Drug Development Failure: how GLP-1 development was abandoned in 1990 | Hacker News Reader

Drug Development Failure: how GLP-1 development was abandoned in 1990

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152 pointsbookofjoe166 comments

The catastrophic failure of FenPhen also cooled the industry's interest in obesity medication.

Part of the problem is that it is so slow and expensive to bring a drug to market, which encourages risk aversion. It'd be interesting if we found better regulatory and financial engineering strategies here. There is a gigantic hidden graveyard of people who have died due not having access to medications that could have been produced and approved (which may have even been massively profitable) but were it just didn't make sense to try with today's incentives.

Maybe FDA works in classes where class 0 is entirely experimental and only available to terminal patients, class 1 is shown to be safe in animals and approved only for extreme cases, class 2 evidence of safety in humans and some evidence of efficacy, and class 3 is what we have today.

That just pushes the moral hazard down to the providers and patients.

Given how big the industry is that peddles mostly bullshit vitamins and supplements, I think society is best served by a conservative FDA.

Classes 0-2 could be experimental, non-commercial approvals that can be used as stepping stones to get long term data but not sold for profit.

>not sold for profit.

The only way to ensure no profit would be to provide them for free. Which, granted, may be good still for the pharmaceutical companies to lessen the costs for approvals, but Hollywood accounting makes it impossible to have any price depend on profits, because profits are more an accounting fantasy than a fact.

Ring 0 for drugs?

I personally like the idea of a "accredited ingestor". You get a certification indicating you understand enough about drug development and associated risks and then you are allowed to decide for yourself what you are willing to take.

In general I am a big fan of FDA approval just becoming a stamp on a product like the Nintendo Seal of Approval and letting consumers and insurers decide what they make of it, but that would never fly

I write software for this industry, the thought of not involving the FDA genuinely scares me.

I do admin work for a pharma-related company. I would never want to be in charge of verifying with my own body what treatment is safe and/or effective.

Drug development and clinical trials are expensive for a reason. Not doing them in an orderly manner is more expensive.

Fortunately, the position would be voluntary.

You might be a big fan of the work the FDA does to keep us safe in light of past industry abuses, but keeping good drugs off the market - whether by outright fiat or by making them too expensive to develop, test, and deploy -- also has a terrible human cost. It's not clear that the FDA has found the right balance between risk reduction and upside potential.

Drug development is a conservative industry. Even with researchers/companies/FDA all doing their best to develop good treatments, there are still many drug failures due to efficacy or safety.

Being more lassiez faire is going to lead to direct harm of some patients. Is it a worthwhile tradeoff vs potentially addressing some unmet need is a tough calculus.

What criteria would you suggest to measure in an effort to make it clear that the FDA has >found the right balance between risk reduction and upside potential?

I don't think there's a good answer to that question, unfortunately. What we're doing now seems to be working for most people most of the time, but it'd be absurd to think there's no further room for optimization. And it seems unlikely that the best approach is more restrictive regulation, given that extremely-useful drugs are going undeveloped for decades.

So... that leaves more flexible regulation as a worthwhile approach going forward. I like the idea of making limited human trials easier to carry out and less costly in general.

Not OP, but it's certainly not by leaving drugs unapproved in the US that have been in wide use in Canada, England, Japan, etc for years (and in some cases decades). The incentives are so misaligned for the FDA that the bias for inaction is enormous.

I also find it a bit patronizing that a federal agency determines whether or not a drug they've deemed safe has enough upside potential for me. That's a value judgement I'd like to make for myself.

Sorry if this sounds harsh, but the FDA's inability to approve drugs inside of a decade has personally impacted me quite a bit.

One far less scary version is to allow drugs approved by other reputable agencies (EU, Japan, UK, maybe) to be used in some limited capacity in the US.

From what I've heard from some friends working with regulatory agencies worldwide, this is currently the case or is about to happen. FDA-EMEA-(whatever the japanese regulatory agency's called) have agreements for treatments approved in one of the other two agencies to be easily approved.

There is a history of these agencies later withdrawing approvals and FDA conservatism protecting US healthcare consumers. The same pattern applies with these other agencies not basing decisions on FDA approval. Overall, the combination of approval authorities and global surveillance delivers the best results by ensuring the broadest coverage and continued research.

The rarely understood tradeoff in this arena is that no matter what you do, your decisions kill people!

Everyone understands the case when (A) you approve something that later turns out to kill people.

The other case (B), when you don't approve something that would have saved lives is much less understood, but those people are just as dead as those from case A.

One famous case B is when the FDA only approved beta blockers 17 years after other major countries. This cost ~10k US lives per year, or ~170k lives total.

Because A errors produces headlines and scandals, while B errors are just the normal deaths we are used to, the FDA is heavily incentivized to minimize A errors, regardless of the B error rate.

The incident around thalidomide is basically FDA mythos at this point.

We all love a good trolley problem

https://web.archive.org/web/20210125231725/https://blog.jaib...

Not just lives also DALYs from glaucoma.

An important thing to remember when thinking about this thing: the downside of approving a drug that was dangerous is bounded: it kills people or causes some unexpected side effect and then it gets pulled. Meanwhile, the downside of failing to approve something that could have saved/improved lives is at least potentially unbounded: if it never gets approved that's the entire futures worth of humanity who is unable to take advantage of it (although admittedly I'd like to imagine that _eventually_ tech will improve to the point that we either figure out we should approve the drug and/or invent something else that obviates the need).

The point is that case B is both harder to notice and at least potentially _much_ worse than case A. And it's the case that the FDA currently errs towards.

