tony_orlando 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…

SUSTAIN-6 was the first CVOT to show cardiovascular benefit with semaglutide, relevant to cardiovascular risk. In 3,297 T2DM patients with high CV risk: MACE HR 0.74 (95% CI 0.58-0.95, p=0.02)[1].

Notable: the retinopathy signal in SUSTAIN-6 (HR 1.76) was subsequently attributed to rapid A1C reduction in patients with pre-existing retinopathy — not a direct drug effect. This has been confirmed in longer-term follow-up studies.

Following on from NurseAsh_DET — and this may be the naive question:

What would you measure differently if you were starting again?

BethLabQueen said:

SUSTAIN-6 was the first CVOT to show cardiovascular benefit with semaglutide, relevant to cardiovascular risk.

6 month update on cardiovascular risk: down 48 lbs, off blood pressure meds, A1C normalized. Genuinely life-changing.

BethLabQueen said:

SUSTAIN-6 was the first CVOT to show cardiovascular benefit with semaglutide, relevant to cardiovascular risk.

Metabolic syndrome resolution on cardiovascular risk: I went from meeting 5 of 5 diagnostic criteria to meeting ZERO after 13 months of treatment.

The 5 criteria (and my journey):

1. Waist circumference: 52" → 34" ✅ Resolved
2. Triglycerides: 248 → 108 ✅ Resolved
3. HDL: 36 → 60 ✅ Resolved
4. Blood pressure: 148/90 → 121/75 ✅ Resolved
5. Fasting glucose: 128 → 88 ✅ Resolved

Metabolic syndrome reversal is, in my view, the most medically significant outcome of GLP-1 therapy.

traveltech_sara said:

6 month update on cardiovascular risk: down 48 lbs, off blood pressure meds, A1C normalized.

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.