Dr.SleepRoch said:

I want to bring up the cardiovascular angle on cardiovascular risk.

There is a second half to this that has not been said yet. Steady state is the thing most people miss. The terminal half-life is about a week, so every dose step takes four to five weeks to fully express itself. Judging a step at day ten is judging the ascent, not the plateau, and it is the single commonest reason people escalate before they needed to.

Dr.SleepRoch said:

I want to bring up the cardiovascular angle on cardiovascular risk.

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.

A narrower follow-up, since the general answer is now clear:

What the dose-response curve actually looks like above 1.7mg, because the trial means hide how few people account for the extra loss?

SleepDoc_PDX said:

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

Senior perspective on cardiovascular risk: I'm 64 years old and started this journey skeptically. My cardiologist recommended it after years of failed interventions.

14 months later: down 47 lbs, more mobile, pain reduced, medications simplified. My quality of life has improved dramatically. I wish this existed 20 years ago.

To other older adults hesitating: the SELECT trial proved benefit in our age group. You deserve to feel good in your body regardless of age.

SleepDoc_PDX said:

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

SleepDoc_PDX 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.