Glucagon receptor agonism and hepatic lipid oxidation — need advice

Taking the question as asked, rather than the general version of it. The pharmacokinetics explain nearly every practical question asked here. Albumin binding above 99% slows clearance enough to make weekly dosing possible; a terminal half-life near a week means four to five weeks to steady state and therefore a four-week titration interval; subcutaneous bioavailability around 89% means injection site barely matters. Those three facts answer most timing questions before they are asked.

If somebody has the primary source to hand I would rather cite it than paraphrase it.

BethLabQueen said:

The pharmacokinetics explain nearly every practical question asked here.

Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were relying on physical fullness feel the effect fade while the appetite effect is still working.

I would rather be corrected than agreed with, if it comes to it.

mike_mod said:

Watching the glucagon co-agonists for the liver endpoints and finding almost nothing written about them that is not a press release.

Adding a me-too, because a thread of one person's experience is not much use.

Clinical perspective, offered as context rather than as advice.

Glucagon receptor pharmacology in triple agonists (retatrutide), relevant to the glucagon co-agonists: the glucagon component is the most controversial because glucagon traditionally raises blood glucose. So why include it in an anti-obesity drug?

Key insight: glucagon increases energy expenditure (thermogenesis), promotes hepatic lipid oxidation, and reduces appetite through distinct CNS mechanisms. The hyperglycemic effect is counterbalanced by the GLP-1 component's insulin secretagogue action.

Net result: more weight loss through increased expenditure (glucagon) + decreased intake (GLP-1/GIP), with neutral or improved glycemia. An elegant pharmacological balancing act[1].