KevinCompounds said:

I did go to 2.4mg in the end, and the honest report is that it bought me less than the step before it and cost me two bad weeks.

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.

Happy to go further on any of that.

KevinCompounds said:

I did go to 2.4mg in the end, and the honest report is that it bought me less than the step before it and cost me two bad weeks.

Mendelian randomization evidence supporting GLP-1 pathway modulation for cardiovascular risk: genetic variants in the GLP1R gene region associated with lower BMI also show associations with reduced cardiovascular risk, confirming a causal pathway[1].

This "natural experiment" (people born with genetically higher GLP-1 signaling being leaner and healthier) provides orthogonal evidence supporting the pharmacological approach. When genetic epidemiology, clinical trials, and mechanistic studies all converge, confidence in the therapeutic approach is high.

KevinCompounds said:

I did go to 2.4mg in the end, and the honest report is that it bought me less than the step before it and cost me two bad weeks.

Saving this. It is the first explanation that did not require me to already understand it. Taking it to my next appointment.

From the other side of the consultation, briefly.

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

The SELECT trial demonstrated a 20% reduction in MACE with semaglutide 2.4mg[1]. This is practice-changing because the CV benefit appears to be independent of the degree of weight loss — suggesting direct vascular and anti-inflammatory mechanisms.

For cardiovascular risk, this means we need to think beyond the primary outcome and consider the cardiovascular implications. The all-cause mortality reduction (HR 0.81) is the most clinically meaningful signal.

Dr.SleepRoch said:

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

Can confirm. Same sequence, different timescale.