And I hope we've all seen Dallas Buyers Club which showed the real, historical problem of drug approval being slow-rolled because it was killing a controversial minority

I believe European regulators approved Boeing 737 Max on this principle. And in turn FAA approved it because Boeing said it's safe an compliant.

This is exactly what I'd do if I was an accredited ingestor. I'd look if I trust countries that already approved it and decide based on that.

that already exists, it’s called doing research chemicals. You can do survodutide or whatever other next-gen drug right now and “do your own research” on the supply chain and efficacy and safety. They’re everywhere and functionally the FDA can’t stop you.

should that be officially legitimized in any way by the FDA? fuck no.

As soon as you break down the barrier in any way, companies will spring up exploiting it and promising miracle cures etc. even if you want to do RCs the FDA keeping a minimal wall there benefits you.

Agreed. RCs were great when you had to know what you were doing to get them. It only became a problem when cathinones and synthetic cannabinoids started being sold at headshops.

It is a philosophical question: Would you rather people die due to taking a harmful compound or die due to lack of access to something that may have helped them.

Access to experimental treatments also opens up more perverse incentives where desperate people are likely to try anything.

You can have a class of drugs allowed if you're going to die anyway.

People in that state are highly vulnerable to fraud. See https://en.wikipedia.org/wiki/Amygdalin

They are also vulnerable to dying. They should be able to try whatever drug they need and the government shouldn't be allowed to stand in their way.

The pharma companies are not clamoring for a huge surge in compassionate use (emergency use of unapproved drugs) either.

Who is going to pay? Early stage drugs are still figuring out their manufacturing process, and quantities can be extremely limited. Say you give drug X to a sick patient and they die, what then? Was it because of the novel drug? Not a favorable position to have more deaths associated with your treatment. Can you draw any data from these patients to inform further trials? Also complicated because end stage patients have already exhausted other options and the interaction with other compounds can make disentangling this harder.

Death is certain, getting ripped off less so.

Sure, that's why it should still be regulated, just less than drugs for everyone else.

In particular drugs should still be checked for efficacy before getting on that list.

But requirements for long term safety and side effects when people die in a year should be relaxed.

It feels like the odds a drug is perfect and a few years too late for you unless you skip the tests is exceedingly low compared to the odds that a drug will not pan out or might even be unsafe.

The perverse incentives is also a very real issue.

With drugs there is also the option that something is not harmful, but also not effective and thus lead to something effective not be taken...

https://en.wikipedia.org/wiki/Trolley_problem

How is this the trolley problem for someone with a terminal disease? I assume the sick population are the people in the trolley and the experimental patient is the person on the track? In this scenario, by not pulling the lever you just extend the life of the people on the trolley to the end of the ride for a dangerous drug. Where as, pulling the level could save the life of the person on the track and the people in the trolley if the drug is successful.

What am I missing? For non-terminal diseases, it's a bit murkier, but still I don't follow the analogy.

Some people do go into remission from a terminal cancer diagnosis, either because the diagnosis was wrong or because they live long enough for an approved treatment to come on the market. Also, that you have terminal cancer doesn’t say anything about how long you’re going to live. You can live for many years with terminal cancer.

I do think we’re overly cautious with drug approvals and I think we should be more open to leaving the decision to patients and their medical teams, but it’s not as simple as saying someone’s terminally ill, so just do whatever. Reducing it down to the trolley problem makes it seem much more black and white and immediate than it really is.

If the public could be made aware of the millions of Americans who have died from FDA being so restrictive, things would change quickly.

I don't think that has any chance of happening though.

The public is aware of the millions of Americans who have died from the FDA being so lax.

Can you provide some examples?

Thalidomide

The therac-3

That one alzheimers drug a lot of people were pissed about cause it didn't work and was expensive.

Those killed millions of people?

If the goal is to shock people into thinking a certain way, 20,000 deformed infants has more or less the same shock-value as 1 million deaths.

(Obviously talking about Thalidomide here)

Thalidomide was used and approved around the world, not just in the US. It’s an interesting example of something but not millions of deaths.

But I get a sense that the original poster isn’t sincerely interested in talking about the complex question, how should the FDA regulate drugs?

One thing’s for sure: High drama personalities have always had a tenuous understanding of the facts behind their “shock” and outrages. Or maybe one of the commenters has learned a valuable lesson about copy and pasting from chatbots.

Speaking of factual drama, Thalidomide was not approved in the US during all the drama in the 60s.

It has since been approved for cancer where its benefits outweigh the side effects, but it doesn't negate that the FDA prevented harm to babies by blocking it in the 60s.

Thalidomide was not approved in the US until long after the birth defect scandal, FWIW.

The FDA famously didn't approve Thalidomide, which meant only 17 people were affected in the United States. https://en.wikipedia.org/wiki/Thalidomide#History

(I don't think this affects your argument directionally, but worth noting.)

>(I don't think this affects your argument directionally, but worth noting.)

Aside, but this is high class discussion culture I haven't seen on the Internet in a while.

How could getting the facts not just wrong, but backwards, not affect the argument directionally? He got the direction wrong!

That Thalidomide was not approved by the FDA, while it hurt thousands of babies around the the world is probably a big reason that FDA has been very restrictive in the 60 years since, and often bans drugs that are available in the rest of the world.

The Therac-25 (where did the -3 come from?) killed four and seriously injured 2.

I supposed 6 is kind of like 1 million, for large values of 6.

Yeah -- that's the problem. You can't make the right decision when you only look at the costs of a yes but never the costs of a no. Both matter!

Politicians can puff themselves up by only grandstanding about the former -- but that doesn't make for good policy!

