Love this!

I tried tirz earlier but moved to the 10 mg reta plus 2 mg sema combo and am keeping that for maintenance. Reta is weak on GLP-1R, so the two pair well and probably got me to the 30 % mark. Sema was my starting point because insurance paid for it; I dropped about 12 % quickly then plateaued. Adding tirz 10 mg pushed me to roughly 25 %, and reta took it further. Sema is strong on GLP-1R compared with tirz or reta, so even a small amount stacked with them makes sense and should add at least another 5 % loss.

I like sema as well and cannot recall why I stopped stacking it. So right now you are on 10 mg reta, 2 mg sema, and 1 mg elora, or did you only use the elora to reach goal and then stay on the reta/sema combo?

Yes, that is exactly what I am doing: 1 mg elora with the 10 mg reta and 2 mg sema. I plan to finish the current vial of elora, then stop it and see whether the reta/sema pair holds the weight for maintenance. It is still early, but I will check back in a month or two.

Please let us know how it goes. I might try adding a little sema to my own stack.

Your point about biased agonism is fair: tirzepatide prefers the cAMP route and avoids beta-arrestin internalization, while sema activates both paths and therefore causes more internalization. Both reta and tirz are built on the GIP backbone, whereas sema is essentially GLP-1 with changes that extend half-life and albumin binding. Even so, the actual EC50 and Ki data still show sema is markedly more potent at GLP-1R. The reason higher tirz doses are tolerated with fewer side effects is precisely because it is less efficient at that receptor despite the bias; GIP activation itself does not produce those side effects.

Glad it helped. I do not see it as a full substitute for the GLP-1 drugs, but it did get me past a stubborn plateau.