GLP-1 non-responders?

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Izzy

Well-known member
Check this out: Kowalski et al. (2025). Understanding incretin unresponsiveness - a model for categorizing treatment variations with GLP-1 receptor agonists. Journal of Endocrinology, 68, 122.
 
Ok, so basically, not everyone gets the same results from GLP-1s. The article says there are different reasons WHY some folks don't respond. If we can figure out the reason, maybe we can find a way to make the meds work for them later.
 
In a nutshell, the article suggests that if GLP-1 receptor agonist therapy isn't effective, it's not necessarily a drug failure. The person's body might not be receptive at the moment due to receptor problems, signaling pathway issues, or insufficient hormone release. Identifying the specific mechanism could lead to more tailored treatment strategies instead of just upping the dose or switching meds blindly. However, the authors also mention that there aren't readily available, validated tests to determine which "type" a person falls into yet.
 
That's really insightful. Appreciate the explanation. My experience with tirzepatide has been less dramatic than others'. Maybe I'm in that receptor resistance group. I'm okay with slower progress, as long as I'm moving in the right direction. It's hard to see day to day.
 
I barely lost any weight on tirzepatide for like, 8 months, only about 5 lbs. I was on the max dose and had terrible side effects: bloating, queasiness, sulfurous burps, exhaustion, just generally feeling awful.

But about 2 months ago, I switched to retatrutide with cagrilintide, and I've already dropped 30+ lbs. Once I started the cagri, the constant food thoughts just stopped. We need way more research into non-responders. I definitely don't seem to fit into any of those categories mentioned.
 
So, people with secretory deficiencies caused by messed up enteroendocrine cell function? Sounds like it could explain why some folks complain about GI issues even at tiny doses? I'm not one of them (at 5mg and no problems yet, knock on wood!), but they're talking about sulfur burps, diarrhea, and other fun stuff that makes them want to quit. The article says they're "excellent responders to exogenous incretin therapy". If I was super-sensitive, I'd be looking into incretin therapy. Seems like the studies are mostly about T2D for now:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397999/
 
I actually managed to say "impaired enteroendocrine cell dysfunction" five times, but I did it super slowly, and definitely not in front of anyone. Trying to say it fast would be like me trying to dunk a basketball. Not gonna happen. I can't even say IECD fast five times.
 
This is super interesting! Thanks for sharing, @Izzy. So, @Med_Queen499, am I understanding correctly that the people with receptor-level resistance might do better on reta if tirzepatide isn't working?
 
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I'm just a random person, not a scientist! But yeah, I read the article and got the same idea, but the authors had a bunch of conditions that you left out. You were just trying to be more straightforward, I guess. They thought GIPR agonists could help that first group, but they want more research first. They said those agents offer a different path around receptor issues... Possible causes of being that first type of nonresponder? They only listed possible reasons.
 
I've read that some people try increasing their dose if they plateau, but always talk to your doctor first. Also, make sure you're drinking enough water and getting enough fiber and protein. Sometimes that helps break through it.
 
Danielle_Path said:
I've read that some people try increasing their dose if they plateau, but always talk to your doctor first. Also, make sure you're drinking enough water and getting enough fiber and protein. Sometimes that helps break through it.
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Thanks for the advice! I'll try upping my fiber. Been slacking on that lately.
 
Izzy said:
It's wild how differently people respond to these meds. I saw one person online lost almost 40 lbs in 8 months and they look amazing!
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Individual variability in drug response is a very complex area. Factors like genetics, lifestyle, and gut microbiome composition can all play a role.
 
Response variability is mostly receptor density - super-responders tend to have higher baseline GIP/GLP-1 receptor expression.
 
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