What fibroblast growth factor‑21 (FGF‑21) analogue drugs are available for an obese adult with biopsy‑confirmed non‑alcoholic steatohepatitis (NASH)/metabolic dysfunction‑associated steatotic liver disease (MASLD) fibrosis stage F2‑F3, type 2 diabetes mellitus, and dyslipidaemia, and how should they be incorporated into therapy?

FGF-21 Analogue Drugs for NASH/MASLD

Currently Available FGF-21 Analogues

No FGF-21 analogue drugs are currently approved or recommended for clinical use in NASH/MASLD treatment. While multiple FGF-21 analogues have been developed and tested in clinical trials, none have received regulatory approval or guideline endorsement as MASH-targeted therapies 1, 2, 3.

FGF-21 Analogues in Clinical Development

The following FGF-21 analogues have been studied in clinical trials for NASH/MASLD:

• Pegbelfermin (BMS-986036): A PEGylated FGF-21 analogue that demonstrated reduction in hepatic fat fraction and improvements in liver fibrosis biomarkers in Phase II trials 1, 2, 3

• Efruxifermin (EFX/AKR-001): A long-acting Fc-FGF21 fusion protein showing significant reductions in liver fat content and improvements in fibrosis markers in Phase II studies 3, 4

• Other investigational agents: Multiple FGF-21 mimetics and agonistic monoclonal antibodies targeting the FGFR1-β-klotho receptor complex are in various stages of development 1, 2

Clinical Trial Evidence

Meta-analysis of FGF-21 analogues in NASH trials shows:

• Fibrosis improvement ≥1 stage: Relative risk 1.79 (95% CI 1.29-2.48) compared to placebo 4
• NASH resolution: No statistically significant difference versus placebo, though this finding is unstable 4
• Hepatic fat reduction: Significant improvements in hepatic fat fraction across multiple trials 4, 5
• Metabolic benefits: Improvements in triglycerides, HDL-C, LDL-C, and liver injury markers (ALT, AST) 4

Recommended Treatment Approach for Your Patient

For an obese adult with biopsy-confirmed NASH F2-F3 fibrosis, type 2 diabetes, and dyslipidemia, FGF-21 analogues should NOT be used, as they are not approved and have no guideline support. Instead, follow this evidence-based algorithm:

Primary MASH-Targeted Therapy

Resmetirom is the only medication with strong guideline recommendation for non-cirrhotic MASH with fibrosis stage ≥2, demonstrating histological efficacy on steatohepatitis and fibrosis in Phase III trials with acceptable safety 6.

• Indication: Adults with non-cirrhotic MASH with significant liver fibrosis (stage ≥2) 6
• Efficacy: Demonstrated histological improvement in both steatohepatitis and fibrosis 6
• Limitation: Data on long-term sustainability, liver-related outcomes, and safety are not yet available 6

Treatment of Comorbidities (Prioritized)

GLP-1 receptor agonists should be used for type 2 diabetes and obesity, as they improve cardiometabolic outcomes and are safe in MASH 6:

• Semaglutide 2.4 mg weekly: Preferred if established cardiovascular disease is present (26% reduction in CV death, MI, or stroke) 7
• Tirzepatide 15 mg weekly: Preferred for maximum weight loss (≈21% weight reduction at 72 weeks) 7
• Hepatic benefit: Substantial weight loss induced by GLP-1 RAs may provide histological benefit, though not extensively documented 6
• Important caveat: GLP-1 RAs cannot be recommended as MASH-targeted therapies due to lack of robust Phase III histological data 6

SGLT-2 inhibitors should be used for type 2 diabetes, heart failure, or chronic kidney disease indications 6:

• Safe to use in MASLD but insufficient evidence as MASH-targeted therapy 6
• Continue for proven cardiovascular and renal benefits 7

Statins must be continued for dyslipidemia and cardiovascular risk reduction 6:

• Safe in compensated cirrhosis and chronic liver disease 6
• Strong recommendation to reduce cardiovascular events 6

Additional Considerations

Pioglitazone may be considered but cannot be recommended as MASH-targeted therapy 6:

• Safe in non-cirrhotic MASH 6
• Lacks robust Phase III histological efficacy data 6
• May improve cardiovascular outcomes in patients with or without diabetes 6

Bariatric surgery should be considered for BMI >40 kg/m² or BMI >35 kg/m² with metabolic complications 6, 8:

• Most effective intervention for severe obesity and NASH 8
• Can achieve histologic NASH resolution in up to 85% of patients 8
• Requires compensated liver disease without decompensation 8

Lifestyle Interventions (Essential Foundation)

Weight loss targets 6:

• ≥5% weight reduction to reduce liver fat
• 7-10% to improve liver inflammation
• ≥10% to improve fibrosis

Dietary modifications 6:

• Mediterranean dietary pattern emphasizing vegetables, fruits, whole grains, legumes, olive oil 8
• Avoid sugar-sweetened beverages and ultra-processed foods 6
• Protein intake 1.2-1.5 g/kg daily to prevent sarcopenia 8

Exercise prescription 6:

• ≥150 minutes/week of moderate-intensity OR 75 minutes/week of vigorous-intensity physical activity 6
• Vigorous-intensity exercise (≥6 METs) preferred for NASH severity and fibrosis improvement 8

Why FGF-21 Analogues Are Not Ready for Clinical Use

Despite promising preclinical data, FGF-21 analogues face several obstacles 1, 2:

• Failed primary endpoints: Clinical trials have not met glycemic control endpoints 1
• Interspecies variations: Divergence in FGF-21 biology between animals and humans 1
• FGF-21 resistance: Possible obesity-related resistance mechanisms 1
• Pharmacokinetic limitations: Native FGF-21 has poor biophysical properties requiring analogue development 1
• No regulatory approval: None have progressed beyond Phase II/III trials to approval 3

Common Pitfalls to Avoid

• Do not use vitamin E: Cannot be recommended as MASH-targeted therapy due to lack of robust Phase III efficacy and potential long-term risks 6
• Do not withhold statins: They are safe in compensated cirrhosis and essential for cardiovascular protection 6
• Do not use metformin as MASH-targeted therapy: Insufficient evidence, though safe for diabetes indication 6
• Do not prescribe FGF-21 analogues off-label: They are investigational only and not approved for any indication 1, 3