SURMOUNT-4: Weight regain despite continuing lifestyle and diet modifications

[Calm Logic]

There are alternatives to staying on GLP-1 for life, such as moving to Contrave after stopping GLP-1. One university also found that non-diabetics are able to keep the weight off by moving to metformin after stopping the GLP-1.

The study:

https://onlinelibrary.wiley.com/doi/10.1002/oby.24177

In a real-world study, individuals maintained their weight loss for up to 24 months by transitioning from 12-month GLP-1 RA therapy to generic AOMs.

The most frequently used AOMs for weight maintenance after GLP-1 RA therapy were metformin (used by 80% of patients), topiramate (used by 32.5% of patients), and bupropion (used by 32.5% of patients).

Older, cost-effective anti-obesity medications maintain weight loss after GLP-1 therapy

Participants enrolled in a GLP-1 receptor agonist weight-loss program maintained their weight loss at long-term follow-up after transitioning to older-generation, generic anti-obesity medications, researchers reported in Obesity. “Given the high cost and limited access to GLP-1 receptor...

www.healio.com

 

[tubby]

I have to point out that these “study” participants were taken from a THERAPEUTIC dose to zero. This is an important nuance. If it were an SSRI (depression med) it would be malpractice. We don’t start taking 10mg of tirz out of the gate, that’s absurd. Why would anyone expect anything different than failure going from 10mg to zero? (Picking 10mg randomly.)

Not entirely true. The half-life of popular GLPs is about a week, which is to say that blood levels decrease by about 50% per week. Meanwhile SSRIs often half a half-life of a day or two, leading to a much more rapid drop off in blood levels.

I've thought about that problem before and I'm not sure what the right answer is there for how best to discontinue taking a GLP if one chose to do so. If you stop cold turkey and just tear the band aid off, blood levels are going to slowly decrease over a 1 month period from from supraphysiological (way higher levels than your body could naturally achieve) to high physiological (levels that are still elevated relative to a normal person, but feel really low to you). In month 2 levels would continue to decrease from high (for a normal person not on GLPs) to physiologically normal, at which point your body's natural system would be able to properly signal your brain again.

2 months is already a pretty long tapering off period as it is and I find myself wondering if stretching that out into an even longer period would be advised, as it's really just prolonging the misery.

To be clear (for those with reading comprehension challenges), I'm not saying people should or shouldn't stop taking GLPs. I'm thinking about what would happen if people choose to stop taking GLPs and how they could best do that.

 

[tubby]

The study:

Loading…

onlinelibrary.wiley.com

Older, cost-effective anti-obesity medications maintain weight loss after GLP-1 therapy

Participants enrolled in a GLP-1 receptor agonist weight-loss program maintained their weight loss at long-term follow-up after transitioning to older-generation, generic anti-obesity medications, researchers reported in Obesity. “Given the high cost and limited access to GLP-1 receptor...

www.healio.com

That was an interesting study and thanks for sharing.

Some critiques I might have of it is that it appears to be subject to some biasing factors that may make the approach appear more effective than it actually is. I'm not sure how they could correct for those factors so I'm not criticizing the researchers or suggesting it's a misleading study, though.

Specifically, they only took the participants who were able to get their BMI under 30 on GLPs into the next phase. That means the people studied in phase 2 (mainly metformin treatment) were either those who responded exceptionally well to GLPs or those who started at lower BMIs to begin with. I'm not sure how this biasing will affect the end result, but I think it should be obvious that some degree of cherry picking applies here due to that decision. I also acknowledge that researchers were probably forced to design the study this way to get it past an ethics review board, which may have objected to taking those who were still obese off of GLPs as part of the study design.

The author also notes that some number of the participants may have continued (secretly) taking GLPs after being moved to metformin, since these are real world people who just lost a bunch of weight and if they see the scales starting to move back up may decide that they value keeping the weight off more than they value study integrity. "I'm sure the other participants will follow the rules even if I break them" or something along those lines.

 

[Foggy-Hollow]

In month 2 levels would continue to decrease from high (for a normal person not on GLPs) to physiologically normal, at which point your body's natural system would be able to properly signal your brain again.

I don’t know if we know whether normal signals start back up. I’m not in the medical field. We expect the body to turn on and off like a switch - and sometimes it does. But sometimes it doesn’t, women coming off of years of birth control sometimes can’t conceive.

