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
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. If the honest answer is that nobody knows, that is a useful answer and I would rather have it.
tony_orlando 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…
Continuous metabolic monitoring dashboard for cardiovascular risk — I track everything in a spreadsheet and here's the month-over-month trend for my key markers:
Weight: consistent downtrend, -2.3 lbs/week average
Fasting glucose (finger stick): stable at 86 mg/dL
Blood pressure (home): 118/72 average
Resting heart rate: 66 bpm (down from 82)
Waist circumference: down 16 inches total
The resting heart rate improvement correlates with cardiovascular fitness gains. Everything is moving in the right direction.
tony_orlando 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.
That is the short version; the long version is somebody else's post.
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View Resultsamsterdam_pete said:The "earlier than weight loss explains" argument is weaker than this thread makes it sound.
SUSTAIN-6 was the first CVOT to show cardiovascular benefit with semaglutide, relevant to cardiovascular risk. In 3,297 T2DM patients with high CV risk: MACE HR 0.74 (95% CI 0.58-0.95, p=0.02)[1].
Notable: the retinopathy signal in SUSTAIN-6 (HR 1.76) was subsequently attributed to rapid A1C reduction in patients with pre-existing retinopathy — not a direct drug effect. This has been confirmed in longer-term follow-up studies.
[1] Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844.
HPLC_Greg said:Continuous metabolic monitoring dashboard for cardiovascular risk — I track everything in a spreadsheet and here's the month-over-month trend for my…
Can confirm. Same sequence, different timescale. I had assumed I was the exception until I read this.