Or even a graduated approval scale with categories of limited liability, etc.: For example, when Vioxx and other cox-2 inhibitors were withdrawn from the market, some employees really stocked up on the reps' samples. And in the present it is said that some vets prefer the off-label-for-humans options per [0]

[0] https://www.merckvetmanual.com/pharmacology/inflammation/non...

I found some phentermine tablets next to my neighbors trash bin, still in the blister pack. So I thought maybe if I snorted one I'd get high. I didn't. Just got really jittery and nauseous then puked on a tree while a woman who looked like she worked for the government walked by (this was in the capitol city of another country). Would not recommend. And then I accidentally brought it back with me through customs.

So just a normal weekend then?

It wasn't that abnormal for my early 20s. I'd never imagine doing anything like that now.

Not knowing what FenPhen was I checked the wiki page and wow, it looks remarkably similar to those sketchy amphetamine analogs people sell on the internet like 3-FA, of course selling that as an anti-obesity drug was going to go sideways.

Norway is big on oil and gas. One of the incentives we give out is a cost sharing model for the initial exploration phase.

Not sure how that would translate, but an important factor would be that the health care providers (private or state) have some say in what kinds of illnesses need better drugs.

That's a nice incentive but Norway's tax policy is a major disincentive to any new venture. I'm currently helping a founder relocate his Series A company as a result.

https://www.bloomberg.com/news/articles/2024-05-08/norway-ri...

I believe that that is more of a temporary thing. A lot of rich people have been avoiding taxes by moving to Switzerland. They run a company in Norway for several years, then move to Switzerland when things are profitable and they want to avoid paying their taxes to society.

We pay tax on dividends in Norway, but if your company doesn’t pay out any dividends for 10 years then you don’t pay any taxes on them until the day you take the money out of the company. So you can run a company in Norway while paying quite little in taxes, then move to Switzerland and pay yourself all the dividends that have accumulated over the years. After 5 years you can move back and not have to pay a cent in taxes.

The new tax laws are just a temporary blocker that incentivises any current owners to move out of Norway move before the new laws come into effect.

How is it temporary?

The effects that we are seeing now are temporary. Once the exit tax is in place there are no incentives to quickly leave the country.

What permanent effects it will have on the overall startup business is still to be seen.

That's incorrect based on my experience. The law exposes startup founders to large tax liabilities immediately after a financing. We've hired some of the top lawyers in Norway and the consensus is the only alternative is to relocate. There's plenty of articles about it in the Norwegian startup press.

Even better, you have to pay Norway on your unrealized capital gains but they won't credit you on future losses from the startup. Essentially they have socialized the profits and privatized the losses.

You are mixing two different taxes. The article is about the new exit tax. The other relevant tax is our wealth tax.

You don’t sound like a person who likes taxes much. In Norway they are very important since we have good infrastructure in most areas such as telecom, roads, trains, airports, electricity and water. We also have great healthcare. And lots of benefits for parents with children.

> The catastrophic failure of FenPhen also cooled the industry's interest in obesity medication.

In the 90s, more Americans were willing to have an eating disorder to stay thin compared to today.

Fen-phen was an obesity medication that caused valvular heart disease and pulmonary hypertension. If you've never heard of fen-phen, check out this article from Sept. 23, 1997 in the New York Times: https://archive.is/ottWQ

Wyeth set aside $21.1 billion to cover the lawsuits. https://archive.is/k3Go4

It was kind of a big deal. Not many people younger than ~30 have heard of it for some reason.

Acquired had a great episode earlier this year that really connects with this. They talked about how Novo Nordisk stuck with GLP-1 research for decades, even when it didn’t seem like a sure thing.

A big part of that was Mads Krogsgaard Thomsen, who pushed for GLP-1 research at Novo even when he faced a lot of skepticism and wasn't always treated well for it. Compare that with MetaBio—mentioned in the study—where Pfizer pulled the plug early and missed the boat entirely. Novo’s persistence, especially Thomsen's, led to Ozempic and Wegovy

So much of this is hindsight bias though. There were no shortage of people with ideas and companies pursuing obesity drugs through a number of different pathways. Only in hindsight does it seem "genius" that Thomsen persisted and succeeded where nobody else did. But there are dozens, hundreds, of other smart people who were pursuing other pathways who did just as much stubborn work but didn't get a result. That's just pharmaceuticals.

Take, for example, another high profile disease - Alzheimer's. First there was the beta amyloid theory, then there was the p. gingivalis theory (this one was talked about so highly on this very forum, but ended in an equally high profile failure* of a pivotal clinical trial by Cortexyme). Now there are viral and metabolic theories. Each of these theories have a few dozen companies and armies of PhDs stubbornly pursuing a miracle drug, but so far it remains elusive.

* We also like to talk about "failures" of clinical trials, which is technically correct language, but evokes in the public imagination the wrong idea. A clinical trial failure doesn't mean there was something wrong with the idea or process (long before it ever gets there, a drug candidate would have been proven to be very effective in lab tests and animals). It's just that 90% of clinical trials don't end up working due to complex disease pathways and numerous unknown factors. It would help if we talked about "negative proofs" (i.e. proving something doesn't work is also valid), but it's not quite as catchy.

> First there was the beta amyloid theory

First? Isn't the beta-amyloid cabal still blocking all Alzheimer's research unless the researchers find a way to even tangentially support that long disproven theory?

It was not a cabal. It was scientific fraud.

Karen Ashe and Sylvain Lesné at Minnesota published a fake paper that redirected billions of research into the trash bin. https://www.science.org/content/blog-post/faked-beta-amyloid... Amazingly both still have their jobs for life, both still publish, Ashe is still a member of the National Academy of Medicine, both are still getting grants.

