“MY GLP IS NO LONGER WORKING.” · Peptides: Out of the Shadows

“MY GLP IS NO LONGER WORKING.”

I've been seeing some version of this more and more:

Response begins to decline → increase the dose of the same GLP → response declines again → increase the dose again.

Eventually the question becomes:

“Why isn't my GLP working anymore?”

I recently listened to Alex Kikel discuss this issue, and he raised an interesting theory that I think is worth digging into.

Kikel questions whether continually titrating the same GLP agonist upward as response declines is necessarily the answer.

We've all seen the pattern:

My GLP isn't working like it used to.↓

Increase the dose of the same GLP.↓

Response declines again.↓

Increase the dose again.

But what if continually pushing the same agonist through the same receptor pathway isn't the answer?

Kikel's hypothesis is that with prolonged and increasingly aggressive GLP agonist exposure, we may eventually be dealing with something beyond simple tolerance or temporary receptor desensitization.

He uses the term “receptor decay.”

In other words, what if continually pushing the same signaling pathway harder eventually changes the availability or responsiveness of the receptors we're trying to stimulate?

Likel bases this theory on his own research and observations of what he has seen with prolonged GLP use. I think his observations raise a legitimate question that is worth taking into the published research and investigating further.

SO WHAT DOES HE PROPOSE?

Instead of automatically continuing to increase the dose of the same GLP agonist, Kikel discusses changing the agonist and changing the receptor signaling profile.

That also fits with something Kikel has consistently advocated:

Use the lowest possible dose that produces the desired benefit.

The idea isn't:

“My GLP stopped working, therefore I need more.”

It's questioning whether continuing to push the same agonist at increasingly higher doses makes sense when the response has already begun to decline.

Look at the different receptor profiles:

Semaglutide → GLP-1

Tirzepatide → GLP-1 + GIP

Retatrutide → GLP-1 + GIP + glucagon

Moving to a different compound changes the signaling profile rather than simply continuing to increase stimulation from the same agonist.

And when beginning that different GLP-based compound, Kikel's philosophy remains the same:

Start with the lowest effective dose and evaluate the response.

THEN KIKEL SAID SOMETHING THAT REALLY GOT MY ATTENTION

He discussed what he called an:

“SS-31 RESET.”

His hypothesis is that SS-31 (elamipretide) may potentially help address the receptor problem he believes can develop with prolonged GLP agonist exposure.

And that's where I really started paying attention.

SS-31 is primarily associated with mitochondrial function, cardiolipin and the inner mitochondrial membrane.

So I immediately had questions. Can prolonged GLP agonism actually cause meaningful receptor downregulation or loss? Can changing agonists and receptor targets restore responsiveness?

And most interesting to me- Is there actually a biological pathway through which SS-31 could preserve or restore GLP-1, GIP or glucagon receptor function?

Kikels position comes from his own research and observations.

I'm sharing it because I found the concept interesting and thought it was worth bringing to Dark Horse for discussion.

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“MY GLP IS NO LONGER WORKING.”