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…

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.

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…

I read this differently from Dr.RaviCardio, on substance rather than tone. 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.

Dr.GutHealth said:

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

I'm 48 years old and want to share my perspective on cardiovascular risk as an older member of this community.

My doctor was initially hesitant because of my age, but the SELECT trial included patients up to 72 and showed consistent benefit across age groups. We started at the lowest dose with closer monitoring.

15 months later: down 52 lbs, off atorvastatin, A1C from 8.4% to 5.3%. My cardiologist is thrilled. cardiovascular risk is absolutely relevant for older adults — don't let anyone tell you otherwise.

DataDave said:

Mendelian randomization evidence supporting GLP-1 pathway modulation for cardiovascular risk: genetic variants in the GLP1R gene region associated…

This matches mine closely enough to be worth saying so out loud. I had assumed I was the exception until I read this.