ones even more so

This is really going to be the second leg of adoption and will catapult GLP1s even further IMO. Rybelsus has not really seen a ton of popularity compared to the injections. That said, Orforglipron is Eli Lilly's upcoming oral GLP1 and it looks to have really good results:

https://glp1.guide/content/updates-from-maritide-orforglipro...

It's completely illegal -- the drug is not for sale, obviously is not FDA approved, and is not manufactured anywhere, the only safe/legal way to get it is a via an ongoing trial:

https://trials.lilly.com/en-US/trial/580035

As one might imagine though, capitalism found a way. A LOT of compounding pharmacies are now very good at manufacturing GLP1s (not necessarily the case that the knowledge transfers, but I imagine networks/knowledge sharing groups do), so gray market has sprung up to supply adventurous people with Retatrutide.

I'm incredibly interested -- it's just not legal yet, and the drug is in trials by Eli Lilly:

https://trials.lilly.com/en-US/trial/580035

Just to be very explicit here, my profit incentive is selling newsletter subscriptions not selling drugs, if that was the worry.

The thing is that we just won't get any high quality data from the official trials for a very long time, but it looks like it's going to be even better than Tirzepatide which is the current king.

Outside of being simply well-researched, the best thing about GLP1s is that they are safe enough to be taken by millions of people (and they are) -- so anecdata is valuable. It's valuable to know what the "first adopters" are doing and what they're finding and what trends show up there.

[EDIT] Maybe I'm reading the comment wrong -- to answer with good intent assumed, I think GLP1s are basically the answer to obesity on any reasonable time frame.

GLP1s not the answer we wanted (most people would have preferred better food ingredient regulation, more people choosing healhtier lifestyles, etc), but it's the solution we're getting, it seems like.

Right now the only thing I think most can do to help this wave along (unless you're a drug manufacturer, insurer, or politician) is to share as much information as possible on positive and negative side effects, how the drugs work, why they work, etc.

[EDIT2] - Clearly there was no positive intent. I guess it's my own fault I took the time to seriously respond.

The original comment (now edited) was a question about me seeming like a disinterested third party and asking why I am discussing a gray market drug.

If you think Ozempic (Semaglutide) is good, Retatrutide is going to blow it out of the water:

https://glp1.guide/content/a-new-glp1-retatrutide/

Currently the only people experimenting with it are the underground gray market peptide enthusiasts (you can find them on reddit and elsewhere), but the results are quite intense.

[EDIT] Just to be clear, gray market Retatrutide is illegal, I'm not encouraging you to buy it or do even take GLP1s in general. The point is that we have a preview of anecdata from people (with obviously high risk tolerance) taking this drug.

Nope, because the change is actually in the brain.

https://glp1.guide/content/research-on-glp1-signaling-in-the...

https://glp1.guide/content/research-suggesting-glp1-is-a-bra...

https://glp1.guide/content/are-glp1s-primarily-brain-drugs/

This is the killer feature of Semaglutide and GLP1 Receptor Agonists widely. They were originally commonly thought about as digestion-slowing, and while that is part of it, the real change is that it's a brain drug.

Oh also, on whether people gain back the weight:

https://glp1.guide/content/do-people-regain-all-the-weight-l...

tl;dr - most people (i.e. over 50%) do not.

Nope! It won't be, because capitalism.

In 2026, patent protections that lapse are going to cause a tidal wave:

https://glp1.guide/content/novo-nordisk-patent-protections-l...

For context, the previous calculus was:

https://glp1.guide/content/patent-expirations-for-glp1-recep...

(~2033 for the US)

Theoretically, the tidal wave of generic Semaglutide wouldn't hit the US or EU due to patent protections there... But see the aforementioned note about capitalism.

Note that there is already generic Liraglutide as well:

https://glp1.guide/content/another-generic-liraglutide-launc...

Tirzepatide (Mounjaro/Zepbound) > Semaglutide (Ozempic/Wegovy/Rybelsus) > Liraglutide

But having any of these available is a step change.

> (...who might be the target market - being overweight might be a disease of affluence)

This might be true on the margin but is mostly untrue these days. The lack of access to healthy unprocessed food and the free time to exercise are becoming increasingly problems for those who are NOT wealthy.

> I'm not a fan because it's expensive and once you go off of the drug the weight comes back on (at least from what I've read). That's not a trade-off I want to take lightly.

This isn't true

https://glp1.guide/content/do-people-regain-all-the-weight-l...

The rest of the incorrect points other people have basically covered, so won't repeat.

Is teaching the discipline lesson worth the shorter life people would live without this medication? Maybe we could find another way to teach people discipline that doesn't maintain a threat to their health?

> I don't find any of that unreasonable to me. I'm saying this as a type-2 diabetic who could stand to lose a lot of weight.

Gonna be incredibly blunt, but talk to your doctor and get on GLP1s. Take a low dose if you want.

GLP1s are incredibly well researched and effective. Imagine dying of a heart attack early because you refused to properly research effective, low-risk medication that is being used by millions and recommended by professional organizations and doctors widely. Real Steve Jobs energy.

We also like to keep track of all the bad ones too[0] (tl;dr they're actually pretty reasonable).

It's amazing what lowering inflation, reducing body weight can do to the body. It's almost becoming irrelevant that GLP1 Receptor Agonists were originally for type 2 diabetes (i.e. reducing HbA1c) -- the effects are profound. Kidney health, heart health, overall health, longer lives -- all for the low low cost of gastrointestinal problems (which can be serious, especially if dehydrated).

[0]: https://glp1.guide/content/are-glp1-side-effects-all-the-sam...

Don't worry, GLP1 RAs are nothing like those other drugs. In fact I'd really challenge you to examine even one of the correlations there, the scale of research, use, known side effects, effectiveness is completely different.

The idea that people might only benefit from something like Ozempic a little if they were doing some other intervention before is irrelevant, because no one is doing those other interventions. Requiring people to suffer before providing useful, known-safe and well-researched medication is silly.

Medication is technology.

I agree with this take but want to add that once everyone is doing it, these opinions will change drastically and everyone will pretend like they were never against it.

Another interesting question is where do people go from there? What is the next signal of virtue, I wonder.