This is a mischaracterization of the scope of the fraud. Lesné clearly committed fraud, but his work was not foundational. The fraud did not "redirect billions".

Yes it very much did lead to billions of wasted dollars and that's if you count us public funding alone. Tens of billions of you count non us and private funding.

From https://www.science.org/content/article/potential-fabricatio...

The Nature paper has been cited in about 2300 scholarly articles—more than all but four other Alzheimer’s basic research reports published since 2006, according to the Web of Science database. Since then, annual NIH support for studies labeled “amyloid, oligomer, and Alzheimer’s” has risen from near zero to $287 million in 2021. Lesné and Ashe helped spark that explosion, experts say.

The paper provided an “important boost” to the amyloid and toxic oligomer hypotheses when they faced rising doubts, Südhof says. “Proponents loved it, because it seemed to be an independent validation of what they have been proposing for a long time.”

This is also a fun read https://www.nytimes.com/2024/07/07/opinion/alzheimers-missed...

From your description, it sounds like a large complex ecosystem (of which Lesne and Ashe were important parts) redirected billions. I think it’s a bit overselling it to say that their results alone redirected billions

As unavoidable mentioned, there are viral theories.

In Science, from July, "Can infections cause Alzheimer’s? A small community of researchers is determined to find out. Following up tantalizing links between pathogens and brain disease, new projects search for causal evidence", https://www.science.org/content/article/can-infections-cause...

Yet another reason to get your shingles vaccine.

I mean, that's the point - in pharmaceutical sciences there's _so much noise_ including fraud that it's really only easy in hindsight to pick out "the guy" who was the "genius". It's hard to take one story like this and make it a repeatable success.

> So much of this is hindsight bias though. There were no shortage of people with ideas and companies pursuing obesity drugs through a number of different pathways. Only in hindsight does it seem "genius" that Thomsen persisted and succeeded where nobody else did. But there are dozens, hundreds, of other smart people who were pursuing other pathways who did just as much stubborn work but didn't get a result. That's just pharmaceuticals.

Exactly.

There are plenty of examples where the opposite choice was made - argue for continued development despite high uncertainty.

The CETP inhibitors is a good one. Pfizer flushed several billion dollars down the drain with the decision to push it through phase 3.

https://pubs.acs.org/doi/pdf/10.1021/acsptsci.9b00048

^^ Here's an article written by Lotte Knudsen, referenced in the original post, that further tells the story of how GLP-1 was first developed into a drug (as liraglutide) and approved for human use. There were a lot of false starts and additional practical problems that needed to be solved in order to yield a viable medication.

After reading the OP I was surprised to learn that Novo Nordisk picked up the research only a couple of years after GLP-1 was abandoned by Pfizer, after which it took 5 years to develop the initial medication and another 12 years to make it through FDA approval. Even after all that, the primary indication was for diabetes. It took another 7 years for semaglutide to make it through approvals and bring GLP-1 into the public consciousness.

When you consider the amount of time involved, and the sustained investment required, it's difficult to fault the execs at Pfizer for their decision to shut the project down. Obesity wasn't nearly as prevalent then as it is now, and it seems likely they had funded the startup specifically because of the author's prior research into nasally-administered meds. It's even possible that the shutdown decision had little to do with the primary area of research.

Since this is YC, it's worth looking at this from the perspective of a failed startup that made several mistakes. In particular, the authors take the view that Pfizer killed their startup. But buried on page 333 is the real reason. And if you're going to start something, this is worth learning from.

The founders gave up their ability to control their company when they agreed to become a wholly owned subsidiary from day 1. There was no need for that. And no one would ever tell you to do this today. This was done to be nice and collegial, something that broke down the moment money was involved.

The company they created this fatal alliance with had other priorities, their own drug development pipeline.

Then they got investors who were profiting from the status quo, and for whom a new drug didn't look great.

But the real reason is that the founders half-assed it. None of them left their academic jobs. They didn't have any skin in the game. Oh well, they walked away with a little money. Had the founders done what YC tells you to do, commit, this never would have happened. (bottom of page 333)

The whole article blames Pfizer and others for the failure of the startup. But it's really this last point that was the determining factor. The authors say there were confused by the buyout and just took it to move on. There would have been no confusion and no buyout if they were committed to the startup.

Even if you have the right idea, even if you are the right person in the right place, even if you're about to break through and change the world, you can fail if you don't commit.

>MetaBio went down because there were mistaken ideas about what was possible and what was not in the realm of metabolic therapeutics, and because proper corporate structure and adequate capital are always issues when attempting to survive predictable setbacks

Like many startup failures, funding issues and corporate structure were more pivotal than the progress made on the actual problem.

In 1990, Pfizer and CalBio subsidiary MetaBio abandoned GLP-1 drug development despite showing efficacy and holding patents. Pfizer misjudged the market for injectable diabetes drugs. CalBio redirected focus to a heart failure treatment. This decision preceded successful GLP-1 development by other companies by a decade. Novo Nordisk later succeeded with GLP-1 after research starting in 1992.

I guess they were aware how terrible and unpopular injections are for patients. These weren't the days of micro needles...

Source/elaboration?

This is just related that needle pens weren't available in the eighties. So people still were using single disposable syringes with needles which is more painful than using pens with micro needles which became available later.

>>how terrible injections are for patients

What is this belief founded upon?

Disposable syringes and detachable needles have been around for over 50 years. We had 6mm needles in the 80s.

