I presume you're referring to receptor upregulation in response to the drugs. Bear in mind as you read my comment that this isn't my primary area, and it's been a while since I last studied cell biology and signalling around G-protein coupled receptors. I also have not gone out of my way to read papers about the cell signalling pertaining to these drugs, only papers around clinical outcomes for these class of drugs.
After discontinuation, most patients regain around 60-80% of the weight they've lost with the medication - but this figure is limited to the study duration, so the weight regain might have continued beyond that. A good starting point for dipping your toes into outcomes would be the STEP and SURMOUNT trials, these were the trials they did for marketing approval. (They did multiple rounds of these, I believe STEP4 and SURMOUNT4 specifically had groups that stopped therapy mid-way).
We see this rebound effect with weight loss mediated solely via lifestyle modification as well, however. Still no idea why. Very broadly speaking, only a small proportion of obese/overweight patients will manage to keep the weight off, and the rest of the patient population tends to be divided into two groups: those who regain most of it (usually around half of the lost weight will be regained within 2 years, and 80% by follow up year 5), and those who regain more weight than they had lost. There hasn't been a way to tell preemptively which group the patient will land in at the time of beginning of lifestyle modification.
On top of this, yoyo-ing is also a phenomenon we tend to see. Obese and overweight patients who've managed to lose weight once will regain, lose again and so on. This phenomenon is associated with worse outcomes than being obese alone, so it is important to do long-horizon thinking when initiating therapy (be it lifestyle or pharmacotherapy) e.g. is the patient willing to stay on pharmacotherapy indefinitely? what about an indefinite maintenance dose if the patient succeeds with lifestyle modification alone? has the patient had lost and regained significant amount of wt prior? etc.
Definitely not a good idea to be on it longer than 2 months. If we can't treat the underlying condition and the patient needs life-long acid suppression therapy, we switch to H2 receptor antagonists, like cimetidine.
Long term PPI use has non-trivial risks, including magnesium and other micronutrient deficiencies, and can lead to things like SIBO and other primarily gut related morbidity.
I would definitely suggest sitting down with your doctor if you were not specifically instructed to take it for that long.
I personally believe you are right to be weary about holding off on long term use before the long term efficacy and risk profile of a drug has been established, but GLP1 class drugs have been around for a long time now.
GLP1 agonist type incretins have been available for over 20 years at this point. The first marketing approval was in 2005 for exenatide (Byetta), indicated for T2DM. Exenatide was the first in class for GLP1 agonists. Then came Liraglutide (Victoza) for the same indication around 2010, and received marketing approval for weight loss (as Saxenda) 4 years later. After that around 2017 was semaglutide (Ozempic & Wegovy).
T2DM is a chronic disease, so patients who started exenatide had to stay on it life long.
These drugs are nothing new and were already being used for T2DM. It only caught public attention because semaglutide achieved double the mean BW loss over liraglutide, making it meaningful for weight loss. Novo Nordisk first got approval for Ozempic for T2DM in 2017 and then received approval for it to be marketed for weight loss under Wegovy only in 2021, but by then clinicians were already prescribing it off-label, strictly speaking, for weight loss.
I don't know how much we could extend this "they've been around for a long time" to tirzepatide (Eli Lilly: Mounjaro & Zepbound) because it's the first dual agonist. It targets GLP1 and GIP, and thus it's meaningfully separated from the others. This goes for retatrutide (again Eli Lilly) as well if it eventually comes to market as it would be the first triple-agonist targeting the aforementioned + GCGR, the glucagon receptor.
It's not that I don't believe people can't be trusted with information. I regularly introduce basic diagnostic/statistical concepts to patients to explain why a certain test is needed, and why another would be wasted time and anxiety.
Tools are only effective in their purpose when one knows when and how to use them. Most things are imperfect, or a game of balancing benefits vs. shortcomings.
If a patient learns the potential pitfalls and strengths of a testing method, then I would trust them to apply it judiciously. But a biweekly medical scan you can go to as easily as a spa is not that.
Similarly: data matters, sure, but the quality of the data matters just as much. If the signal to noise ratio is too low then what's the point of gathering it?
This is a tough problem for sure, and I resonate with your sentiment that something has to be done with it.
In my personal (fully anecdotal) view, I think clinicians desperately need to get better at communication, as well as meta-communication. Right now the rift between the patient and practitioner is enormous, because Drs do not take the time to dutifully explain things and processes, and what pitfalls there may be, and like you said, just boil it down to "it has to be this way" and shrug.
Some of this is down to systems design, i.e. not enough time per patient;insufficient support staff (simple example is no nurse being present to take down history concurrently as you spend time with the patient, or no dictation facilities available so you have to manually type everything down during the consult, eating away what precious time you have w/ the patient); a specialist getting bombarded with things a generalist should have treated w/ no referral needed; jurisdictions where violence towards healthcare workers is prevalent and so on..
But I would wager that compassionate listening and communication is the lion's share in why there's this huge rift. We currently do not teach effective communication in medical school, students just see how their attending treats a patient, and they copy their style. Which is funny, because the first thing we were taught in preliminary internal medicine was that 80% of making a diagnosis (any diagnosis) is down to history taking and communication.
As for how exactly we would get institutions to take communication seriously, I have no idea.
Thank you, I appreciate you sharing your views on this.
Coincidentally, I've only recently learned of the Overton Window [0] which describes that the spectrum of acceptable ideas in a society is subject to shift.
you raise a good point, I was trying to take the example to the logical extreme by specifically using berating. in essence, the example would be the same as whistleblowing (mechanistically speaking)
So one would have to weigh the risks of being let go (and legal consequences if it was indeed whistleblowing) depending on the level of criticism being levied.
the way I see US infrastructure, I feel like they (like most of the world) will never be able to claw their way back out of car dependence.
