Unless long-term data on the fifth compound eventually reveals harm tied to glucagon activation, that outcome seems fairly improbable. There's substantial research behind the second compound already, so genuinely surprising new side effects seem unlikely. And those higher-dose trials on the first compound, at amounts well above standard, predictably showed elevated nausea and vomiting rates along with somewhat underwhelming extra weight loss, but nothing beyond the already-documented risk profile, just more of it. So for this drug class broadly, the safety track record over time looks genuinely solid, even at doses that seem excessive just reading about them. Pretty reassuring for the GIP mechanism specifically, though research on the fourth and fifth compounds is still much earlier stage.
The one piece of research that hints at possible receptor damage is that recent post covering a stop-and-restart pattern in animal models causing complications and reduced effectiveness. Beyond that there's really nothing else pointing to long-term issues, and weight loss held steady across five full years at a fixed dose without any upward creep, if tolerance to the effect were building over time, that trend line would show it
