Temporal and subgroup disparities in mediation effects on cardiovascular outcomes with liraglutide and semaglutide: a post-hoc analysis of LEADER and SUSTAIN-6 trials
Authors' conclusion
The HbA1c-mediated effects of liraglutide and semaglutide varied over time and across patient subgroups. HbA1c consistently explained a larger proportion of mediation compared to UACR and SBP, with patterns suggesting that mediation through HbA1c may differ by underlying risk factors.
Study context
- Population
- Patients with T2D in the LEADER and SUSTAIN-6 trials; age around 64.2–64.4/64.4–64.8 years, 64.0%-64.5%/58.5%-63.0% male, diabetes duration 12.8–12.9/13.2–14.3 years9,340 LEADER
- Participants
- 4,668 / 4,672 / 1,648 / 1,649
- Comparison
- Mediation of liraglutide's and semaglutide's effects on 3P-MACE via HbA1c, urine albumin-to-creatinine ratio (UACR) and systolic blood pressure (SBP)
- Liraglutiden = 4,668
- Placebo (LEADER)n = 4,672reference
- Semaglutiden = 1,648
- Placebo (SUSTAIN-6)n = 1,649reference
- Primary endpoint
- Proportion of the GLP-1RA effect on 3P-MACE (nonfatal stroke, nonfatal MI, CV death) mediated by HbA1c, UACR and SBP
- Follow-up
- End of each trial
Methodological detailscausal mediation analysis, individual-level data
- Causal mediation analysis
- Individual-level data
Primary result
As reported in the abstract
Proportion of effect on 3P-MACE mediated
- Liraglutide: mediated by HbA1c
- 38.2% (95% CI 13.8%-194.5%)
- Semaglutide: mediated by HbA1c
- 51.8% (95% CI 29.6%-86.7%)
- Liraglutide: mediated by UACR (8.5%-61.9%)
- 17.9%
- Semaglutide: mediated by UACR (6.1%-32.4%)
- 12.4%
- Liraglutide: mediated by SBP (2.2%-31.0%)
- 6.8%
- Semaglutide: mediated by SBP (2.9%-11.7%)
- 6.7%
Further findings
HbA1c-mediated effect over the trial period
- Liraglutide: increased from 31.3% to
- 38.2%
- Semaglutide: remained stable from 52.5% to
- 51.8%
Mediation in patients with estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m²
- Semaglutide: HbA1c (leading mediator)
- 35.2%
- Liraglutide: HbA1c
- 7.2%
- Liraglutide: UACR
- 11.8%
- Liraglutide: SBP
- 5.1%
- Liraglutide mediation effects seemed similar and smaller
Mediation in patients with established cardiovascular diseases (CVDs)
- Liraglutide: HbA1c (leading mediator)
- 25.3%
- Semaglutide: HbA1c (leading mediator)
- 51.2%
Original publication
Temporal and subgroup disparities in mediation effects on cardiovascular outcomes with liraglutide and semaglutide: a post-hoc analysis of LEADER and SUSTAIN-6 trials. Cardiovasc Diabetol. Published 24 November 2025. doi:10.
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