Dr.RaviCardio 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…

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.

Dr.RaviCardio 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…

This is where I part company with the consensus forming above. 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.

BenResearch_OR said:

The "earlier than weight loss explains" argument is weaker than this thread makes it sound.

BenResearch_OR said:

...cardiovascular risk is just another fad...

I understand the skepticism — we've all seen "miracle" weight loss solutions come and go. But consider what makes GLP-1 agonists different:

• Phase 3 RCTs with thousands of participants (not 20-person pilot studies)
• Published in NEJM, JAMA, Lancet (not press releases)
• Replicated across multiple independent research groups
• Proven cardiovascular and renal benefits beyond weight loss
• Biological mechanism fully characterized at the receptor level

This isn't a fad — it's a new drug class supported by the highest level of clinical evidence. The comparison to past fads is understandable but inappropriate.

BariatricNurseD said:

SUSTAIN-6 was the first CVOT to show cardiovascular benefit with semaglutide, relevant to cardiovascular risk.

Can confirm. Same sequence, different timescale.