This is the version of the explanation I wish somebody had given me, written down before I forget what confused me. It is about cardiovascular outcomes, and it is deliberately narrow — everything I am not confident about is marked as such.
What is actually established
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.
The condition it depends on
The qualification that SELECT enrolled a secondary-prevention population. Extrapolating a 20% relative reduction to a healthy 35-year-old with a BMI of 31 is not what that trial showed.
The practical version
Relative versus absolute is the distinction that gets lost: a 20% relative reduction on a high baseline risk is a large absolute benefit, and the same relative figure on a low baseline risk is a small one.
What I am not sure about
So the question, as narrowly as I can put it: how much of the SELECT benefit is plausibly independent of the weight loss, and whether that distinction changes anything practical. If the honest answer is that nobody knows, that is a useful answer and I would rather have it.
pam_stl 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, though "tolerable" needs defining. A dose you tolerate by eating almost nothing is not tolerated, it is being paid for somewhere else — usually in lean mass, sometimes in adherence three months later.
pam_stl 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…
Pushing back on pam_stl here. 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.
Happy to go further on any of that.
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Browse GL BiochemAnswering the narrow version, because the broad one does not have a single answer. The dose-response is real but shallow at the top. Across STEP 1 and STEP 4 the gap between 1.7mg and 2.4mg is a couple of percentage points of body weight on average, and the average is carrying a wide spread — plenty of people at 1.7mg sit above the 2.4mg mean. If a dose is working and tolerable, "working" is the relevant variable, not "maximal".
Correct me if the detail matters more than I have assumed.
PharmacoVig_BOS said:Agreed, though "tolerable" needs defining.
All true, with one condition: that curve is for people who reached the dose on schedule. Anyone who slowed the ladder for tolerability is on a different, flatter curve, and comparing yourself with the published mean will make you feel like a non-responder when you are not.