Writing this once so I can stop repeating it across threads. 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 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. Tell me what I have not thought of.
Dr.NephBHM_UK 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…
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.
Dr.NephBHM_UK 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 Dr.NephBHM_UK 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.
PeptideDetective — Independent Peptide Analytics
Community-driven peptide testing and vendor rating platform. Transparent results. Unbiased analysis. Trusted by thousands.
View ResultsDr.MetabolicMD said:The "earlier than weight loss explains" argument is weaker than this thread makes it sound.
CRP reduction on cardiovascular risk — this is the lab result that excites me most:
Baseline hsCRP: 12.0 mg/L (high cardiovascular risk)
Month 6 hsCRP: 2.5 mg/L (moderate risk)
Month 12 hsCRP: 0.8 mg/L (low risk)
This level of inflammatory marker reduction is comparable to what you'd see with statin therapy. Combined with the weight loss, my 10-year ASCVD risk score dropped from 19% to 5%. My cardiologist is genuinely impressed.
TrialTracker_MD said:Anti-inflammatory mechanisms of GLP-1 agonists and cardiovascular risk: beyond weight loss, GLP-1R activation directly suppresses NF-κB signaling,…
Adding a me-too, because a thread of one person's experience is not much use. The detail I would add is minor and it is already implied above.