Has anyone dealt with select trial: 20% mace reduction?

raj_cambridge said:

Anti-inflammatory mechanisms of GLP-1 agonists and cardiovascular risk: beyond weight loss, GLP-1R activation directly suppresses NF-κB signaling,…

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.

raj_cambridge said:

Anti-inflammatory mechanisms of GLP-1 agonists and cardiovascular risk: beyond weight loss, GLP-1R activation directly suppresses NF-κB signaling,…

CRP reduction on cardiovascular risk — this is the lab result that excites me most:

Baseline hsCRP: 5.0 mg/L (high cardiovascular risk)
Month 6 hsCRP: 2.5 mg/L (moderate risk)
Month 12 hsCRP: 0.8 mg/L (low risk)

This level of inflammatory marker reduction is comparable to what you'd see with statin therapy. Combined with the weight loss, my 10-year ASCVD risk score dropped from 12% to 5%. My cardiologist is genuinely impressed.

raj_cambridge said:

Anti-inflammatory mechanisms of GLP-1 agonists and cardiovascular risk: beyond weight loss, GLP-1R activation directly suppresses NF-κB signaling,…

Bookmarking. The distinction being drawn above is the one nobody else makes. Sending this to two other people who asked me the same thing last week.

From the other side of the consultation, briefly.

raj_cambridge 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.

Closing the loop on my own question.

Follow-up: I read the paper rather than the summary and the qualifier I was missing was in the second paragraph of the results.