Anecdotally some people get pretty slammed by the signals that have been suppressed /with the two month wear-off. I wouldn’t call it a taper, a taper eases discontinuation symptoms.

 

[Calm Logic]

That was an interesting study and thanks for sharing.

Some critiques I might have of it is that it appears to be subject to some biasing factors that may make the approach appear more effective than it actually is. I'm not sure how they could correct for those factors so I'm not criticizing the researchers or suggesting it's a misleading study, though.

Specifically, they only took the participants who were able to get their BMI under 30 on GLPs into the next phase. That means the people studied in phase 2 (mainly metformin treatment) were either those who responded exceptionally well to GLPs or those who started at lower BMIs to begin with. I'm not sure how this biasing will affect the end result, but I think it should be obvious that some degree of cherry picking applies here due to that decision. I also acknowledge that researchers were probably forced to design the study this way to get it past an ethics review board, which may have objected to taking those who were still obese off of GLPs as part of the study design.

The author also notes that some number of the participants may have continued (secretly) taking GLPs after being moved to metformin, since these are real world people who just lost a bunch of weight and if they see the scales starting to move back up may decide that they value keeping the weight off more than they value study integrity. "I'm sure the other participants will follow the rules even if I break them" or something along those lines.

Yeah, I'm not a fan of the study since metformin and bupropion were not verty helpful for me in the past. Jardiance is more promising, despite more frequent urination.

 

[Calm Logic]

Anecdotally some people get pretty slammed by the signals that have been suppressed /with the two month wear-off. I wouldn’t call it a taper, a taper eases discontinuation symptoms.

After a month of stopping all GLPs cold turkey last October, pizza never tasted better. I was fine until end of week three or so. But it was very humbling at end of week four, with weight going up almost daily in week four.

So if I had to go without GLPs, I like the @lessthanhalf philosophy of avoiding addictive foods almost religiously (which may be less difficult with the diets that promote satiety with starch and protein):

My personal solution was to treat high calorie, highly rewarding foods as dangerous addictive drugs and avoid them totally and hopefully forever, but this is a fairly drastic way to deal with it although in my case it has been extremely effective. But a more limited version of this might be worth considering. I am not sure I can say the other treatment options for binge eating disorder are all that great, cognitive behavioural therapy and lisdexamphetamine are the only standard treatments but neither is really all that great.

 

[tubby]

I don’t know if we know whether normal signals start back up. I’m not in the medical field. We expect the body to turn on and off like a switch - and sometimes it does. But sometimes it doesn’t, women coming off of years of birth control sometimes can’t conceive.

Anecdotally some people get pretty slammed by the signals that have been suppressed /with the two month wear-off. I wouldn’t call it a taper, a taper eases discontinuation symptoms.

So here's the general idea:

I'm just going to make up arbitrary numbers and oversimplify for the case of illustration here. Let's say before GLPs, a level of 1 in your body happens when you haven't eaten in 3-6 hours and a level of 10 in your body happens when you just pigged out at the buffet and really got your money's worth. Your body is able to naturally vary the level between 0 and 20 just fine, but beyond that simply can't produce a level higher than that on its own.

You then start taking injections that knock your level up to 50, coming back down to 25 before the next shot. Over time you titrate up to higher doses and your levels are now fluctuating between 300 and 150.

When you stop taking injections, your body can't really do anything impactful for that particular hormone until the level comes back down under 20 again. That's going to be a while. Now hunger and fullness aren't handled by just one hormone and you'll still experience those sensations between meals due to other hormones and systems involved in the process. But you're not going to be "normal" again until that level degrades not just to 20, but likely another month later when it has degraded all the way down from 20 to 1.25. And even then, since these are complex systems, a few other things may need to fall into balance before hunger is fully "normal" again.

 

[Grogu]

After a month of stopping all GLPs cold turkey last October, pizza never tasted better. I was fine until end of week three or so. But it was very humbling at end of week four, with weight going up almost daily in week four.

So if I had to go without GLPs, I like the @lessthanhalf philosophy of avoiding addictive foods almost religiously (which may be less difficult with the diets that promote satiety with starch and protein):

I've read many anectdotal accounts online of a ravenous hunger returning after stopping glp-1 treatment, which quite honestly has me convinced the longterm use is the only way forward, at least for me.

