Clinical Takeaway

Domain

Key Finding

Evidence Level

CV Benefit: Continuous Use

~18% relative risk reduction in MACE at 3 years vs. sulfonylureas (333,000+ patients)

Large observational cohort; target trial emulation

CV Risk After Discontinuation

Benefit fully erased at ~18 months off; +22% excess risk at 24 months vs. continued use. Risk returns toward — not above — pre-treatment baseline.

Xie, Choi & Al-Aly, BMJ Medicine 2026

Muscle Composition Under GLP-1/GIP Therapy

SURPASS-3 MRI (N=246): muscle volume loss with tirzepatide was proportionate to weight loss and not significantly different from population norms (p=0.22). Intramuscular fat was reduced beyond population-based predictions — a potentially favorable effect on muscle quality.

Sattar et al., Lancet Diabetes Endocrinol. 2025; RCT post-hoc MRI substudy

Real-World Discontinuation

Up to 50% of patients stop within 12 months — driven by cost, insurance barriers, and tolerability, not drug failure

Multiple real-world adherence studies

Clinical Bottom Line

GLP-1s behave like every other chronic disease medication: they work while you take them. The crisis is a systems failure, not a pharmacologic one.

Strong mechanistic & outcomes consensus