Summary: In this participant-level exploratory analysis of the AMPLITUDE-O randomised trial (n=4059 with type 2 diabetes at high cardiovascular risk), baseline FIB-4 score was not associated with incident cardiovascular events (MACE hazard ratio per 1 SD higher score 1.00, 95% CI 0.89-1.13). Efpeglenatide’s cardiovascular benefit was consistent across FIB-4 tertiles (all interaction p values ≥ 0.64), indicating that estimated liver fibrosis did not modify the treatment effect.
PICO Summary
| Element | Detail |
|---|---|
| Population | 4059 of 4076 participants (99.6%) with type 2 diabetes at high cardiovascular risk from the AMPLITUDE-O trial, with baseline FIB-4 available and divided into tertiles; multicentre, multinational randomised controlled trial; median follow-up 1.8 years. |
| Intervention | Once-weekly subcutaneous efpeglenatide (GLP-1 receptor agonist), analysed across FIB-4 tertiles within the randomised efpeglenatide arm. |
| Comparison | Placebo (no efpeglenatide), with the prognostic value of higher versus lower baseline FIB-4 also assessed across the whole cohort. |
| Outcome | Baseline FIB-4 was not associated with MACE (HR per 1 SD higher score 1.00, 95% CI 0.89-1.13). Incidence of MACE, expanded MACE, and MACE-or-death did not differ across FIB-4 tertiles (P for trend ≥ 0.25). Efpeglenatide’s effect on all MACE outcomes did not vary by FIB-4 tertile (all interaction p values ≥ 0.64). This is a null/exploratory finding; no ARR or NNT was derived for the FIB-4 question. |
Expert Commentary
This is a pre-specified exploratory, participant-level analysis of an existing randomised cardiovascular outcomes trial, and it should be read as hypothesis-clarifying rather than confirmatory. The verdict is a clean null on both questions posed: estimated liver fibrosis, as captured by FIB-4, was not prognostic for cardiovascular events in this high-risk cohort, and it did not modify the benefit of efpeglenatide. The tight confidence interval around a hazard ratio of 1.00 and uniformly high interaction p values are reassuring, suggesting clinicians need not expect a differential cardiovascular response according to a patient’s FIB-4 band. The principal limitation is the short median follow-up of 1.8 years, which constrains the ability of any biomarker to express prognostic signal and means a longer-horizon relationship between hepatic fibrosis and cardiovascular risk cannot be excluded; FIB-4 is also only a surrogate for fibrosis, not a histological standard. Can I use this with my patients? Cautiously yes, for the narrow purpose of reassurance: in a high-cardiovascular-risk patient with type 2 diabetes being considered for a GLP-1 receptor agonist, a raised FIB-4 should not by itself dissuade you from expecting cardiovascular benefit. It does not establish efpeglenatide as a liver therapy. The trial was sponsored by the manufacturer, so independent confirmation and dedicated hepatic endpoints would strengthen confidence. Future analyses should pair FIB-4 with imaging or histology and longer follow-up.
References
Del Prato S, Li Z, Ramasundarahettige C, Branch KRH, Lam CSP, Lopes RD, et al. Impact of baseline FIB-4 score on efpeglenatide benefits on cardiovascular outcomes in people with type 2 diabetes: a participant-level exploratory analysis of the AMPLITUDE-O trial. Cardiovasc Diabetol. 2024;23(1):352. doi:10.1186/s12933-024-02432-7