CarlaRPh_TPA said:The glucagon component looks paradoxical and is not.
This is where I part company with the consensus forming above. 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.
The figures, for anyone assembling their own picture. For anyone tracking the class: GLP-1 alone gets you appetite, GLP-1 plus GIP adds tolerability and lipid handling, and adding glucagon adds expenditure and liver-fat reduction. Each addition also adds a receptor system that can generate side effects.
Worth separating that from retatrutide, which this thread keeps folding into the same question. They behave differently and the advice does not transfer.
MikeFit_NJ said:The "earlier than weight loss explains" argument is weaker than this thread makes it sound.
Mendelian randomization evidence supporting GLP-1 pathway modulation for cardiovascular risk: genetic variants in the GLP1R gene region associated with lower BMI also show associations with reduced cardiovascular risk, confirming a causal pathway[1].
This "natural experiment" (people born with genetically higher GLP-1 signaling being leaner and healthier) provides orthogonal evidence supporting the pharmacological approach. When genetic epidemiology, clinical trials, and mechanistic studies all converge, confidence in the therapeutic approach is high.
[1] Zheng SL, et al. Lancet Diabetes Endocrinol. 2023;11(12):869-879.
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Browse GL BiochemA narrower follow-up, since the general answer is now clear:
Why adding glucagon agonism to an anti-obesity drug is not self-defeating, given that glucagon raises blood glucose?
OP back with an update, since a thread like this is useless without one.
Rereading it with the dropout table open changed my view. I still think it is the most interesting molecule in the pipeline; I no longer think the 24% is the number that will end up on a label.