How should I treat an adult with biopsy‑confirmed NASH (MASLD) and fibrosis stage F2‑F3 who is obese, has type 2 diabetes and dyslipidaemia using a GLP‑1 receptor agonist off‑label, including preferred agent, dosing schedule, monitoring, contraindications, and alternative therapies?

GLP-1 Agonist Therapy in MASLD with F2-F3 Fibrosis

GLP-1 receptor agonists should be used in adults with biopsy-confirmed NASH (MASLD) and F2-F3 fibrosis primarily for their approved indications of type 2 diabetes and obesity management, not as NASH-targeted therapy, with semaglutide or tirzepatide as preferred agents when substantial weight loss is needed. 1

Guideline-Directed Positioning of GLP-1 RAs

The 2024 EASL-EASD-EASO guidelines establish a critical distinction: GLP-1 receptor agonists are safe to use in MASH (including compensated cirrhosis) and should be used for their respective indications—namely type 2 diabetes and obesity—as their use improves cardiometabolic outcomes. 1 However, these agents cannot be recommended as MASH-targeted therapies due to lack of robust demonstration of histological efficacy on steatohepatitis and liver fibrosis in large Phase III trials. 1

The only medication with a strong recommendation as MASH-targeted therapy is resmetirom for non-cirrhotic MASH with fibrosis stage ≥2, which demonstrated histological effectiveness on both steatohepatitis and fibrosis. 1, 2 GLP-1 RAs occupy a complementary role—treating the metabolic comorbidities that drive MASLD progression rather than directly targeting liver pathology. 1

Preferred Agent Selection

Semaglutide 2.4 mg Weekly

Choose semaglutide when:

• Established cardiovascular disease is present (26% reduction in CV death, nonfatal MI, or stroke; HR 0.74) 1
• Patient requires proven cardiovascular benefit alongside weight loss 1, 3
• Mean weight loss of 14.9% at 68 weeks is acceptable 4, 3

Tirzepatide 15 mg Weekly

Choose tirzepatide when:

• Maximum weight loss is the priority (20.9% at 72 weeks vs. 14.9% with semaglutide) 1, 4
• Patient has severe obesity (BMI >35) with multiple metabolic complications 4
• Superior cardiometabolic improvements are needed (greater triglyceride reduction, waist circumference reduction) 4

Both agents require no dose adjustment across all stages of chronic kidney disease, including eGFR <30 mL/min/1.73 m². 1, 4

Dosing Schedule

Semaglutide 2.4 mg (Wegovy)

• Week 1-4: 0.25 mg subcutaneously once weekly 4
• Week 5-8: 0.5 mg weekly 4
• Week 9-12: 1.0 mg weekly 4
• Week 13-16: 1.7 mg weekly 4
• Week 17+: 2.4 mg weekly (maintenance) 4

Tirzepatide (Mounjaro/Zepbound)

• Week 1-4: 5 mg subcutaneously once weekly 4
• Week 5-8: 10 mg weekly (if tolerated) 4
• Week 9+: 15 mg weekly (if additional benefit needed) 4

Slow titration every 4 weeks is essential to minimize gastrointestinal adverse events (nausea 17-44%, diarrhea 12-32%, vomiting 7-25%). 4 These symptoms are typically mild-to-moderate and resolve within 4-8 weeks at each dose level. 4

Monitoring Requirements

Baseline Assessment

• FIB-4 score and liver stiffness measurement (if not already performed) to confirm F2-F3 fibrosis 1, 5
• HbA1c and fasting glucose 1
• Comprehensive metabolic panel (renal function, liver enzymes) 1
• Lipid panel 1
• Screen for personal/family history of medullary thyroid carcinoma or MEN 2 (absolute contraindication) 1, 4

During Titration (Every 4 Weeks)

• Weight and blood pressure 4
• Gastrointestinal tolerance 4
• Signs of pancreatitis (persistent severe abdominal pain) 1, 4
• Signs of gallbladder disease (right upper quadrant pain) 1, 4

After Reaching Maintenance Dose (Every 3 Months)

• Weight stability 4
• HbA1c (if diabetic) 1
• Blood pressure and cardiovascular risk factors 4
• Liver enzymes (reasonable in known liver disease) 5
• Medication adherence 4

Treatment response should be evaluated at 12-16 weeks on maximum tolerated dose; discontinue if <5% weight loss after 3 months. 1, 4

Contraindications

Absolute

• Personal or family history of medullary thyroid carcinoma 1, 4
• Multiple endocrine neoplasia type 2 (MEN 2) 1, 4
• Pregnancy or breastfeeding 4
• Severe hypersensitivity reaction to the agent 1

Relative Cautions

• History of pancreatitis (use with caution; causality not definitively established) 1
• Symptomatic gallbladder disease (38% increased risk of cholelithiasis/cholecystitis vs. placebo) 4
• Severe gastroparesis or GI motility disorders 4
• Child-Pugh B cirrhosis (use cautiously); Child-Pugh C cirrhosis (contraindicated) 5

Concomitant Medication Adjustments

When initiating GLP-1 RA therapy:

