Dr.NutriCornell said:

6 month update on cardiovascular risk: down 52 lbs, off blood pressure meds, A1C normalized.

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.

FranDenver said:

Prescribed on cardiovascular grounds rather than for weight, and almost everything written for patients assumes the opposite.

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.PeteFamMed said:

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

Dr.PeteFamMed said:

...we don't know the long-term effects of cardiovascular risk...

This is a fair point, and I think intellectual honesty requires acknowledging it. GLP-1 agonists in their current form have ~8-10 years of human exposure data. That's not nothing, but it's not 30+ years either.

However: the risk-benefit calculation should also consider the KNOWN long-term effects of untreated obesity — diabetes, cardiovascular disease, cancer, joint destruction, reduced lifespan by 5-10 years.

Uncertainty about GLP-1 long-term safety vs certainty about obesity consequences. The calculus seems clear to me, but reasonable people can disagree.

One thing that is still open after cory_ATX’s answer:

What did you change at the same time, and can you separate the two now?

andrew_nyc said:

Dr.PeteFamMed said: ...we don't know the long-term effects of cardiovascular risk...

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:

These NNTs are clinically meaningful and comparable to accepted cardiovascular interventions.