This interesting article proposes dividing patients non-responsible to GLP-1 drugs into three different categories

[keangkong]

Fajkić, et al. (2025). Decoding incretin resistance - a mechanistic framework to reclassify therapeutic variability for GLP-1 receptor agonist therapy. Amino Acids 57, 55.

 

[YoYoFat]

Can you explain this in lay person?

 

[keangkong]

Can you explain this in lay person?

Not very well. Only that there are different people don't respond to GLP-1 drugs. And figuring out which reason applies may one day help turn those nonresponders into people who benefit from GLP-1 drugs.

 

[Jfrick11]

Can you explain this in lay person?

The article essentially says......when someone doesn’t respond well to GLP-1 receptor agonist therapy, it’s not just because “the drug failed” — it might be because their biology isn’t suited (for now) to that therapy, due to receptor issues, signalling issues, or lack of endogenous hormone release. They argue that this could make it important in recognizing which mechanism is at play can help choose a more appropriate therapy, rather than simply increasing dose or changing drug without any insight. Having said that...they also say that currently there is no simple, validated diagnostics in every day practice to say definitively which “type” a person is.

 

[lostlakebear]

This is very interesting. Thank you for posting. My response to tirz has been somewhat muted compared to many on this forum. I fit the receptor-level resistance profile. I can live with slow and steady. I feel stuck unless I look back siz months at a time.

 

[eyfm!]

I didn’t respond to Tirzepatide at all for nearly 9 months and only lost about 6 pounds. I was on the highest dose and dealt with awful side effects like bloating, nausea, sulfur burps, fatigue, and just feeling miserable overall.

About 2.5 months ago, I switched to Retatrutide plus Cagrilintide, and I’m already down 33 pounds. Once I added cagri, the food noise basically disappeared. I think we need much more research on non-responders, because I definitely don’t fit into any of the categories described here.

 

[JoonyO]

Those who have secretory deficiencies which are due to impaired enteroendecrine cell dysfunction? That would seem to explain ( to me anyway ) why some complain of " pronounced GI symptoms at low doses"? I'm not one of 'em ( I'm at 6mg -5 days and have not had any of what I've heard others complain of...YET🤞 ) but they relate their having sulpher burps, diarrhea and other GI issues at extremely low doses making them question whether they should continue use as treatments for weight loss.
It also says that they're "excellent responders to exogenous incretin therapy". Were I one of these super or hyper responders ( whatever the hell label they're given ) I would think I'd be looking into incretin therapy. And like GLP-1s initial introduction it seems that the studies are around T2D.

Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits - PMC

pmc.ncbi.nlm.nih.gov

 

[skeptick]

Those who have secretory deficiencies which are due to impaired enteroendecrine cell dysfunction? That would seem to explain ( to me anyway ) why some complain of " pronounced GI symptoms at low doses"? I'm not one of 'em ( I'm at 6mg -5 days and have not had any of what I've heard others complain of...YET🤞 ) but they relate their having sulpher burps, diarrhea and other GI issues at extremely low doses making them question whether they should continue use as treatments for weight loss.
It also says that they're "excellent responders to exogenous incretin therapy". Were I one of these super or hyper responders ( whatever the hell label they're given ) I would think I'd be looking into incretin therapy. And like GLP-1s initial introduction it seems that the studies are around T2D.

Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits - PMC

pmc.ncbi.nlm.nih.gov

impaired enteroendecrine cell dysfunction Bet you can't say that fast five times

 

[JoonyO]

impaired enteroendecrine cell dysfunction Bet you can't say that fast five times

Awe hell.🙁 I tried. Didn't even make it through the FIRST time without stumbling! 🤣🤣🤣

 

[keangkong]

impaired enteroendecrine cell dysfunction Bet you can't say that fast five times

I said "impaired enteroendocrine cell dysfunction" five times correctly (in my view). I said the phrase quite slowly. I also did not say it in front of people. I'm not going even try saying it fast five times; that would not work. That would be like me trying to jump twenty feet into the air; it's not going to happen. I can't even say IECD fast five times.

 

[keangkong]

Awe hell.🙁 I tried. Didn't even make it through the FIRST time without stumbling! 🤣🤣🤣

@JoonyO I didn't see the entire 50 shades of gray. I did watch part of the movie before becoming bored and turning it off. As a result, I figure I watched about 15-20 shades of gray.

 

[Thistley]

Very interesting! Thank you kindly for posting. So if I am reading this correctly @keangkong, it’s saying that the first type of non responder the - receptor level resistance group, should respond to Reta if they find Tirz hasn’t worked for them?

And so the causes of non response in this group come about because of faulty/damaged receptors interactions in the pancreas caused chronic hyperglycemia/ inflammation/ or epigenetic modifications affecting receptor gene transcription.