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

[Grogu]

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.

I usually tell my gym bros I'm supplementing with "T" — "Testosterone Replacement Therapy" is too many words. Just kidding, I'm not on T. Yet.

But that's actually a useful analogy for why "replacement therapy" doesn't quite fit here.

With TRT, you're restoring a hormone the body genuinely can't produce in adequate amounts. That's not what's happening with GLP-1 agonists. Most people with obesity don't have a GLP-1 deficiency — and as @woundcarping noted, the dosing is supraphysiologic anyway. The deeper issue is that native GLP-1 has an extremely short half-life (minutes, not days) because it's designed to be a brief postprandial signal. These drugs don't replace deficient GLP-1; they engineer an entirely different pharmacokinetic profile — one that converts a transient pulse into a week-long continuous signal at levels the body never naturally produces. That's not replacement therapy. That's something new.

 

[Calm Logic]

The GLP medications are overkill in a way, but we (as a group) definitely have a dysfunctional incretin system regarding GLP-1, GIP, amylin, etc:

Endogenous Incretin Insufficiency in Obesity: Etiological Defect or Metabolic Maladaptation?

"Evidence consistently demonstrates stimulus-dependent impairment of GLP-1 secretion and functional GIP resistance , both partially reversible following weight loss."

The Roles of Incretin Hormones GIP and GLP-1 in Metabolic and Cardiovascular Health: A Comprehensive Review

"The precise molecular mechanisms underlying this GIP resistance , and whether this state can be pharmacologically reversed to restore GIP’s insulinotropic efficacy, remain areas of intense clinical investigation."

Lactobacillus rhamnosus GG Supernatant Improves GLP-1 Secretion Through Attenuating L Cell Lipotoxicity and Modulating Gut Microbiota in Obesity

" Obesity is associated with decreased secretion of glucagon-like peptide-1 (GLP-1) , which may result from lipotoxic damage to L cells caused by elevated levels of free fatty acids (FFAs)."

https://onlinelibrary.wiley.com/doi/abs/10.1002/mnfr.202300195

" Glucagon-like peptide-1 (GLP-1) deficiency occurs in obesity-related pathologies due to defects in the intestinal lumen. And expanding the L-cell population has emerged as a promising avenue to elevate GLP-1 secretion to tackle metabolic disorders."

https://onlinelibrary.wiley.com/doi/full/10.1038/oby.2002.147

"The elevated amylin levels in obesity may lead to down-regulation of amylin receptors and lessen the impact of postprandial amylin secretion on satiety and gastric emptying. Amylin administration may overcome resistance at target tissues, delay gastric emptying, and have potential for inducing weight loss in obese individuals."

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.111.258285

" Hyperamylinemia is common in patients with obesity and insulin resistance, coincides with hyperinsulinemia, and results in amyloid deposition. Amylin amyloids are generally considered a pancreatic disorder in type 2 diabetes. However, elevated circulating levels of amylin may also lead to amylin accumulation and proteotoxicity in peripheral organs, including the heart."

 

[Grogu]

The GLP medications are overkill in a way, but we (as a group) definitely have a dysfunctional incretin system regarding GLP-1, GIP, amylin, etc:

Endogenous Incretin Insufficiency in Obesity: Etiological Defect or Metabolic Maladaptation?

"Evidence consistently demonstrates stimulus-dependent impairment of GLP-1 secretion and functional GIP resistance , both partially reversible following weight loss."

The Roles of Incretin Hormones GIP and GLP-1 in Metabolic and Cardiovascular Health: A Comprehensive Review

"The precise molecular mechanisms underlying this GIP resistance , and whether this state can be pharmacologically reversed to restore GIP’s insulinotropic efficacy, remain areas of intense clinical investigation."

Lactobacillus rhamnosus GG Supernatant Improves GLP-1 Secretion Through Attenuating L Cell Lipotoxicity and Modulating Gut Microbiota in Obesity

" Obesity is associated with decreased secretion of glucagon-like peptide-1 (GLP-1) , which may result from lipotoxic damage to L cells caused by elevated levels of free fatty acids (FFAs)."

https://onlinelibrary.wiley.com/doi/abs/10.1002/mnfr.202300195

" Glucagon-like peptide-1 (GLP-1) deficiency occurs in obesity-related pathologies due to defects in the intestinal lumen. And expanding the L-cell population has emerged as a promising avenue to elevate GLP-1 secretion to tackle metabolic disorders."

https://onlinelibrary.wiley.com/doi/full/10.1038/oby.2002.147

"The elevated amylin levels in obesity may lead to down-regulation of amylin receptors and lessen the impact of postprandial amylin secretion on satiety and gastric emptying. Amylin administration may overcome resistance at target tissues, delay gastric emptying, and have potential for inducing weight loss in obese individuals."

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.111.258285

" Hyperamylinemia is common in patients with obesity and insulin resistance, coincides with hyperinsulinemia, and results in amyloid deposition. Amylin amyloids are generally considered a pancreatic disorder in type 2 diabetes. However, elevated circulating levels of amylin may also lead to amylin accumulation and proteotoxicity in peripheral organs, including the heart."

I think that the issue is that the body is complicated and there is a lot that science doesn't know about the various mechanism that lead to obesity. But agree, there is definitely some dsyfunction in the mind-gut signaling system of most obese individuals.

The last two articles are the most interesting to me. Mostly because I'm obsessed right now (like a mad scientist or lunatic ) about eloralintide and the amylin receptor pathways.

