SELECT cost-effectiveness — looking for input

Dr.PulmRoch said:

NNT calculation for cardiovascular risk clinical endpoints: NNT = 1/ARR (absolute risk 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.

One thing that is still open after Dr.PulmRoch’s answer:

What would you measure differently if you were starting again?

raj_cambridge said:

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

Anti-inflammatory mechanisms of GLP-1 agonists and cardiovascular risk: beyond weight loss, GLP-1R activation directly suppresses NF-κB signaling, reduces NLRP3 inflammasome activation, and decreases monocyte/macrophage adhesion to endothelium[1].

Clinical correlates: hsCRP reduction of 30-60% (consistently seen across trials), reduced carotid intima-media thickness, and decreased coronary plaque inflammation on PET imaging.

These anti-inflammatory effects likely contribute to the cardiovascular benefit seen in SELECT — and may explain benefits beyond what weight loss alone would predict.

raj_cambridge said:

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

raj_cambridge said:

...cardiovascular risk is just another fad...

I understand the skepticism — we've all seen "miracle" weight loss solutions come and go. But consider what makes GLP-1 agonists different:

• Phase 3 RCTs with thousands of participants (not 20-person pilot studies)
• Published in NEJM, JAMA, Lancet (not press releases)
• Replicated across multiple independent research groups
• Proven cardiovascular and renal benefits beyond weight loss
• Biological mechanism fully characterized at the receptor level

This isn't a fad — it's a new drug class supported by the highest level of clinical evidence. The comparison to past fads is understandable but inappropriate.

raj_cambridge said:

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

This answered a question I did not know how to ask. Sending this to two other people who asked me the same thing last week.