Stopping and Restarting Certain GLP-1s to Lose Weight May Make the Drug Less Effective

[woundcarping]

You’re probably right and I admit I’m likely not who these were originally designed for. In the grand scheme of things my situation wasn’t as severe as a lot of people here. That said I’m glad they exist because having that food noise toned down even a little this early in has already been a bigger quality of life improvement than I expected. We’ll see how the story ends but cautiously optimistic for now.

What was your starting height/weight?

 

[Grogu]

You’re probably right and I admit I’m likely not who these were originally designed for. In the grand scheme of things my situation wasn’t as severe as a lot of people here. That said I’m glad they exist because having that food noise toned down even a little this early in has already been a bigger quality of life improvement than I expected. We’ll see how the story ends but cautiously optimistic for now.

I had a feeling that this was the case, but really no judgment on my part as far as who should and shouldn't take these medication. The medications were "designated" for certain populations, but that doesn't mean that the medications are not helpful or advantageous for other populations. Glp-1s weren't originally "designated" for individuals with alcohol use disorder, but that population appears to benefit immensely from treatment. Maybe someday they will say that these medications are also a good idea for overweight individuals. More power to you for finding an intervention that can help you reach your goals.

We just have to be careful on both ends of the spectrum. I can't assume that everyone must continue on glp-1s to be successful, just because that's my reality. But on the other end, some big guy like me might read your post and think that life without glp-1s is possible without knowing your medical history or status starting these medications.

 

[RJ760]

What was your starting height/weight?

Before starting Reta I was 230lbs at 6’2. Highest I’ve ever been is 280lbs about 5 years ago.

Down to 209 today after 5 weeks on Reta.

 

[RJ760]

I had a feeling that this was the case, but really no judgment on my part as far as who should and shouldn't take these medication. The medications were "designated" for certain populations, but that doesn't mean that the medications are not helpful or advantageous for other populations. Glp-1s weren't originally "designated" for individuals with alcohol use disorder, but that population appears to benefit immensely from treatment. Maybe someday they will say that these medications are also a good idea for overweight individuals. More power to you for finding an intervention that can help you reach your goals.

We just have to be careful on both ends of the spectrum. I can't assume that everyone must continue on glp-1s to be successful, just because that's my reality. But on the other end, some big guy like me might read your post and think that life without glp-1s is possible without knowing your medical history or status starting these medications.

That’s a really fair point and something worth keeping in mind. Context matters a lot and what works for one person’s situation isn’t a blueprint for someone else’s. Appreciate you adding that nuance because the last thing I’d want is for someone in a completely different situation to read my post and draw the wrong conclusions from it.

 

[Devilseye]

Unfortunately, the data dosen't support the idea that folks reach "metabolically healthy" positions, even over time. For those suffering from an underlying metabolic dsyfunction that led to their obesity, tirzepatide provides treatmeant, but not a cure.

This is from SURMONT, the beautiful thing about the graph is the nearly flat line after 75 weeks of tirzepatide up to 176. So, for almost 2 years on tirzepatide, participants didn't gain any weight while on treatment. As soon as they discontinued in week 176, we can clearly see what happened. We have no reason to think that the flat line wouldn't have continued on treatment, but also no reason to think that at anytime that treatment is stopped that the increase noted isn't going to happen.

View attachment 21581

Thanks for that. I wasnt aware of that study. It completely echoes my experience. Whats frightening about it is the steepness of the curve when weight rebound occurs at 176 weeks. Pretty alarming overall and why i probably wont stop completely, probably ever.

 

[Devilseye]

The medications were "designated" for certain populations, but that doesn't mean that the medications are not helpful or advantageous for other populations. Glp-1s weren't originally "designated" for individuals with alcohol use disorder, but that population appears to benefit immensely from treatment. Maybe someday they will say that these medications are also a good idea for overweight individuals. More power to you for finding an intervention that can help you reach your goals.

We just have to be careful on both ends of the spectrum. I can't assume that everyone must continue on glp-1s to be successful, just because that's my reality. But on the other end, some big guy like me might read your post and think that life without glp-1s is possible without knowing your medical history or status starting these medications.

GLP1s are becomming increasingly popular in the longevity community for their cardiovascular benefits and reduction in mortality. So many more healthy weighted individuals are microdosing them for those reasons. We’ll see how the data pans out in some 10 years from now.

 

[5byfive]

I'm not someone who wants to be on medication forever unless it's medically necessary. My goal is to use the reduced cravings and quieter food noise to actually build better eating habits so I can slowly titrate down and eventually off GLPs once I hit my goal weight.

