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

Primary Qualification Criteria

• The American Diabetes Association recommends considering GLP-1 receptor agonists or dual GIP/GLP-1 agonists as adjunctive therapy to lifestyle interventions for glycemic management and weight loss in patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) who have overweight or obesity 1, 2
• Adults with type 2 diabetes and MASLD with overweight or obesity qualify for GLP-1 RA therapy as an adjunctive to lifestyle interventions, according to the American Diabetes Association 1, 3
• Patients with biopsy-proven metabolic dysfunction-associated steatohepatitis (MASH) or those at high risk for liver fibrosis based on noninvasive tests should receive preferential treatment with GLP-1 RAs for glycemic management, as recommended by the American Diabetes Association 1, 2, 3

Risk Stratification Approach

• The American Diabetes Association suggests starting with FIB-4 score calculation in all patients with MASLD, and if FIB-4 indicates indeterminate or high risk, proceeding to liver stiffness measurement (LSM) or ELF testing 3
• Patients with clinically significant fibrosis (≥F2) on noninvasive testing qualify for preferential GLP-1 or GIP/GLP-1 RA therapy, according to the American Diabetes Association 1, 3

Contraindications and Safety

• GLP-1 receptor agonists are contraindicated in patients with Child-Pugh C cirrhosis, as stated by the Journal of Hepatology 4
• Child-Pugh B cirrhosis requires cautious use of GLP-1 RAs, according to the Journal of Hepatology 4

Combination Therapy Considerations

• 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, as recommended by the American Diabetes Association 1, 2

Common Pitfalls to Avoid

• The American Diabetes Association advises against delaying treatment waiting for liver biopsy confirmation in patients with high-risk noninvasive test results and diabetes requiring treatment 1, 3
• The American Diabetes Association recommends not discontinuing GLP-1 RAs in patients who develop compensated cirrhosis, as they remain safe in this population 3, 5

GLP-1 Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Current Evidence and Recommendations

• GLP-1RAs are safe to use in patients with MASLD, including those with compensated cirrhosis, and should be used for their approved indications of type 2 diabetes and obesity, as they improve cardiometabolic outcomes 6, 7
• In the absence of formal demonstration of histological improvement in large phase III trials, GLP-1RAs cannot be specifically recommended as MASLD-targeted therapies (Level of Evidence 5, strong recommendation) 8, 9
• When substantial weight loss is induced by GLP-1RAs, hepatic histological benefits could be expected, although this has not been extensively documented 10, 11

Safety Profile

• GLP-1RAs have demonstrated safety in patients with MASLD, including those with compensated cirrhosis 7, 9
• Baseline liver function tests should be obtained in patients with known liver disease, and periodic monitoring is reasonable during treatment 12

Potential Benefits in MASLD

Weight Loss Effects

• Weight loss is a key mechanism by which GLP-1RAs may benefit MASLD patients 13
• The LEAN trial (Liraglutide Efficacy and Action in Non-alcoholic steatohepatitis) showed more frequent resolution of NASH with liraglutide compared to placebo, though the study was small 13
• Studies have demonstrated that GLP-1RAs reduce hepatic fat and steatosis 13

Clinical Considerations

Patient Selection

• The American Diabetes Association suggests that semaglutide may be particularly beneficial for patients with MASLD or NASH as it can improve both metabolic parameters and liver histology 12

Practical Approach

• For patients with MASLD who also have type 2 diabetes or obesity, GLP-1RAs are appropriate treatment options for these indications 10, 9
• The primary focus for MASLD management should remain lifestyle modifications, with GLP-1RAs considered as metabolic therapy rather than specific MASLD treatment 6, 10
• In patients achieving substantial weight loss with GLP-1RAs, monitor for potential liver histological improvements 11

Management of MAFLD in Diabetic Patients

Introduction to Guideline Recommendations

• The European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) do not recommend saroglitazar as a MAFLD/MASLD-targeted therapy due to lack of large Phase III trials demonstrating histological improvement in liver fibrosis or steatohepatitis 14, 15, 16
• The EASL-EASD-EASO guidelines prioritize GLP-1 receptor agonists (such as semaglutide, liraglutide, tirzepatide) as preferred agents for diabetic patients with MASLD, given their proven benefits on cardiometabolic outcomes and potential hepatic histological benefits with substantial weight loss 14, 15, 16
• SGLT2 inhibitors (such as empagliflozin, dapagliflozin) are considered safe in MASLD and should be used for their approved indications (diabetes, heart failure, chronic kidney disease), though insufficient evidence exists for MASH-targeted therapy 15, 16

Lifestyle and Pharmacological Management

• The American Gastroenterological Association recommends lifestyle modification, including weight loss (7-10%), Mediterranean diet, and 150-300 minutes of moderate-intensity exercise weekly, as first-line approach for diabetic patients with MAFLD 14, 17
• Risk stratification using the FIB-4 score is recommended; if the score is >1.3, liver stiffness measurement should be performed to identify clinically significant fibrosis (≥F2) 17
• GLP-1 receptor agonists (such as semaglutide, liraglutide) or dual GIP/GLP-1 agonists (such as tirzepatide) are preferred for patients with overweight/obesity, especially those with high-risk fibrosis 14, 15, 16
• SGLT2 inhibitors are considered an alternative for cardiovascular/renal protection 15, 16
• Metformin should be continued if already prescribed, as it is safe in compensated cirrhosis and may improve transplant-free survival 15, 16

Considerations for Saroglitazar Use

• Saroglitazar may be considered in specific contexts, such as when guideline-recommended therapies are unavailable, unaffordable, or contraindicated, but this represents off-guideline use based on observational data only 15
• Patients should be counseled about the lack of robust evidence for liver-specific outcomes, and transition to guideline-recommended therapies should occur when feasible 15