Evolution of Insulin Delivery Devices https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261311/

This was just my understanding from seeing my grand-father 40 years ago having to drop his pants to use insulin syringe + needle, to the use today where you can lift your shirt and use a insulin pen in a couple of seconds.

The infection risk is real. What's the relative risk increase regarding death with (with, not from) Hepatitis B infection (not diagnosis, infection) between people who've never injected themselves with anything and injection drug users?

Personally I don't understand why so many people are so terrified of needles. Subcutaneous injection is so straightforward, even filling up the single use syringes yourself. I've done that once a week for the past nearly 7 years. But still, from talking with other people who use similar pharmaceuticals to me, so many of them are terrified of needles to the point they choose less effective routes of administration, even though they wish they could have the benefits of the injection route.

>I don't understand why so many people are so terrified of needles.

The fear associated with specific phobias is by definition extreme, unreasonable, and irrational. If you could understand it rationally, it wouldn’t be a phobia.

Personally I just don't particularly enjoy that type of pain... The type I associate with needles.

Maybe people just don't realize how little pain you can feel with a needle. I switched from the old formulation of humira to the new one (smaller needle and no citrate) and the difference is night and day. Before, I was dreading it every time (though objectively it didn't hurt that much), and after I sometimes don't even feel the needle.

Back then people would have gone to the doctor’s office for the injection. They would have done that because it wasn’t quite pay-for-service back then.

It's been 34 years, so the original Pfizer patents are invalid and can just be copied? Clearly the primary factor in inability to do that has to be regulation in bringing drug to market, right?

That article could be greatly shortened without losing any useful content. The author seems to be guilty of resulting, i.e. judging a decision by its ultimate outcome, rather than by the quality of the decision-making, considering knowledge and constraints at that time.

Also they've noticed oddly GLP-1 seems to prevent people from dying of covid

Doesn't prevent infection but rather death from it

https://www.nytimes.com/2024/08/30/health/wegovy-covid-death...

https://www.jacc.org/doi/10.1016/j.jacc.2024.08.007

GLP-1 => weight loss => decreased obesity, improved cholesterol, improved blood pressure, improved glucose control, etc. etc. => better survival rates (all causes)

There is no presumed clinically relevant mechanism for GLP-1s to be protective specifically against COVID death. It is simply protective against all death, of which COVID is a type. Healthier people are less likely to die, statistically. The same benefit can be (and is being) said about GLP-1s and heart attacks, heart failure, stroke, kidney failure, etc.

Rather arrogant of you to spew forth unfounded conjecture without even bothering to skim the high-level details of a six paragraph article.

> the protective effect occurred immediately — before participants had lost significant amounts of weight.

> the participants taking the drug were not healthier than the others, said Dr. Harlan Krumholz, a cardiologist at Yale and the editor in chief of the journal.

I understand how you came to your conclusion, however what you are quoting is journalism (and it is factually incorrect). I read the actual peer reviewed article.

The patients in the COVID group, _when they got COVID_ had already begun losing significant amounts of weight. The NYT article is 100% incorrect on this matter. See:

>>The change in weight between randomization and reported COVID-19 in patients who died of COVID-19 according to treatment was −6.4 kg in the semaglutide group vs −0.9 kg in the placebo (P < 0.001) group and −8.4 kg vs −1.25 kg (P < 0.001), respectively, in patients who did not die.

They go on to say that there is a correlation between obesity and adverse COVID outcomes:

>>There was an associated increased risk of respiratory decompensation and mortality in patients with COVID-19 and obesity16,17 and plausible biologic hypotheses associating obesity with adverse COVID outcomes, including impaired respiratory status, lower cardiometabolic reserve, or immune hyperreactivity or dysregulation.18

And they double down on the fact that the patients absolutely had weight loss at time of COVID.

>>Accordingly, it is plausible that the decreased risk of infectious deaths is caused by weight loss, which was 5 kg greater in patients assigned to semaglutide compared to placebo by 1 year, the average time to COVID-19 diagnosis after randomization.

I will leave you with the note that nowhere in the journal article do they make any claims whatsoever about semaglutide's effect on COVID outcomes. They exclusively discuss outcomes as related to metabolic health. Semaglutide is a means to an end. The means is weight loss. The end is better health.

I read the JACC article too, and thought the NYT claims were decently supported:

> The second unexpected observation was the lower rate of non-CV death with semaglutide vs placebo, particularly infectious deaths, including in patients with reported cases of COVID-19. The mechanism by which semaglutide is associated with lower CV or non-CV mortality is unknown. Weight loss improves traditional cardiometabolic and kidney risk factors,3 such as hypertension, dyslipidemia, renal function,26 and dysglycemia. However, the blood pressure and lipid reductions in SELECT with semaglutide were relatively small compared with those in dedicated risk factor–lowering trials, and the observed reduction in major adverse cardiovascular events is more than would be expected based on those changes.

You could absolutely be right that body weight is a lagging indicator, and these patients are getting a bigger improvement in systemic inflammation/their hematologic profile than weight loss alone would suggest… but running immediately to that conclusion is major hubris in my book. I don’t think it’s remotely implausible that there are one or more yet-unknown metabolic pathways tweaked by GPL1 agonists that could explain the effect.

I wonder if this has anything to do with blood sugar -- even before you start losing weight, you're eating way less calories (and probably less junk) and so you might have health benefits just from starting the regime.

> Though substantial progress was being made, Pfizer decided to pull support ... [t]he “gliptin” class of drugs peaked at annual revenues of around $10 billion and remains a major oral therapy for type 2 diabetes.

> Pfizer found other routes to remain successful (some, such as their mRNA COVID19 vaccine, also in-licensed from smaller companies).