• Reduce basal insulin by 20% to prevent hypoglycemia 1, 4
• Discontinue or reduce sulfonylureas by 50% due to additive hypoglycemia risk 1, 4
• Stop all DPP-4 inhibitors (no additional benefit with concurrent use) 1, 4
• Continue metformin unless contraindicated 1, 5
• Continue SGLT2 inhibitors for complementary cardiovascular/renal benefits 1
• Continue statins for cardiovascular risk reduction (safe in compensated cirrhosis) 1

Expected Hepatic Benefits

In the context of substantial weight loss induced by GLP-1 RAs, hepatic histological benefit could be expected, although this has not been extensively documented in large Phase III trials. 1 The LEAN trial with liraglutide showed more frequent resolution of NASH compared to placebo, though the study was small. 5 Semaglutide 0.4 mg daily achieved NASH resolution in 59% of patients versus 17% on placebo, but fibrosis improvement did not reach statistical significance. 1

The primary mechanism of hepatic benefit is weight loss-mediated: 7-10% weight reduction through lifestyle modification plus GLP-1 RA therapy reduces hepatic steatosis and may improve inflammatory markers. 5, 6 However, GLP-1 RAs should not be prescribed solely for liver-directed therapy—their role is treating the metabolic drivers (diabetes, obesity) that perpetuate MASLD progression. 1

Alternative and Complementary Therapies

Resmetirom (MASH-Targeted Therapy)

If locally approved, adults with non-cirrhotic MASH and fibrosis stage ≥2 should be considered for resmetirom as the only medication with strong guideline support for histological improvement in both steatohepatitis and fibrosis. 1, 2 Resmetirom can be used alongside GLP-1 RAs when residual active MASH with F2-F3 fibrosis persists despite metabolic therapy. 1

Pioglitazone

Pioglitazone may be used in non-cirrhotic MASH for metabolic effects but cannot be recommended as MASH-targeted therapy due to lack of robust Phase III histological data. 1, 2 Combination therapy with pioglitazone plus a GLP-1 RA can be considered for patients with biopsy-proven MASH or high-risk fibrosis. 5

SGLT2 Inhibitors

SGLT2 inhibitors (empagliflozin, dapagliflozin) are safe in MASLD and should be used for type 2 diabetes, heart failure, and chronic kidney disease indications, though insufficient evidence exists for MASH-targeted therapy. 1, 2, 5

Bariatric Surgery

Bariatric surgery should be considered for patients with MASLD and BMI >35, as it provides superior long-term weight loss and metabolic improvement compared to pharmacotherapy alone. 1, 6

Common Pitfalls and How to Avoid Them

Do not delay GLP-1 RA initiation in eligible patients with F2-F3 fibrosis, type 2 diabetes, and obesity—early treatment improves cardiometabolic outcomes and may slow fibrosis progression. 1

Do not prescribe GLP-1 RAs as "liver-directed therapy" without addressing their approved indications (diabetes, obesity)—this misrepresents the evidence base and guideline positioning. 1

Do not discontinue GLP-1 RAs if the patient progresses to compensated cirrhosis—these agents remain safe in Child-Pugh A cirrhosis. 1, 5

Do not assume fibrosis improvement based on weight loss alone—while steatosis and inflammation may improve, fibrosis regression with GLP-1 RAs has not been consistently demonstrated in large trials. 1

Do not overlook the need for lifelong therapy—discontinuation of GLP-1 RAs results in regain of 50-67% of lost weight within one year, potentially reversing metabolic and hepatic benefits. 4

Do not combine GLP-1 RAs with other GLP-1 RAs or DPP-4 inhibitors—this offers no additional benefit and increases adverse event burden. 1, 4

Do not start at maintenance doses—rapid titration markedly increases gastrointestinal adverse events and discontinuation rates. 4

Clinical Decision Algorithm

1. Confirm eligibility: Biopsy-proven NASH with F2-F3 fibrosis + type 2 diabetes and/or obesity (BMI ≥30 or ≥27 with comorbidities) 1, 5

2. Screen for contraindications: Personal/family history of MTC or MEN 2, pregnancy, severe gastroparesis 1, 4

3. Select agent:

   • Established CVD present → Semaglutide 2.4 mg weekly 1, 4
   • Maximum weight loss priority → Tirzepatide 15 mg weekly 4
   • Either agent acceptable → Consider cost, patient preference, insurance coverage 4

4. Adjust concomitant medications: Reduce insulin 20%, reduce/stop sulfonylureas, stop DPP-4 inhibitors 1, 4

5. Initiate slow titration: Follow 4-week dose escalation schedule 4

6. Monitor closely: Every 4 weeks during titration, then every 3 months at maintenance 4

7. Evaluate response at 12-16 weeks: Discontinue if <5% weight loss; continue if adequate response 1, 4

8. Consider resmetirom if residual active MASH with F2-F3 fibrosis persists despite GLP-1 RA therapy and adequate weight loss 1, 2

9. Plan for lifelong therapy if effective—stopping GLP-1 RAs leads to rapid weight regain and loss of metabolic benefits 4