Even the Dutch had to fight tooth and nail for it. I've lived in Germany for a while and there are cities here where even I would be snubbing taking kids to school with a bakfiets, because the biking infra is not good enough, or in other words the mingling I'd have to do with other traffic would be too out of my comfort zone.
Urban planning should prioritize walking and biking very first, and cars and other utilitarian-but-dangerous/harmful transport methods should be integrated in a way that's not engulfing the more human-scale side of things. But I think the costs (both monetary and in terms of "cognitive shift") are so high that I don't think I'll see this change in my lifetime. And that's before accounting for the power of corporate interest
Am I crazy for thinking that an employer should and has no say in whatever the fuck I do outside of work? As long as I'm not messing with company IP, I should be able to do what I want, no?
Like, I should be able to even berate my employer, as long as I'm not doing it from a persona that's directly tied to my employer e.g. my real name or git handle etc. They might not like it, but they sure as shit shouldn't be able to fire me for it. This would include working on extending a company's products, so long as I don't use the proprietary knowledge I'm privy to.
I realize that this guy published his thing under an alias directly tied to his work. My question was sparked from the general sentiment of your reply - and I am being genuine, sometimes I feel like this stance of mine is somehow "too radical"
I understand that this is not reality in most of the world, but I'm genuinely asking. I'm in the EU and I'm not in the software/silicon valley industry; if that helps with context.
This is exactly why it's a bad idea. I agree that if this technology comes to fruition, it should be in every clinical and research setting as a tool for us to further our understanding.
It shouldn't be a commodified test anyone can do at any time they feel like it. There are so many examples this leading to over or misdiagnosing already. I've seen patients who thought they had diabetes because they got a CGM over the counter and it showed a blood sugar spike during exercise (as in, their body doing exactly what it was supposed to do). He also now avoids oatmeal because "it spikes my blood sugar". Surprise: reddit and tiktok are awash with such stories as well.
I've seen a patient who on a whim decided to get 24hr blood pressure monitoring done, and thought they have severe hypertension because their systolic reached 170 when they were climbing stairs and during a football match because they were cheering and shouting.
In a similar vein, there are shady practicians who offer full body MRI scans, and fMRI brain scans to the well-to-do as a way of diagnosing things, when in fact neither are specific enough to actually diagnose something on their own.
23andme tests sending patients into clinics because they found a specific SNP that may be associated with worse outcomes for a disease.
We have neither the resources nor a specific enough technology (scan shows something: not specific enough to tell us what it is, but it sure is something) to unleash these for the general population to use.
We can and do full body scans. Typically in the context of research, or for focus/metastasis search in current clinical settings.
The problem is that, in clinical practice, with every imaging technology there are trade-offs. Just because we see something out of the ordinary in a scan doesn't immediately tell us whether it's pathology, pathology worth investigating/treating, or if it's just a normal physiological variation.
Which means that, when "something" is seen on a scan, we must do further testing, either increasingly invasive, or increasingly time consuming and expensive.
I agree with the sentiment that if we had a way cheap, fast, and harmless way to scan an entire body we would unlock many new research areas and that it would further our medical understanding, and eventually ripen for clinical use.
However currently, I do not see any benefit in giving access to the population to such a technology, because we neither have the resources to chase down every single region of interest in a scan, nor do we have efficacious treatments for everything we might come across on a scan. Which is why we've settled on scanning things if there are other signs of disease, and only treating something when it significantly impairs life quality and/or expectancy.
Should such a quick and easy scan be in every hospital and research center? Yes. Should it be a spa for people to go to whenever they feel like? No.
Let us not forget that, low cost carriers and full service carriers alike _all_ have artificially lower prices, prices below what it would actually cost to render their services, as the entire commercial aviation industry is subsidized in the form of fuel, tax and other subsidies. At least in the EU.
They wouldn't be able to turn a profit even if they squeezed you hard enough.
A few years ago, I applied for a customer service job for an outsourcing company that was contracted by Ryanair. They had a two week unpaid training, I tapped out on day 3 of the training, but until that point, I was given all the training material, including the spiels they train the agents on, which they actually call spiels.
Unless a customer mentions, specific wording (I forget what exactly now) - wording that matches the underlying regulation that entitles the customer to some kind of recourse by law, the agents are instructed to deny and weasel out of it. As in, even though they are legally obliged to give you that specific recourse, unless you demonstrate to them that you have proper knowledge of the law, they will simply act like you have no rights.
It was very slimy, and I literally couldn't stomach it. I don't know how they train their customer service agents now, but I would highly recommend doing a few google searches and some prompting to see exactly, literally, what words one must utter to a customer service agent.
Of course, that alone is not enough, the stars also have to align so that the agent you're talking to commands enough of the English language to have comprehended their training, and what you're saying; and not be bogged down with the 7 simultaneous chat tickets they must handle concurrently, in addition to the calls.
I think the reality is much more grim. I believe we are now firmly in the territory where it is incontestable. (My opinion was cemented after reading Overshoot: How the World Surrendered to Climate Breakdown by Andreas Malm, Wim Carton)
We will be spending much of our upcoming years trying to get people and capital to accept that fact, before we can even start thinking about what little we can even do. By which point, we may actually just be having to scramble to mitigate the immediate sequelae of the changed climate, rather than focus our efforts to fix the underlying cause.
I agree with your sentiment, but I have a hard time imagining any alternative action scientists could take besides publishing and warning.
Science is best when it’s purely that, I’ve seen plenty of living examples and read about past ones where science mixed with politics or overt profit motives don’t end well. Surely there must be examples where the contrary has been the case, but I am biased, and I would wager that it ended poorly more often than well.
I would much rather have politicians that heed scientific results than scientists springboarding into politics.