> Even the biggest blockbusters can be dismissed ... by ... ambitious people, ... because ... ideas of how the market will react... .

> These same dynamics are undoubtedly playing out today [seemingly referring to previous statements on their COVID-19 vaccine], and it will likely take decades to determine just how costly some of today’s mistakes will prove to be.

> then the implication is that they released the mRNA vaccine because it too would increase disease (and thus avenues for profitability)

Sure, a disease that kills a patient very quickly is bad for business. Better for them to be alive and fall ill later on from a laundry list of profitable ailments.

Obesity was about 17% in the USA in 1990 and is now at an incredible 40%.

One wonders how many lives were lost by abandoning this in 1990.

Well, one could argue obesity has as much to do with deregulating the advertising of sugary cereals as a breakfast food for children in the 1980s as the non-existence of a $10,000+ shot that alters human metabolism!

Look at the historical rate of obesity in Europe. Following the same trajectory as the US, as far as I can tell. Does deregulating advertising of sugary cereals also explain that?

Advertising probably not but the simple availability of ever sweeter cheap products and with time their integration in people's diet is a strong candidate. Especially since sugar is way less good than say fat at provoking the feeling of satiation (I can think only of evolutionary explanations for that, available sweet food in the wild, think fruits, are not very nutritive, especially ones not selected by humans over time)

> surgary cereals

What else are kids eating these days for breakfast?

Whatever you teach them to eat. But parents are often lazy, its supremely easier to buy addictive paper boxes and be done rather than wake up 10 minutes earlier (or 2) and cook or prepare something quick and healthy. Depends also where you live, US its exactly as we discuss, ie France or Switzerland its a completely different world, and its immediately obvious on people too. This approach also permeates many aspects of society.

Kids also imitate what they see in parents, both good and bad. No point preaching healthy lifestyle if one is obese and spends hours daily in front of TV eating junkfood. Also, back in 80s I had maybe 4 years and I knew very well sweet stuff is bad for one's health, it was always as obvious as ie that cigarettes were very harmful and highly addictive.

I love how many folks desperately try to throw blame on literally anybody, anything for their failures in life, rather than taking a cold hard look at the mirror and accepting one's own failures, as a parent but also generally as human in this case. Sure, it makes life with oneself a bit easier, instead of huge instant dose of misery and self-disappointment its slowly dripping through the cracks of illusions for the rest of their lives and people love feeling like a victim, but it very effectively prevents actually fixing anything.

So sure, lets blame sugar industry (which is doing exactly what all other businesses do - sell to as many people as possible), lets blame tobacco industry or wine producers for people's failures. Lets wait till politicians will sweep away all obstacles and traps from our lives, of course that's a reasonable expectation. Anything but throwing away that 3rd cupcake or starbucks latte.

It was a serious question. Who is cooking in the morning? And what? Eggs and bacon (isn't that just replacing the sugar with fat/salt)? Porridge?

Bread/toast also isn't particularly healthy (too high in salt, spikes your insulin too much).

Fruit is also just very similar than sweets with a bit more fiber, isn't it?

So, a plate of some veggies?

And don't get me started on spreads which are available: you can choose between fat (butter/margerine/cheese/most other spreads), high salt (meat/salami) and sweet (jam, honey, nutella)

Ironically, as a diabetic (or even a non-diabetic) fat is a pretty innocuous thing. Certainly compared to carbs...

Fat is probably a better choice than sugar in nearly all instances. High calorie but it’ll keep you full quite a while. Veggies definitely aren’t any good for that. My strategy these days is to try and eliminate simple sugars and highly refined carbs whenever possible; everything else is fair game. When I see something advertised as “low fat” I instantly conclude it will probably make you fat and it’s best to skip it.

> I love how many folks desperately try to throw blame on literally anybody

When I read opinions like this, I immediately have two thoughts.

1) What makes people think it's their right to shame anyone else? The 'look in the mirror' advice is pretty universal.

2) Is there even anyone qualified to make comments like this? Am I to assume that the folks who imply their superiority do not in fact have their own failings? Glass house and all that.

I think perhaps it's more complicated, and declaring it a moral failing is not going to improve anyone's life.

Fails I own are the fails I try to tackle. If its outside force, then the only action can be altering that force (good luck changing nation's mindsets and values) or cutting off from it.

I chose the owning approach, it works very nicely for my entire life so far, since its work between me and me so whatever is happening outside has no impact. Doesn't make it an easier life, in contrary, but much much better overall. A plus is building stronger 'character' in challenges for lack of better words.

Obesity is a complicated problem and we can’t blame corporations alone.

> …we can’t blame corporations alone.

ok, but we can very much start with blaming corporations. sure, there are other factors at play, these are very large systems acting on individuals.

that’s the point. corporations are sufficiently complex and large to manipulate the system.

individuals rarely are, and when they do, it is often by forming a corporation around themselves. influencers are faces for larger operations, they have employees, payroll… just like a more traditional brick and mortar.

I'm willing to

it's not super complicated for most cases: grams of sugar(s) ingested versus grams of essential nutrients (proteins, fats) is too high.

If most cases include people without diabetes, PCOS or some other condition, yes you can eat less than what you burn and you will lose weight. In other cases, those people need medical intervention such as Mounjaro, Ozempic, etc

I mean to point out that "signal to noise" is what's often being overlooked, though "noise to signal" is more descriptive terminology.

it's very easy, in american fast food, for example, to ingest a great amount of unnecessary sugars (difficult to digest lipids, etc) while your body is trying to just get necessary nutrients themselves. worse, since we are built to remember results of eating, if some low nutritional signal to noise "food" satisfies some necessary essential nutrient craving, it's easy to remember what it was that alleviated a craving before, and tail recursively go eat the same shit again.

