Causal mediation analysis of LEADER and SUSTAIN-6 reveals that GLP-1 drug cardiovascular benefits are only partly explained by HbA1c, blood pressure, and kidney markers, with effects varying over time.
Only partially mediatedTraditional metabolic factors (HbA1c, blood pressure, kidney markers) explain only part of GLP-1 drug cardiovascular benefits
What the researchers found
HbA1c, UACR, and systolic blood pressure only partially mediate GLP-1 RA cardiovascular benefits, with time-varying effects that differ between liraglutide and semaglutide and across patient subgroups.
Why it matters
Understanding why GLP-1 drugs protect the heart helps identify who benefits most and may reveal new cardiovascular protection mechanisms that could be targeted by future drugs.
The numbers in context
LEADER: 9,340 subjects. SUSTAIN-6: 3,297 subjects. Ages ~64. Causal mediation analysis for HbA1c, UACR, and SBP effects on 3P-MACE over time.
How the study worked
Post hoc causal mediation analysis of the LEADER (liraglutide) and SUSTAIN-6 (semaglutide) randomized controlled trials, assessing time-varying mediation of 3P-MACE outcomes.
Who was studied
Adults with T2D at high cardiovascular risk from LEADER and SUSTAIN-6 trials
What this study cannot tell us
Post hoc analysis — findings are hypothesis-generating. Mediation analysis has inherent assumptions about causal pathways that may not hold. Unmeasured confounders may exist.
How to read the evidence
Post hoc mediation analysis of two landmark RCTs — sophisticated statistical methodology applied to high-quality data, but inherently hypothesis-generating.
When this study was published
Published in 2025, applying modern causal inference methods to data from the foundational LEADER and SUSTAIN-6 trials.
The bigger picture
The cardiovascular benefits of GLP-1 drugs appear to go beyond just improving metabolic numbers. Identifying the additional mechanisms could lead to new cardiovascular therapies.
Questions still open
- What unknown mechanisms explain the cardiovascular benefits not captured by HbA1c, UACR, and blood pressure?
- Do anti-inflammatory effects of GLP-1 drugs account for the unexplained cardiovascular protection?
Common questions
How do GLP-1 drugs protect the heart?
Do liraglutide and semaglutide protect the heart the same way?
Read the original research
Temporal and subgroup disparities in mediation effects on cardiovascular outcomes with liraglutide and semaglutide: a post-hoc analysis of LEADER and SUSTAIN-6 trials.
Cardiovascular diabetology, 24(1), 465
Citation
Peng, Zi-Yang; Lee, Yu-Hsuan; Ou, Huang-Tz; Kuo, Shihchen. (2025). Temporal and subgroup disparities in mediation effects on cardiovascular outcomes with liraglutide and semaglutide: a post-hoc analysis of LEADER and SUSTAIN-6 trials.. Cardiovascular diabetology, 24(1), 465. https://doi.org/10.1186/s12933-025-03007-w