Food noise has been something I've dealt with my whole adult life and I was never great at building sustainable habits around it. I was an expert at crash dieting though. Drop to 1200 calories or less, hit my goal weight as fast as possible, and never once put any real effort into building a better relationship with food. The weight always came back.

I tend to feel the same way about medicstion so I understand how you feel. I started Tirz after losing about 90 pounds and building a sustainable diet (Ozempic was just becoming a thing when I started). I never expected to get down to as low a bodyfat percent as I did (I actually overshot after a bad Dexa scan). What I realized was that, although it should be harder to maintain this low, honesty it wasn't any harder than maintaining 20% or even 40% becuse it was always harder than it should be. No matter where I'm at, the food nosie is constant and I never really feel full unless I substantially over eat. Tirz has substantially improved my quality of life and from what we know at this point, it seems like there are a lot of health benefits to being on it that are not directly tied to weightloss. It also seems to have fixed my metabolism so that the calories I'm burning actually make sense based on my activity; it has always been low for how active I am. I don't see coming off it unless something in our understanding of its long term effects changes substantially.

 

[byefatlicia]

Not that I'm looking at start another thread about the pros and cons of lifetime glp-1 use, since I think we've recently beaten that horse dead. But this article is a somewhat different twist and talks about cycling glp-1s and the potential for reduced effectiveness when cycling over staying on the medication consistently. The underlying study is just a rat study at this point. For the visually inclined the results are :

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Stopping and Restarting Certain GLP-1s to Lose Weight May Make the Drug Less Effective | Newswise

Inconsistent use of some GLP-1 weight-loss medications, like Ozempic and Wegovy, may significantly lessen their effectiveness, according to a new preclinical study.

www.newswise.com

Thank you for posting this. I had heard others talking about a break to reset receptors. And I was considering it to get back to better numbers at the scale. Now, I'm glad to have read this first

 

[Grogu]

GLP1s are becomming increasingly popular in the longevity community for their cardiovascular benefits and reduction in mortality. So many more healthy weighted individuals are microdosing them for those reasons. We’ll see how the data pans out in some 10 years from now.

I totally get it. I'm currently microdosing a statin because of all of the positive health benefits beyond lower LDL. There are a lot of them.

I originally had slightly elevated LDL, but that has long since resolved, so now I cut my pills in 1/2 and skip some days just to keep the dose low. The only reason I do all that is my cholesterol was so low it stopped the production of testosterone. Who knew, but you need some fat in your blood to produce T. Not enough fat and your body thinks it's in survival mode and no need to procreate .

 

[Grogu]

Thank you for posting this. I had heard others talking about a break to reset receptors. And I was considering it to get back to better numbers at the scale. Now, I'm glad to have read this first

I've, too, have run across chatter online about giving your receptors a break and a chance to "reset", but I've seen nothing from the scientific community that would support the concept.

I think the chatter stems partly from people trying to explain weight loss plateaus and reduced appeptite supression. These effects are more likely adaptations of the body, and not receptor failures. The chatter is probably also based in reality since there are medications that exhibit true receptor tolerance. First thing that comes to mind are opiods. Over time, the same dose of opiods produces a smaller effect because receptors become less responsive.

But with glp-1 receptors, that hasn't been the case in the real world. If it were the case, we'd see the medication not working the way it's supposed to over time. We'd see worsening blood sugar, clearer hunger rebound, weight regain, and less/no response to higher doses.

If receptors were being "burned out" the slide I posted above from SURMONT wouldn't look like that. Those folks took 5mg, 10mg, or 15mg weekly for years. No burnout.

 

[Loscar]

Big pharma is still trying wrangle all of it. With Eli trying to re-classify it. Then these studies. I am interested in seeing what the next 5 years of this will look like.

At the end of the day big Pharma, and Uncle Sam need to eat. If America is going to get skinny there needs to be a subscription service to it so you can never quit.

In the mean time, not trying to be like the cycled rat!

 

[lessthanhalf]

Thanks for posting that study. It is interesting. And I am surprised at just how large the effect was.

I had noticed several people on here talking about how they had stopped GLP's for a while and then restarted either the same or a different one and say it was not working or not working as well. My usual explanation for this is that they were usually doing this in the context of having lost quite a bit of weight, so metabolic rate will have dropped and hunger increased , just making it look like they were not working as well.