If I had to go without glp-1s, I'm not sure anything would work. Focusing on protein and whole foods along with behavioral modifications sounds great, but has never worked for me in the past. Luckily, we don't have to face a future without glp-1s.... Maybe I should stock up on another 10,000milligrams... oh, that's another thread

 

[tubby]

After a month of stopping all GLPs cold turkey last October, pizza never tasted better. I was fine until end of week three or so. But it was very humbling at end of week four, with weight going up almost daily in week four.

So if I had to go without GLPs, I like the @lessthanhalf philosophy of avoiding addictive foods almost religiously (which may be less difficult with the diets that promote satiety with starch and protein):

I have been curious about how that will play out, but have a ways to go before I'll discover it first-hand. It will be interesting to see if various strategies work better or worse for coping with that period. Probably not a great time to schedule a cruise! LOL

One of the problems here is that most people who more seriously study different dietary strategies tend to poo-poo GLPs and that's the group who would actually have the most interesting case studies to read about, since they'd be in the best position to approach such a period strategically.

 

[Sparky757]

I was in the REDEFINE 4 study in the tirzepatide cohort. No taper period. “Your last dose is Sept 30, and you have one in person blood draw in six weeks” to make sure I wasn’t dead I guess. They gave cursory nutritionist counseling about rejoining the ranks of mere mortals, but nothing more than “continue your healthy habits!” The supervising physician even said to me in my last visit, “the bad news is you will almost assuredly gain all this weight back,” which I thought was an especially prickish way to put it. Then he told me he had eaten keto for like 20 years and that “fruit is God’s candy shop” so I was not convinced I was missing some sage wisdom from him.

It was indeed a rough 6 weeks until I could figure out how to get back on the sauce. However, I had become readdicted to the gym during the 18 month study and liked how eating above maintenance jacked me up right quick.

 

[Calm Logic]

“fruit is God’s candy shop” so I was not convinced I was missing some sage wisdom from him.

Even worse is "sugar causes cancer," a great slogan for promoting the animal protein industry, which conflated starch with sugar anyway.

 

[Foggy-Hollow]

So here's the general idea:

I'm just going to make up arbitrary numbers and oversimplify for the case of illustration here. Let's say before GLPs, a level of 1 in your body happens when you haven't eaten in 3-6 hours and a level of 10 in your body happens when you just pigged out at the buffet and really got your money's worth. Your body is able to naturally vary the level between 0 and 20 just fine, but beyond that simply can't produce a level higher than that on its own.

You then start taking injections that knock your level up to 50, coming back down to 25 before the next shot. Over time you titrate up to higher doses and your levels are now fluctuating between 300 and 150.

When you stop taking injections, your body can't really do anything impactful for that particular hormone until the level comes back down under 20 again. That's going to be a while. Now hunger and fullness aren't handled by just one hormone and you'll still experience those sensations between meals due to other hormones and systems involved in the process. But you're not going to be "normal" again until that level degrades not just to 20, but likely another month later when it has degraded all the way down from 20 to 1.25. And even then, since these are complex systems, a few other things may need to fall into balance before hunger is fully "normal" again.

My point is we don’t know if the body will necessarily start making GLP-1 again, maybe not at month 2 maybe not at month 4. There is an assumption that we don’t have data on.

No one indicated they don’t understand half lives.

We know that testosterone supplementation depresses natural production. We know that BCP also suppresses natural production of hormones. In both cases, some systems have trouble bouncing back and returning to “normal.” Even after all the additions and their metabolites have long been processed out.

Why would GLP-1 be any different? Will it take 2 months, 6 months? There is no data.

The body doesn’t “do anything impactful” but IT IS IMPACTED. It has adjusted to life at 50 and the chemical rug is being pulled out. The person is going to feel like poop because they “feel” -25 because 50 became normal, the new zero. The body dgaf it just knows -25 or -50 sucks donkey balls, and that’s what it feels.

It’s called physical dependency. It’s different than addiction. And no the body won’t “do” anything to get back to 50, we already know that, that’s a meaningless measure.

My original point stands: going from a therapeutic dose to no dose instantly-without a taper-should be malpractice. There no reason to expect anything besides withdrawal and regain in these patients. These meds are tapered onto, it makes ALL the sense to taper off.

