Posting this because the summary going around does not say what the paper says, and the difference matters for how people here are using it.
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.
Where I think it is weakest: the subgroup findings are the part I trust least — with enough subgroups something is always significant, and these were not all pre-registered.
What I actually want to know is how much of the SELECT benefit is plausibly independent of the weight loss, and whether that distinction changes anything practical. Happy to be told the question itself is wrong.
Figures above are from the primary publication rather than the press summary. If a number here disagrees with one you have, post yours and we will work out which of us is reading a secondary source.
DeniseRN_TPA 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…
DeniseRN_TPA said:...we're creating a generation dependent on cardiovascular risk...
I understand the concern, but consider this analogy: are we "creating a generation dependent on" blood pressure medication? Cholesterol medication? Thyroid medication?
Obesity is a chronic disease with biological drivers. Treating it with medication is no different from treating any other chronic condition. The "dependency" framing implies weakness or moral failure — neither of which is accurate.
If ongoing medication is what keeps someone healthy, that's successful treatment, not dependency.
DeniseRN_TPA 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 DeniseRN_TPA 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.
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View ResultsLibrarianMeg 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.
TrialTracker_MD said:DeniseRN_TPA said: ...we're creating a generation dependent on cardiovascular risk...
Second this.