Emerging Therapeutic Approaches for Metabolic Dysfunction Associated Steatotic Liver Disease

Comprehensive Summary: Emerging Therapeutic Approaches for Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD/MASH)

Presenter: Mazen Noureddin, MD, MHSc

Format: CME/Medical Conference Lecture

1. Main Clinical Topics Discussed

• Weight loss strategies (lifestyle, pharmacologic, endoscopic, surgical) as foundational MASLD/MASH therapy
• Emerging and pipeline pharmacotherapies targeting MASH/NASH histology and fibrosis
• FDA regulatory pathways for MASH drug approval
• Current screening recommendations for high-risk populations
• Role of established agents (Vitamin E, pioglitazone) in contemporary practice

2. Key Learning Points, Guidelines, and Recommendations

Weight Loss Thresholds

• ≥5% body weight loss → improvement in inflammatory/injury features (ballooning, inflammation)
• ≥10–20% body weight loss → associated with fibrosis improvement
• Critical limitation: Only ~10% of patients achieve ≥10% weight loss through lifestyle alone, underscoring the need for pharmacologic intervention

Dietary Recommendations

• Mediterranean diet remains the guideline-endorsed dietary pattern for MASLD/MASH
• Emerging evidence supports low-carbohydrate diets and intermittent fasting
• Clinicians should individualize dietary counseling, accounting for cultural background and food-related social practices
• Coffee consumption is recommended for patients with MASLD

Screening Recommendations

• Current guidelines (AGA Call for Action 2021, AACE, AASLD, and international bodies) recommend screening high-risk populations for MASLD
• Guidelines have become more liberal regarding management of cardiovascular comorbidities and diabetes in MASLD patients
• For MASLD F2–F3 patients, GLP-1 receptor agonists are increasingly recommended for comorbidity management (diabetes, obesity), even absent a dedicated MASH FDA indication

Established Pharmacotherapy

• Vitamin E (Sanyal et al., NEJM 2010, NASH CRN):

- Improves NASH/NAS scores and promotes NASH resolution

- Does not reliably improve fibrosis

- Side effect concerns: possible prostate cancer risk, cardiovascular effects

• Pioglitazone:

- Demonstrated histological NASH improvement and resolution in diabetic and non-diabetic patients

- Fibrosis improvement remains controversial (meta-analyses suggestive but data considered questionable by speaker)

- Largely superseded by newer PPAR agonists (lanifibranor, saroglitazar)

Regulatory Framework for MASH Drug Approval

• Phase 3 histological endpoints (FDA-required):

- NASH resolution without fibrosis worsening

- Fibrosis improvement (≥1 stage) without NASH worsening

• Subpart H approval (accelerated): based on histological endpoints
• Full/final approval: requires outcomes data from compensated cirrhosis (MASH-cirrhosis) trials demonstrating benefit on liver-related clinical events (MALE – Major Adverse Liver Events)

3. Specific Clinical Data and Study Results Cited