The first of the two article really shows how fast knowledge is being created in this area. Just in 2012, the authors speculate that amylin administration has the "potential" of inducing weight loss. Fast forward 14 years and elora is not only effective at inducing weight loss, but also appears to provide equivalent weight loss as glp-1 pathways, which can provide excess weight loss comparable to gastric surgery, which had been the standard of care for the truly obese for decades. Who would have thunk that there was an entire different pathway that could induce such large weight loss? But what does this mean. I think it means that obesity is complicated.

The second of the two amylin articles is also interesting. I never thought about amylin levels being too high in the obese. And it looks like too high levels can result in aggregation of fibrils in the heart. Just when I was convinced that fibrils weren't going to make their way to my brain, now I have to worry about my heart .

 

[Calm Logic]

You can even see GLP-1 "granules" in the imaging of the L-cells secreting them:

Experience with 20mg/wk reta?

I am at 12mg/wk reta with 3mg/wk cagri though these numbers may be ~20% low due to overfill. As I approach normal BMI, my loss rate has slowed from .24lb/day to .18lb/day over the past 4 months. I am considering titrating up again (likely to ~15mg/wk reta, ~4mg/wk cagri), as my loss rate has...

glp1forum.com

"At the highest magnification, the individual GLP-1 granules are visible."

 

[geoguy78]

I think the problem is people are getting off the drug too early. It takes a while for body to adjust to new set weight/metabolism, that's the reason of the weight regain. Our body wants to get back to previous weight, by increasing cravings. I think at least 6 months maintenance with the lowest possible dose that keep us from maintaining healthy lifestyle is a MUST. I'd be confident to stop using tirz/reta once I know I'm metabolically healthy.

The studies I've read suggest that fat cells not only have a "memory" of their largest size, but that they live for approximately 8 years. It will be interesting to see what happens to people that maintain goal weight for long periods of time (I'm talking years) that discontinue. Can we actually create a new set point if enough of our fat cells from the obesity years die off? I would like to discontinue at some point but it will be a few more years of maintaining before I'll seriously entertain the thought.

 

[UpDownLeftRightAS*]

"The findings suggest that short-term weight loss may not immediately reduce the risk of some disease conditions associated with obesity, including type 2 diabetes and some cancers," says co-lead author Claudio Mauro, an immunologist at the University of Birmingham in the UK.

"Instead, ongoing weight management following loss will see the 'obesity memory' slowly fade," Mauro says.

"This may take several years of sustained weight loss maintenance, likely five to 10 years, though this requires further study, to fully reverse the effects of obesity on T cells." https://www.sciencealert.com/immune-cells-remember-obesity-long-after-weight-loss-study-finds

 

[Pin&Play]

"The findings suggest that short-term weight loss may not immediately reduce the risk of some disease conditions associated with obesity, including type 2 diabetes and some cancers," says co-lead author Claudio Mauro, an immunologist at the University of Birmingham in the UK.

"Instead, ongoing weight management following loss will see the 'obesity memory' slowly fade," Mauro says .

"This may take several years of sustained weight loss maintenance, likely five to 10 years, though this requires further study, to fully reverse the effects of obesity on T cells." https://www.sciencealert.com/immune-cells-remember-obesity-long-after-weight-loss-study-finds

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Do you guys also plan to share some good news in this thread?

 

[Grogu]

Do you guys also plan to share some good news in this thread?

The good news is if you continuously stay on glp-1s and don’t take a break you’ll be the skinny rat

 

[ambot88]

Well this confirms my fear that I'll have to be a lifer on a GLP. It kind of stresses me out, like, I don't mind taking them but also LIFE is still kinda long and I have worries about ongoing access in the far future. Even the 8 year fat cell life theory is a little more hopeful - If I think I have to be on for 8 years that seems less alarming than LIFE.

 

[Grogu]

Well this confirms my fear that I'll have to be a lifer on a GLP. It kind of stresses me out, like, I don't mind taking them but also LIFE is still kinda long and I have worries about ongoing access in the far future. Even the 8 year fat cell life theory is a little more hopeful - If I think I have to be on for 8 years that seems less alarming than LIFE.

But, who knows what the future will hold? I wouldn't stress out and get fixated on taking these meds for LIFE, maybe think about it as the foreseeable future, especially if you're young(er).

To me, since these medications correct one or more signaling issues in the endocrine system and given the fact that some people are afflicated and some not, then that would point to genetics playing a role. Maybe one day, if you're young enough, there is a gene therapy.

Also, who knows what the future will hold as far as frequency and even the need to take shots. MariTide is a once a month injectable. Amgen used a monoclonal antibody backbone to extend the half-life. Some of the current pills coming to market might also be a possible more palatable path forward for many on maintenance.

The future is bright for obesity treatments. As much as many of us hate BP sometimes, they did bring us these miracle medications.

 

[alphaamigo]

What would this mean for people who occasionally stack glp1 meds for breaking stalls? Would going up and down have the same impact as start/stopping?

 

[woundcarping]

What would this mean for people who occasionally stack glp1 meds for breaking stalls? Would going up and down have the same impact as start/stopping?

That is a question that hasn't been studied.

It's along the same lines as getting to maintenance and reducing the dose. Some people have good experiences with dose reduction and maintaining weight. There was a study on reducing dose/increasing duration that was "positive" for the idea, but at the moment I don't recall the specific.

 

[HereKittyKitty]

Well this confirms my fear that I'll have to be a lifer on a GLP. It kind of stresses me out, like, I don't mind taking them but also LIFE is still kinda long and I have worries about ongoing access in the far future. Even the 8 year fat cell life theory is a little more hopeful - If I think I have to be on for 8 years that seems less alarming than LIFE.

Just take it one day at a time. You can eat an elephant in small bites.