Introduction:
The interim results of the ongoing ESSENCE trial showed positive results for once weekly semaglutide 2.4 mg vs placebo in patients with metabolic dysfunction-associated steatohepatitis (MASH) and F2/F3 fibrosis. Interim analysis showed significant improvements in histological and non-invasive test (NIT) outcomes and 10.5% mean weight loss with semaglutide vs 2% with placebo. This post hoc analysis examined whether these benefits on liver histology were dependent or independent of weight loss.
Objective:
To determine the relative contributions of weight loss-dependent and weight loss-independent mechanisms to the histological and NIT improvements observed with semaglutide after 72 weeks.
Methods:
- Population: First 800 randomized participants in ESSENCE with biopsy-confirmed MASH and F2/F3 fibrosis.
- Treatment: Once-weekly semaglutide 2.4 mg vs placebo.
- Interim endpoint at Week 72:
- MASH-related NITs: ALT (≥17 U/L reduction), FAST score (≥0.22 reduction), resolution of MASH without fibrosis worsening.
- Fibrosis-related NITs: VCTE (≥30% reduction), ELF score (≥0.5 unit reduction), ≥1-stage fibrosis improvement without MASH worsening
- Analysis: Logistic regression to estimate odds ratios (ORs) for total, weight loss-dependent, and weight loss-independent effects.
Results:
MASH-Related Endpoints (ORs at 72 weeks):
|
Outcome |
Total Effect |
Weight Loss-Independent |
Weight Loss-Dependent |
Percentage not maintained by weight loss |
|
ALT reduction |
4.7 (3.3–6.6) |
3.0 (2.0–4.6) |
1.5 (1.2–2.0) |
71.9% |
|
FAST score reduction |
6.9 (4.3–10.9) |
2.8 (1.7–4.7) |
2.5 (1.8–3.4) |
53.3% |
|
MASH resolution |
3.9 (2.8–5.5) |
2.0 (1.4–3.0) |
1.9 (1.6–2.4) |
51.9% |
FAST - FibroScan-aspartate aminotransferase
Fibrosis-Related Endpoints (ORs at 72 weeks):
|
Outcome |
Total Effect |
Weight Loss-Independent |
Weight Loss-Dependent |
Percentage not maintained by weight loss |
|
VCTE reduction |
3.0 (2.0–4.4) |
1.7 (1.1–2.7) |
1.7 (1.4–2.2) |
48.9% |
|
ELF score reduction |
4.5 (3.1–6.4) |
2.4 (1.6–3.7) |
1.9 (1.5–2.3) |
58.5% |
|
Fibrosis stage improvement |
2.1 (1.5–3.1) |
1.5 (1.0–2.4) |
1.4 (1.1–1.8) |
55.5% |
VCTE – Vibration controlled transient elastography
ELF – Enhanced liver fibrosis
Conclusion:
It was concluded that once weekly semaglutide 2.4mg improved markers of liver inflammation (MASH) and fibrosis after 72 weeks. The improvements were observed with equal contributions of weight loss dependent as well as independent mechanisms. These findings portray that semaglutide aids liver health via dual pathways: direct hepatic actions and weight-mediated mechanisms achieving results beyond weight loss.
ECO, 11-14 May 2025, Malaga, Spain