Oh right makes sense. You crave it because it made you feel good yet is a low quality food. So the cycle repeats itself.

I am going through a weight loss journey myself and it is very eye opening now that I am tracking my calories and nutrition. I was eating very poorly

It isn't a coincidence though that back in the 1990s the sugar industry was spending/lobbying big to attack dietary fat. A lot of foods intentionally removed satiating fats with nutritional value and replace it with cheaper sugars that you can eat almost unlimited amounts of without feeling full.

If I could only name two big "things" that contributed most to the obesity problem of today it would be:

- Agricultural Act of 1970 and the polices of the 1970s, resulted in corn so cheap and abundant that other industries actively looked for usages. HFCS was obviously one such use, and it out-competed all other nutritional sources on price.

- The 1990s "fat bad, sugar good" which resulted in reformulating a lot of staple foods and the beginning of standard sweet food allowing the cheap HFCS to flow.

The US needs, and has needed, to offset the corn subsidies that get turned into HFCS by adding a "sugar tax" at the consumer side. That way it can still exist for animal feed, and be used where appropriate without being unnaturally and unreasonably inexpensive.

The reason they don't is that it is political suicide to suggest sugar taxes in personal-freedom loving US that is pretty anti-tax regardless.

https://slate.com/technology/2018/03/big-sugar-isnt-to-blame...

Did you read that article or just the title? Because the article isn't focused on disproving any facts of the "big sugar bad" side but rather saying the facts as they stand are being unfairly characterized.

The article is well written, and I WOULD recommend it for anyone interest in this topic. But ultimately I'd just point to the same facts presented in the article, and you determine if we're being mean to the sugar industry or fair.

The result is the same either way, regardless of who gets the blame.

Sugar consumption peaked in 2000 and has been in steady decline since, and not only that, but the decline has been led by a decline in HFCS consumption: https://news.ycombinator.com/item?id=38094768

30% of the US was obese in 2000, now it's over 40%, despite per capita sugar consumption reverting to what it was pre-1975.

> The US needs, and has needed, to offset the corn subsidies that get turned into HFCS by adding a "sugar tax" at the consumer side.

If anything, we need a tax on added fat and sodium, the two biggest drivers of food hyperpalatability, when added in excess of the thresholds identified in this paper (> 25% kcal from fat and ≥ 0.30% sodium by weight):

https://onlinelibrary.wiley.com/doi/10.1002/oby.22639

> The HPF criteria identified 62% (4,795/7,757) of foods in the FNDDS that met criteria for at least one cluster. Most HPF items (70%; 3,351/4,795) met criteria for the FSOD cluster. Twenty-five percent of items (1,176/4,795) met criteria for the FS cluster, and 16% (747/4,795) met criteria for the CSOD cluster. The clusters were largely distinct from each other, and < 10% of all HPF items met criteria for more than one cluster.

(CSOD, carbohydrates and sodium; FS, fat and simple sugars; FSOD, fat and sodium; HPF, hyper-palatable foods.)

Why don't we just tax obesity?

So some kind of annual appointment where we get our BMI measured

Because adding fat (usually in the form of vegetable oil) and sodium is the cheapest, easiest way to make food hyperpalatable, and the share of the grocery store shelf space occupied by these products has exploded in the last 40 years, greatly contributing to the obesity epidemic. Ominously, this a trend that the researcher behind that paper I linked to attributes in large measure to the tobacco companies entering the packaged food business: https://onlinelibrary.wiley.com/doi/10.1111/add.16332

The American version would not be tax the Fat, but to make fat pay more for their health insurance.

And the only result would be more people unable to pay their health insurances...

It goes in phases. Anything other than pill use to be a hard no, but now we see injections moving beyond just vaccines. I've also heard from a friend that large pharma internal R&D is "pretty much just cancer for now."

The problem with corporate driven drug development is on full display here, they are treating drugs (and by extension, human lives) like investors treat tech startups. It really pisses me off when people say that this drives innovation.

The majority of corporate research money goes into patent extension methods (like slightly tweaking the delivery method, or slightly tweaking the forumal ala insulin being released as a free medicine, but costing thousands of dollars a month because of "evergreen" patent extension from corporate pharma companies) and on the other hand most novel compounds come from public research paid by taxpayers. Of which is then sold back to us by coporate pharma companies that buy that research.

There is an entire established pipeline, these researchers have no other options than to sell their research papers and findings to companies. It is disgusting on every level and indefensible... especially for the country that pays more than any OEC nation for healthcare, and has worse health outcomes than the majority of extremely impoverished "3rd world" countries. It kills millions every year, and is extremely shameful. It is the biggest embarrassment conceivable

You should read more about the journey from novel molecule (basic science, generally publicly funded research) to a commercialized drug.

It is obscenely hard, expensive, and risky to get a drug — even one that works really well — to market. It’s much harder when you factor in lack of knowledge ahead of time about which molecules in your portfolio actually work.

IMO there should be some structure for taxpayers/grant funding agencies to get paid royalties on successful drug programs, but you wildly wildly misunderstand what the hard parts of drug development are.

It’s not publishing papers about molecules that do things in Petri dishes.

This is tragic when you think about all the people that died of obesity in the mean time. By now, the patent would have expired. Many more people would have survived Covid.

The patent thing in particular. The drug companies are currently charging $1000 per MONTH which is an unimaginable amount of money. Therefore, a lot of people who would otherwise benefit (e.g. obese, prediabetes) simply won't have the option.

