Dr.ReproEndo said:

Steady state is the thing most people miss.

Thank you for spelling out the reasoning rather than just the conclusion. I will report back once I have actually tried it.

Adding the clinical framing, because it changes how the question reads.

Lp(a) and cardiovascular risk: a nuance that matters. Unlike most lipid markers, Lp(a) is 90%+ genetically determined and doesn't really change with weight loss or GLP-1 therapy.

My Lp(a) has remained at 67 nmol/L across all time points. If yours is elevated (>50 nmol/L), you need additional risk mitigation strategies regardless of your GLP-1 response. Don't assume your medication is covering all cardiovascular risk factors.

Dr.MetabolicMD said:

Albumin binding above 99% is the whole reason weekly dosing works, and it is also why the trough matters more than the peak.

This is where I part company with the consensus forming above. The trial means are being read too generously in this thread. STEP populations were selected, supported, and titrated by protocol, and the real-world curves are consistently a few points worse. That difference is not noise, it is what happens when you remove the study infrastructure.

Dr.CardioMD 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.

Moderator note: leaving this open. It is being argued well and the disagreement is the useful part. Carry on.