What are the qualification criteria for treatment with a Glucagon-like peptide-1 (GLP-1) agonist or Glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonist in patients with hepatosteatosis?

Qualification Criteria for GLP-1 and GIP/GLP-1 Agonists in Hepatosteatosis

For patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) who have overweight or obesity, GLP-1 receptor agonists or dual GIP/GLP-1 agonists should be considered as adjunctive therapy to lifestyle interventions for glycemic management and weight loss. 1

Primary Qualification Criteria

For GLP-1 Receptor Agonists

Patients with Type 2 Diabetes:

• Adults with type 2 diabetes AND MASLD with overweight or obesity qualify for GLP-1 RA therapy as an adjunctive to lifestyle interventions 1
• Patients with biopsy-proven metabolic dysfunction-associated steatohepatitis (MASH) or those at high risk for liver fibrosis based on noninvasive tests (such as FIB-4, liver stiffness measurement, or ELF) should receive preferential treatment with GLP-1 RAs for glycemic management 1

Key Clinical Scenarios:

• Biopsy-proven MASH: GLP-1 RAs are preferred agents alongside pioglitazone for treating hyperglycemia in this population 1
• High-risk fibrosis without biopsy: Patients identified through noninvasive testing (FIB-4 followed by liver stiffness measurement or patented biomarkers) showing indeterminate or high risk of fibrosis qualify for GLP-1 RA therapy 1
• Compensated cirrhosis: GLP-1 RAs are safe to use in patients with MASLD and compensated cirrhosis 1, 2

For Dual GIP/GLP-1 Receptor Agonists

Expanded Indications:

• Adults with type 2 diabetes, MASLD, and overweight or obesity should be considered for dual GIP/GLP-1 RA therapy with potential benefits in MASH for glycemic management and weight loss 1
• Patients with biopsy-proven MASH or high risk for liver fibrosis qualify for dual GIP/GLP-1 RA as a preferred agent for glycemic management 1

Risk Stratification Approach

Initial Screening Algorithm:

1. Start with FIB-4 score calculation in all patients with MASLD 1
2. If FIB-4 indicates indeterminate or high risk, proceed to liver stiffness measurement (LSM) or ELF testing 1
3. Patients with clinically significant fibrosis (≥F2) on noninvasive testing qualify for preferential GLP-1 or GIP/GLP-1 RA therapy 1

Important Caveat: While liver biopsy remains the gold standard for NASH diagnosis, its use is reserved for specialist discretion within an interprofessional team due to costs and potential morbidity 1. Most patients can be risk-stratified using noninvasive methods.

Clinical Context and Nuances

Regarding FDA Approval Status:

• Currently, no medications are FDA-approved specifically for NASH treatment 1
• However, GLP-1 RAs and GIP/GLP-1 RAs are approved for type 2 diabetes and obesity, and should be used for these indications in patients with MASLD 1, 2
• The 2024 EASL-EASD-EASO guidelines explicitly state that GLP-1 RAs cannot be recommended as MASH-targeted therapies due to absence of formal demonstration of histological improvement in large phase III trials, but they are safe to use and should be prescribed for their approved indications (diabetes, obesity) as they improve cardiometabolic outcomes 1, 2

Evidence Strength Considerations: The 2025 American Diabetes Association guidelines provide the strongest recent recommendation (Grade B evidence) for using GLP-1 RAs with demonstrated benefits in NASH as adjunctive therapy 1. This represents a pragmatic approach: while histological efficacy data from large phase III trials are pending, the cardiometabolic benefits and safety profile justify their use in this population 1, 2.

Weight Loss as Mechanism:

• Substantial weight loss induced by GLP-1 RAs or GIP/GLP-1 RAs could be expected to provide hepatic histological benefits, though this has not been extensively documented in large trials 1, 2
• The Mediterranean diet combined with aerobic and resistance training should be prescribed alongside pharmacotherapy 1

Contraindications and Safety

Absolute Contraindications:

• GLP-1 receptor agonists are contraindicated in patients with Child-Pugh C cirrhosis 1

Use with Caution:

• Child-Pugh B cirrhosis requires cautious use of GLP-1 RAs 1
• Recent evidence suggests GLP-1 RAs are safe in individuals with NASH and compensated cirrhosis 1

Monitoring:

• Baseline liver function tests should be obtained in patients with known liver disease 2
• Periodic monitoring during treatment is reasonable 2

Combination Therapy Considerations

Preferred Combinations:

• Combination therapy with pioglitazone plus a GLP-1 RA can be considered for patients with biopsy-proven MASH or high risk of liver fibrosis due to potential beneficial effects on MASH 1
• Do not combine incretin classes (GLP-1 RA, GIP/GLP-1 RA, DPP4i) 1

Common Pitfalls to Avoid

1. Do not delay treatment waiting for liver biopsy confirmation in patients with high-risk noninvasive test results and diabetes requiring treatment 1
2. Do not discontinue GLP-1 RAs in patients who develop compensated cirrhosis, as they remain safe in this population 1
3. Do not use GLP-1 RAs solely as liver-directed therapy without appropriate indications (diabetes or obesity), as they are not approved for MASH treatment specifically 1, 2
4. Do not overlook lifestyle modification: structured weight loss and exercise programs remain foundational and should not be replaced by pharmacotherapy alone 1