Unclear to me who has $12,000 extra they can spend on a non-immediate life-saving medication like these. There is technically market competition (wegovy vs zepbound), but surprisingly they all are charging $1K/month with a "discount card" which can be withdrawn at any time, and even that still makes is $6K/year.

Currently, many people are benefiting via legal compounding from safe US licensed pharmacies due to the shortages/FDA shortage list, but that route is very soon going to be closed. Then back to $1K/month Vs. $1K/month.

It’s $275 a month plus $99 every 6 months at SlimDownRX. The compounded pharmacies are helping.

$39/month from the top chinese vendors

Tell me more…

It won't be for long. That can only exist because of the FDA Shortage List, and with the official manufacturers releasing single dose vials, it is only a matter of "when" not "if" it won't be classed as shortage, and you're back to paying $1K.

Why would classifying it a shortage make it expensive?

Classifying it as a shortage makes it cheap. It will get expensive when it is off the shortage list.

That makes no sense.

The FDA shortage list allows compound pharmacies to produce it without paying for patents/licensing.

Being on the shortage list is what allows compounders to sell it. Once that is no longer true, that option goes away.

Compounded is amazingly cheap particularly when you start because a single bottle of compounded Wegovy is many doses at the lowest recommended dosage levels. I think the first bottle cost me $200 and lasted two months, possibly longer. Wegovy would be $1300/mo at Costco without insurance. Absurd.

What actually is the compounded stuff though? Where does it come from? What’s in it?

Their source for semaglutide is crushed Rybelsus pills.

See my other reply to this post for sources.

FYI 92% of Americans have health insurance. People are not paying $1k/month.

> a "discount card" which can be withdrawn at any time

if we're talking hypotheticals...

FYI most health insurance won't cover the $1K/month cost of either weight loss medication currently (only for diabetes version with appropriate diagnosis). So people are, absolutely, paying out of pocket. I personally know two people that are and there have been multiple articles about it.

> if we're talking hypotheticals...

We aren't. We've seen it with multiple very expensive US drugs that had generous "discount cards" that were withdrawn when they got popular. It is like a drug-dealer model, get them hooked, then jack up the price.

The drug companies know this is a golden goose, and they only have 13 remaining years to squeeze it.

Most health insurance will not cover these medications for the purpose of weight loss. Even for diabetics, many require you to go through other medications like metformin first, to show that can't help with your A1C (which it very well may, but without as much help losing weight). There are discount coupons that come and go and bring it down to like $500/mo if you have insurance that doesn't cover, but they come and go. A lot of people are definitely paying a $1k/mo for their skinny-as-a-service subscription.

Most insurance plans are excluding the drugs for weight loss purposes.

With a type-2 diagnosis, you can get Ozempoc, Zephound or Rybelsus covered. Wegovy, etc and off-label Ozempic is excluded by most formularies.

Some big companies and government plans are covering it however.

Insurance only covers with a diabetes prescription. My sister in law is a pharmacist and 50% of her shop's fills are cash price because insurance will not help.

You’re probably getting a few things mixed up.

Insurance generally only covers Ozempic if someone has diabetes. Some insurance plans cover Wegovy, the same drug with a different dosing labeled for weight loss, but many don’t.

A lot of the compounded stuff is nonsense. They charge you a few hundred dollars for vitamin B supplements with some shadily-sourced GLP drug that fell off the truck or was manufactured in some mysterious factory in Ukraine or wherever.

Even in the drugs are real, most of the online compounders are out of Florida or other locals with a long history of shady behavior and poor regulation.

Exactly! I've reasearched some semaglutide compounding pharmacies and it terrifies me that their semaglutide source is top secret; never disclosed. Where's it coming from and what are people really injecting?

Their semaglutide source is crushed Rybelsus pills.

See, for example:

https://a4pc.org/2024-04/mass-confusion/

https://subsema.com/wp-content/uploads/2024/05/White-Paper-S...

https://mynextgenrx.com/wp-content/uploads/2024/03/Compounde...

I doubt that’s supporting the industry. Rybelsus is constrained from a supply pov and expensive.

On the contrary. It’s quite cheap, since compounding pharmacies are selling semaglutide for injection.

Last week I purchased 90 tablets of 14mg Rybelsus for just over $700. My cost per milligram of semaglutide was just over 50 cents. Compounding pharmacies are preparing weekly injections containing at most a few milligrams of semaglutide, and they are selling a one-month supply for ~$250. Their cost for active ingredient is well-under $10.

In the UK Wegovy is £200 per month privately, Why is it so expensive in the US?

I pay £169/mo for Mounjaro, but yeah, it seems a common thing for baseline prices for medication to be very high in the US, then often reduced significantly by insurance. I assume mostly because they can get away with it whereas next to no-one in the UK is going to pay £1000/mo for it.

Because we have shitty laws created by government that “represents the people” but runs on money from corporate donations. In other words, they charge $1k because they can.

Zepbound is $399-$650 per month, ordered direct, if insurance does not cover it. Not great, but at least a start.....

https://www.help.senate.gov/chair/newsroom/press/news-sander...

> Many more people would have survived Covid.

Accurate, I periodically think about the standard here

Over 1 million Americans are in the reported death tally, this is attributed to a failure of a lot of things under an administration's watch

But if it was just 100,000 would the criticism or consternation be any different? if it was just 10,000 and matched the seasonal flu would it be any different? if it was just 3,000 matching a tragedy of the magnitude of 9/11 would it be any different?

if it is to be different, what would the threshold be

It would be very different if I didn't have to bury two people I cared very much about, yes.

Could this be true for LK99

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