Efruxifermin added to GLP-1 receptor agonist therapy reduced liver fat by 65% in 12 weeks in patients with MASH and diabetes, compared to just 10% with GLP-1 drugs alone.
65% liver fat reductionEfruxifermin added to GLP-1 therapy in 12 weeks, versus just 10% reduction with GLP-1 alone
What the researchers found
Adding efruxifermin (an FGF21 analog) to GLP-1 receptor agonist therapy in patients with MASH, liver fibrosis, and type 2 diabetes produced dramatic liver fat reduction: 65% decrease in hepatic fat fraction compared to just 10% with GLP-1 RA alone over 12 weeks (P < .0001). The combination also improved markers of liver injury, fibrosis, glucose metabolism, and lipid levels while maintaining the weight loss benefits of the GLP-1 RA.
Safety was a key focus: the combination appeared well-tolerated with a safety profile comparable to either drug alone. The most common side effects were mild-to-moderate GI events. Only one patient discontinued due to nausea, and there were no treatment-related serious adverse events. Nearly half the patients were on semaglutide, with the remainder on dulaglutide or liraglutide.
Why it matters
MASH (formerly NASH) affects millions of people worldwide and is closely tied to obesity and type 2 diabetes — the same patients increasingly being treated with GLP-1 drugs. While GLP-1 RAs provide modest liver benefits through weight loss, this study shows that adding efruxifermin dramatically amplifies liver fat reduction beyond what GLP-1 drugs achieve alone. This combination approach could be critical because MASH is becoming the leading cause of liver transplants, and effective combination therapies are urgently needed.
The numbers in context
n=31 · 2:1 randomization · efruxifermin 50 mg weekly · 12 weeks · HFF reduced 65% vs 10% placebo · P<.0001 · 48.4% on semaglutide · 45.2% on dulaglutide · 6.5% on liraglutide · 1 discontinuation (nausea) · 0 serious AEs
How the study worked
Double-blind, placebo-controlled phase 2b trial (Cohort D). Adults with type 2 diabetes and biopsy-confirmed MASH with fibrosis (F1-F3) on stable GLP-1 RA therapy were randomized 2:1 to receive efruxifermin 50 mg or placebo weekly for 12 weeks. Primary endpoint was safety/tolerability. Secondary endpoints included hepatic fat fraction (measured by MRI), liver injury biomarkers, fibrosis markers, and metabolic parameters.
Who was studied
31 adults with type 2 diabetes and MASH with fibrosis (F1-F3) on stable GLP-1 receptor agonist therapy
What this study cannot tell us
Small sample size (31 patients) limits statistical power for secondary endpoints. The 12-week duration is too short to assess fibrosis reversal on histology (biopsy). No liver biopsies were performed post-treatment — fibrosis changes were assessed by non-invasive markers only. The study was not powered to detect differences in clinical outcomes. The GLP-1 RA background varied (semaglutide, dulaglutide, liraglutide), making it difficult to determine if the combination works differently with different GLP-1 drugs.
How to read the evidence
This is a randomized, double-blind, placebo-controlled phase 2b trial — strong study design — but with only 31 patients and a 12-week duration. The 'Moderate' grade reflects the rigorous design tempered by small sample size and short follow-up.
When this study was published
Published in 2025, this is a very current trial reflecting the latest in MASH combination therapy research. Larger phase 3 trials are expected to follow based on these promising results.
The bigger picture
The metabolic disease landscape is rapidly evolving toward combination therapies. GLP-1 drugs address weight and blood sugar but have limited direct effects on liver fibrosis. FGF21 analogs like efruxifermin target the liver directly, reducing fat accumulation and inflammation. Combining them could address the full spectrum of metabolic disease — obesity, diabetes, and liver disease — in a single regimen. This is especially important as MASH is on track to become the most common reason for liver transplantation.
Questions still open
- Will the 65% liver fat reduction translate to actual fibrosis reversal on biopsy in longer trials?
- Is the combination more effective with semaglutide specifically, or does the GLP-1 RA choice not matter?
- Could this combination prevent progression to cirrhosis in patients with early-stage MASH?
Common questions
What is efruxifermin and how does it differ from GLP-1 drugs?
Why do MASH patients need something beyond GLP-1 drugs?
Read the original research
Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study.
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 23(1), 103-113
Citation
Harrison, Stephen A; Frias, Juan P; Lucas, K Jean; Reiss, Gary; Neff, Guy; Bollepalli, Sureka; Su, Yan; Chan, Doreen; Tillman, Erik J; Moulton, Ali; de Temple, Brittany; Zari, Arian; Shringarpure, Reshma; Rolph, Timothy; Cheng, Andrew; Yale, Kitty. (2025). Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study.. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 23(1), 103-113. https://doi.org/10.1016/j.cgh.2024.02.022