A reference post rather than a discussion. Corrections are the point; I would rather this be right than mine. 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
What I am after is how much of the SELECT benefit is plausibly independent of the weight loss, and whether that distinction changes anything practical. I would rather have one careful answer than five confident ones.
wei_SG 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…
NNT calculation for cardiovascular risk clinical endpoints: NNT = 1/ARR (absolute risk reduction).
From SELECT trial: MACE at 39 months — 6.5% semaglutide vs 8.0% placebo. ARR = 1.5%. NNT = 67 over 3.3 years.
Compare to established therapies:
| Intervention | NNT | Timeframe |
|---|---|---|
| Semaglutide (MACE) | 67 | 3.3 years |
| Statins primary prevention (MI) | ~100 | 5 years |
| Aspirin secondary prevention | ~77 | 2 years |
These NNTs are clinically meaningful and comparable to accepted cardiovascular interventions.
wei_SG 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…
Filing a mild objection. Mild because I might be wrong; an objection because nobody has addressed the case that does not fit. 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 ResultsCarlaRPh_TPA said:The "earlier than weight loss explains" argument is weaker than this thread makes it sound.
Anti-inflammatory mechanisms of GLP-1 agonists and cardiovascular risk: beyond weight loss, GLP-1R activation directly suppresses NF-κB signaling, reduces NLRP3 inflammasome activation, and decreases monocyte/macrophage adhesion to endothelium[1].
Clinical correlates: hsCRP reduction of 30-60% (consistently seen across trials), reduced carotid intima-media thickness, and decreased coronary plaque inflammation on PET imaging.
These anti-inflammatory effects likely contribute to the cardiovascular benefit seen in SELECT — and may explain benefits beyond what weight loss alone would predict.
[1] Hogan AE, et al. Diabetologia. 2014;57(4):781-784.
julia.endo said:NNT calculation for cardiovascular risk clinical endpoints: NNT = 1/ARR (absolute risk reduction).
Adding a me-too, because a thread of one person's experience is not much use.