HPLC_Greg said:

The pharmacokinetics explain nearly every practical question asked here.

Filing a mild objection. Mild because I might be wrong; an objection because nobody has addressed the case that does not fit. The "earlier than weight loss explains" argument is weaker than this thread makes it sound. Blood pressure and inflammatory markers move fast and are downstream of early weight loss, so the mechanism is not as cleanly separable as the summaries imply.

Adding the numbers, since they settle part of this. Numbers worth memorising for this class: Tmax one to three days for the weekly peptides, terminal half-life about a week for semaglutide and about five days for tirzepatide, steady state at four to five half-lives, subcutaneous bioavailability high enough that site choice is irrelevant.

mike_nyc said:

The "earlier than weight loss explains" argument is weaker than this thread makes it sound.

mike_nyc said:

...we're creating a generation dependent on cardiovascular risk...

I understand the concern, but consider this analogy: are we "creating a generation dependent on" blood pressure medication? Cholesterol medication? Thyroid medication?

Obesity is a chronic disease with biological drivers. Treating it with medication is no different from treating any other chronic condition. The "dependency" framing implies weakness or moral failure — neither of which is accurate.

If ongoing medication is what keeps someone healthy, that's successful treatment, not dependency.

A narrower follow-up, since the general answer is now clear:

Which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working?

Reporting back.

Update — tachyphylaxis to the gastric effect, persistence of the appetite effect. Two curves, and I had been watching the wrong one.