If true pharmacological tolerance developed to GLP's, the drug's core effects would gradually weaken over time—even while continuing the same dose. This would mean the
appetite suppression, satiety signals, and glucose regulation would fade, leading to increased hunger, higher calorie intake, and weight regain while still on the medication.
That's not what the evidence shows in long-term studies (e.g., STEP and SURMOUNT extensions, up to 2+ years).
Instead:
- Weight decreases steadily at first.
- Then it levels off into a plateau—no further loss, but also no regain as long as the drug is continued at a stable dose.
- People maintain the lower weight for extended periods (often 1–2+ years in trials), with sustained appetite control and metabolic benefits.
This happens because GLP-1 agonists don't simply "force" weight loss. They act on brain and gut pathways to mimic signals that tell your body it's at a certain weight level—adjusting hunger, fullness, and energy use accordingly. The medication effectively shifts your body's defended "set point" (or settling point) downward. Once you reach a new equilibrium at that lower weight:
- Energy intake matches the reduced energy expenditure (a smaller body burns fewer calories at rest due to normal metabolic adaptation).
- The drug continues sending appropriate signals for that new level, preventing rebound hunger or regain.
A plateau reflects the balance—not the drug losing effectiveness. True tolerance would cause the signals to weaken, hunger to return, and weight to climb back up despite ongoing treatment. Studies confirm that doesn't occur; regain typically happens only
