SleepDoc_PDX said:

PurityPaulOR said: ...we're creating a generation dependent on cardiovascular risk...

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.

LarryQC_SD said:

Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were…

That reframing is the part I needed. Sending this to two other people who asked me the same thing last week.

SleepDoc_PDX said:

PurityPaulOR said: ...we're creating a generation dependent on cardiovascular risk...

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

From SELECT trial: MACE at 39 months — 6.5% semaglutide vs 8.0% placebo. ARR = 1.5%. NNT = 67 over 3.3 years.

Compare to established therapies:

These NNTs are clinically meaningful and comparable to accepted cardiovascular interventions.

ZaraB_AL said:

My reason for being on this is cardiovascular rather than cosmetic, which puts me in a small minority in most of these threads.

ZaraB_AL 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.

Moderator note: reminder that nothing in this thread is medical advice, and that clinical claims need a source.