 

[tubby]

My point is we don’t know if the body will necessarily start making GLP-1 again, maybe not at month 2 maybe not at month 4. There is an assumption that we don’t have data on.

No one indicated they don’t understand half lives.

We know that testosterone supplementation depresses natural production. We know that BCP also suppresses natural production of hormones. In both cases, some systems have trouble bouncing back and returning to “normal.” Even after all the additions and their metabolites have long been processed out.

Why would GLP-1 be any different? Will it take 2 months, 6 months? There is no data.

The body doesn’t “do anything impactful” but IT IS IMPACTED. It has adjusted to life at 50 and the chemical rug is being pulled out. The person is going to feel like poop because they “feel” -25 because 50 became normal, the new zero. The body dgaf it just knows -25 or -50 sucks donkey balls, and that’s what it feels.

It’s called physical dependency. It’s different than addiction. And no the body won’t “do” anything to get back to 50, we already know that, that’s a meaningless measure.

My original point stands: going from a therapeutic dose to no dose instantly-without a taper-should be malpractice. There no reason to expect anything besides withdrawal and regain in these patients. These meds are tapered onto, it makes ALL the sense to taper off.

I was trying to give you a useful answer based on what you appeared to be referring to. Let's start over on this one. What's your reasoning for thinking that the body ever stopped making GLP-1 or that it would need to restart making it?

And are you referring to production of GLP-1 in the gut (the signal detected by the Vagal nerve) or are you referring to the production of GLP-1 in the brain (the signal your brain is weighting into deciding what kind of hunger signaling to give you)?

 

[lessthanhalf]

You cannot really say that studies just stopping GLP's were unethical. To get the drug approved you first have to prove it is safe and it works, and at least for the earlier studies it was not available yet outside the trials. It is a more valid question about later studies with placebo as the control arm, as opposed to some other drug instead, but to clearly see effects on things like heart disease and mortality , you really need those studies. And while those in the placebo arm are not being helped directly at the time, the knowledge generated will save many lives in the future, and possibly their own once it is available. Trials are not mainly for the benefit of the people in the trials, but for the knowledge they create. Ethics committees do have to approve trials, but it is more about not causing harm than maximising benefit to the trial participants.

 

[MountainsoftheMoon]

I cant imagine getting 36 weeks of appetite suppression and then switching to a placebo . No way the whole group was able to stick to the lifestyle modifications

I call this reflapse

 

[oldjarhead]

Hello darkness my old friend........food noise!

 

[oldjarhead]

I call this reflapse

Relapse! Coined!

Had to wait one minute and 13 seconds to reply. I'm a newbie. A boot. A pleasant. My words and frequency are limited

 

[oldjarhead]

I have tried every diet there is and always gained the weight back. So, it's not a surprise to me. On the other hand, here is what my weight loss and maintenance looks like 75 weeks in. I think I'll stick with the medicine for the rest of my life, thank you very much. View attachment 12478

I'm happy for you. I am only in my 4th mo th of serious healthy goals. I originally thought I could drop 50 lbs in 3 months like my coworker. My coworker was 5' 7" at 245 roided and 40 years old. He is moody mf'r but hard ass worker. He stopped everything and went Tirz. Ate clean and down 50 in three months. Me... down25 in 3.5 months and had zero muscle compared to coworker. Totally disappointed based of coworker but my mindset has changed. I wanted quick weight loss initially, but after three months my.goals have changed. I've been on Tirz compound and have lost weight, but my knee pain pain is the most benefit. At this point, pain gone, I am taking the the slow route on weight loss. I hope to reach my goal weight o. My retirement date 1.5 years in the future. Good bless you and all of your family!

 

[Chili777]

I've already made peace with the fact that I'll be on a GLP1 for my forever. Not just for weight control, but because of all the ancillary benefits. I like the person I am now. I actually have control over food and my habits, not the other way around, and I'm not going to give that up. I've spent half my life trying to fight a losing battle. Been there, done that. I'm older, so it wasn't a hard decision.

 

[Brouette]

I have tried every diet there is and always gained the weight back. So, it's not a surprise to me. On the other hand, here is what my weight loss and maintenance looks like 75 weeks in. I think I'll stick with the medicine for the rest of my life, thank you very much. View attachment 12478

Do you have the same " fear" as me that one day, the medication will stop to work on our body and we will have to look for something else for help?