Chart Showing Comparative Activation of Different Receptors by GLP-1 Drugs Involved

[keangkong]

I saw a chart repeatedly showing the supposed potencies of different weight loss drugs in humans. I assumed that the information in it was wrong, but when I checked, everything matched scholarly sources.

The profiled drugs are semaglutide, tirzepatide, retatrutide, mazdutide, and survodutide.

I realize that there are caveats I should be adding on using the data but I'm so inexpert in this field that I can't even explain well the reason for the caveats.

I'm adding an image of the chart along with sources. I'm also attaching a .pdf document, which will permit you to click on the hyperlinks in order to access the source documents without having to go through a paywall.

 

[PopTart]

Thanks for pulling this together!

 

[indolent]

Thanks.

This seems an important concept for stall-breaking, and a reason to avoid simplistic "more agonists = better" thinking.

Each of the receptors has a primary association with a desirable effect (food noise suppression, gastric slowing, energy allocation or whatever). So switching or stacking retatrutide, for example, might not efficiently solve a patient's particular stall problem.

I'd try to list those associations, but I don't want to do it incorrectly off the top of my head, and right now I'm busy taking a train from Agrigento to Palermo.

 

[YoYoFat]

I saw a chart repeatedly showing the supposed potencies of different weight loss drugs in humans. I assumed that the information in it was wrong, but when I checked, everything matched scholarly sources.

The profiled drugs are semaglutide, tirzepatide, retatrutide, mazdutide, and survodutide.

I realize that there are caveats I should be adding on using the data but I'm so inexpert in this field that I can't even explain well the reason for the caveats.

I'm adding an image of the chart along with sources. I'm also attaching a .pdf document, which will permit you to click on the hyperlinks in order to access the source documents without having to go through a paywall.

Did that chart come from a study or was it created by someone interpreting the studies? Because I’ve seen other charts which switch the GLP and GIP numbers for Tirz (less GLP in Tirz than Sema), which makes a lot more sense to me than this one given how Tirz is so much better tolerated than Sema.

 

[IshimaruKenta]

 

[miss-sanne]

Did that chart come from a study or was it created by someone interpreting the studies? Because I’ve seen other charts which switch the GLP and GIP numbers for Tirz (less GLP in Tirz than Sema), which makes a lot more sense to me than this one given how Tirz is so much better tolerated than Sema.

The Chart does not show humans response.
It came from in vitro studies.
So it's really all theory, because not testet on humans.
Nobody knows if humans have the same.

 

[indolent]

Did that chart come from a study or was it created by someone interpreting the studies? Because I’ve seen other charts which switch the GLP and GIP numbers for Tirz (less GLP in Tirz than Sema), which makes a lot more sense to me than this one given how Tirz is so much better tolerated than Sema.

With the measure shown in that chart, a lower number indicates a greater affinity. Not sure if that jibes with what you're saying, or not.

 

[keangkong]

Did that chart come from a study or was it created by someone interpreting the studies? Because I’ve seen other charts which switch the GLP and GIP numbers for Tirz (less GLP in Tirz than Sema), which makes a lot more sense to me than this one given how Tirz is so much better tolerated than Sema.

I had seen the chart before but I had discounted the likelihood of it being accurate after I did a Google search for it. While I found the chart shown elsewhere, I didn't find it cited in any sources that I consider reliable. By reliable, I mean with references to scholarly stuff. Therefore, I asked ChatGPT to prepare a chart. ChatGPT did so. I then search for authority for everything in the ChatGPT chart. I found authority for all figures except for survodutide. The numbers I found for survodutide were different. Later, I looked again at the same black background chart. I realized that the numbers matched the ChatGPT chart except for survodutide. The numbers it provided for survodutide matched the numbers I found. As a result, I consider the black chart to be accurate.

As to the numbers, the bigger the number, the weaker a drug is at activating a given receptor.

Is semaglutide really that much stronger of an activator of GLP-1? Semaglutide is stronger when taken, however, the chart overstates the practical effect in humans because people take tirz at a much higher dosage. Is there a mathematical way to calculate the relative potencies of different drugs based upon the half life of the drugs, the maximum doses, and the ki values? I don't know how to do such math and I don't know if there is even a mathematical formula that would produce such a result.

 

[keangkong]

The Chart does not show humans response.
It came from in vitro studies.
So it's really all theory, because not testet on humans.
Nobody knows if humans have the same.

The studies were conducted in vitro using human GLP-1 receptors.

 

[Nathanologist]

So… seems like a common complaint switching from Tirz to Reta is a plateau or even regression of weight loss or other desired outcome.

The weaker GLP-1R affinity in Reta (Ki: 7.2 nM) compared to Tirz (Ki: 4.23 nM) could possibly be the reason, no? Pharmacologically, stacking a small dose of Semaglutide with Retatrutide makes sense. It targets all three pathways with maximum binding strength by covering Reta's weakest spot with the strongest available agonist. Thoughts?

I also tasked ChatGPT and Gemini to fact check the charts and my conclusion. They both agreed generally with the figures, but not specifically with them having backing. So take the whole AI thing for what it is. I’d call it close enough for the shady world we navigate.

 

[keangkong]

I saw a chart repeatedly showing the supposed potencies of different weight loss drugs in humans. I assumed that the information in it was wrong, but when I checked, everything matched scholarly sources.

The profiled drugs are semaglutide, tirzepatide, retatrutide, mazdutide, and survodutide.

I realize that there are caveats I should be adding on using the data but I'm so inexpert in this field that I can't even explain well the reason for the caveats.

I'm adding an image of the chart along with sources. I'm also attaching a .pdf document, which will permit you to click on the hyperlinks in order to access the source documents without having to go through a paywall.

I botched the hyperlink for semaglutide. It led the doi, but did not lead to a paywall free article. I fixed that. Comparative Binding Affinities.pdf.

Here is the link to the article: Lau, et al. (2015). Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. Journal of Medicinal Chemistry, 58(18), 7370–7380.pdf.