Putting this up for argument rather than for agreement. I have read it twice and I am still not certain what it supports.
SELECT is the trial that changed the framing of this class, because it was an outcome trial rather than a weight trial: about a 20% relative reduction in major adverse cardiovascular events in people with established cardiovascular disease and overweight or obesity, without diabetes. The effect appeared earlier than the weight-loss curve can comfortably explain, which is the basis for arguing that some of the benefit is direct — anti-inflammatory and vascular — rather than purely a consequence of weight.
Where I think it is weakest: the follow-up is short relative to how long people actually take these drugs, so durability is an assumption here rather than a finding.
The question I want answered is how much of the SELECT benefit is plausibly independent of the weight loss, and whether that distinction changes anything practical. Happy to be told the question itself is wrong.
Dr.RenalNash said:SELECT is the trial that changed the framing of this class, because it was an outcome trial rather than a weight trial: about a 20% relative reduction…
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.
Dr.RenalNash said:SELECT is the trial that changed the framing of this class, because it was an outcome trial rather than a weight trial: about a 20% relative reduction…
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.
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Browse GL BiochemShort answer first, then the reasoning. The mechanism is more central than most summaries suggest. Receptor agonism in the arcuate nucleus activates POMC neurons and inhibits AgRP/NPY signalling, and the downstream MC4R pathway is the same one disrupted in monogenic obesity — convergent genetic evidence that the target is the right one. Peripherally there is glucose-dependent insulin secretion, glucagon suppression and delayed gastric emptying, but the gastric component largely adapts over months while the central effect persists, which is why the durable effect is appetite rather than fullness.
Dr.RaviCardio said:Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were…
Second this.