Collecting this in one place because it comes up every few weeks and the answer is always assembled from scratch. 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
The narrow version of the question is how much of the SELECT benefit is plausibly independent of the weight loss, and whether that distinction changes anything practical. I have searched first, so if this is covered somewhere point me at it and I will read it.
cory_ATX 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…
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.
Correct me if the detail matters more than I have assumed.
cory_ATX 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…
I read this differently from cory_ATX, on substance rather than tone. 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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View ResultsAnswering the narrow version, because the broad one does not have a single answer. Steady state is the thing most people miss. The terminal half-life is about a week, so every dose step takes four to five weeks to fully express itself. Judging a step at day ten is judging the ascent, not the plateau, and it is the single commonest reason people escalate before they needed to.
Dr.SurgeonPGH said:All true, with one condition: that curve is for people who reached the dose on schedule.
That holds for the injectable. The oral formulation has different absorption behaviour and the dose numbers are not interchangeable, which is worth saying out loud because people quote them as if they were.