But this is real new information, and the biological mechanism involved is not at all clear. The appetite and weight control systems built into the body are just ridiculously complicated and redundant, which is the main reason it took so many decades of research to find something that actually worked reasonably well. But it is far from being fully understood, especially what is going on in the obese or post obese state.

Hopefully this result will be looked at as important and be replicated and then repeated in humans. I somehow cannot imagine lily or novo paying for it though, as it complicates the story, and might make the drugs look less effective.

Understanding what is going on to cause this could be useful, something very definitely goes wrong in the appetite and weight regulation systems in obese people, and this is still poorly understood. Weight cycling is generally regarded as a bad idea, I wonder if weight cycling on its own without the glp drugs could cause the same problem. Or if it is the periods of rapid weight gain that does the damage.

It is somewhat convincing evidence that stopping them to "reset your receptors" might be a very bad idea, and might even make me reluctant to stop them for medical procedures unless it was really necessary.

I don't think the two weeks on and off is that relevant to humans , mice have much faster metabolic rates, growth rates and life cycles in general, so 2 weeks in mice might be more comparable to 2 or more months in humans.

 

[HereKittyKitty]

I only casually read the underlying article, but agree it seems interesting. I wish that they have done a cycle more like:

Rat group A: 4 months continuous

Rat group B: 2 months on, one month off, and one month on

But maybe "rat weeks" are more like human months .

I get the impression from the underlying research paper that it's early stage work and probably "published" to keep NIH funding coming in or something. But I do think that there is something to the situation that goes beyond "hunger" returning to actual physiological changes in the body that happen as a result of cycling these medications. Maybe the fat/lean mass balance changes, set point, or something with the endocrine system. If I had to guess, I would say it's the subsequent weight that is gained after discontinuation that is the issue and something to do with insulin or grehlin or something.

Also my experience with stopping.

I lost BP-subsidized access and was without sema for 3 months. My experience getting weight loss to resume has not been a straight line though it has been incredibly frustrating.

 

[Grogu]

Thanks for posting that study. It is interesting. And I am surprised at just how large the effect was.

Yes, definitely an interesting study. The 20% does seem high because that % would be pushing the bounds of being on semaglutide versus being on placebo. That high of a percentage would suggest that cycling is worse than no treatment. Which could actually be a thing.

Human studies are definitely needed, but as you mention, not likely to be funded by NN, EL, or any other BP company. The alternative result from such a study would be that it's okay to stop and restart treatment and it's okay to switch glp-1 agonists. Seems to me that BP is banking on continued use and no pauses for patients on treatment. Lilly even prices their direct product to encourage people staying on the medication and staying on paying.

 

[UpDownLeftRightAS*]

Here is the study. Cycling GLP-1 receptor agonist treatment induces therapeutic resistance and increased adiposity https://insight.jci.org/articles/view/205174/pdf

 

[woundcarping]

 

[BNLFL]

GLP1s are becomming increasingly popular in the longevity community for their cardiovascular benefits and reduction in mortality. So many more healthy weighted individuals are microdosing them for those reasons. We’ll see how the data pans out in some 10 years from now.

This is my take along with some others here. What it's done for my cholesterol is great too. My doctor to me I'll need to start watching it late year. Well, last two blood tests it's been great.

 

[Grogu]

I asked AI to super impose the weight increases the rats experienced with discontinuation of semaglutide to the human data from SURMONT when humans ceased taking tirzepatide, because I thought the slopes of those lines appeared very similar. Make no mistake, rats are very similar biologically to humans .

 

[stoked12]

IMO GLP1 drugs are "Glp1 replacement therapy" or "Incretin replacement therapy"

To many people views these compounds as a "get skinny quick pill", I think the above terms would help average people better understand these compounds AND why they exist.

Just like "Testosterone replacement therapy" sounds better then telling someone your taking Testosterone.

Idk just some thoughts.

 

[woundcarping]

IMO GLP1 drugs are "Glp1 replacement therapy" or "Incretin replacement therapy"

To many people views these compounds as a "get skinny quick pill", I think the above terms would help average people better understand these compounds AND why they exist.

Just like "Testosterone replacement therapy" sounds better then telling someone your taking Testosterone.

Idk just some thoughts.

Replacing endogenous GLP1 with orders of magnitude greater exogenous GLP1 is what we're doing; that would kill folks on TRT.

Some quick reading suggests TRT is 2-3x endogenous levels while Tirz at 15mg is ~100-1000x endogenous GLP1. It would be a wild ride to take 6-60g of test c in a week.