What are the treatment options for metabolic dysfunction‑associated steatotic liver disease (MASLD) that avoid causing weight gain?

Treatment Options for MASLD That Avoid Weight Gain

Resmetirom is the primary MASLD-targeted therapy that does not cause weight gain and should be considered first-line for non-cirrhotic MASH with significant fibrosis (stage ≥2), while pioglitazone represents an alternative option that may cause modest weight gain but improves liver histology through weight-independent mechanisms. 1, 2, 3

Weight-Neutral or Weight-Gain Pharmacological Options

Resmetirom (Thyroid Hormone Receptor β-Selective Agonist)

• This is the first FDA-approved MASH-targeted therapy that directly improves steatohepatitis and fibrosis without requiring weight loss as its mechanism of action. 1, 2, 4, 5
• Resmetirom should be considered for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) if locally approved. 1, 2, 4
• The drug works through weight-independent mechanisms by directly targeting hepatic lipid metabolism, making it ideal for patients who cannot or should not lose weight. 3

Pioglitazone (PPARγ Agonist)

• Despite causing modest weight gain (typically 2-5 kg), pioglitazone improves adipose tissue function and MASLD histology, including potential benefits on fibrosis, through insulin-sensitizing mechanisms independent of weight loss. 3
• This medication improves liver inflammation and fibrosis by enhancing insulin sensitivity and redistributing fat from ectopic sites (liver) to subcutaneous adipose tissue. 3
• Pioglitazone represents a viable option when weight gain is acceptable or when patients have concurrent type 2 diabetes requiring glucose control. 1, 3

Medications With Cardiovascular Benefits (Weight-Neutral)

Statins

• Statins are safe, underutilized, and should be prescribed according to cardiovascular risk guidelines in all MASLD patients, as they reduce cardiovascular events (the leading cause of death in MASLD) without affecting liver disease progression. 4
• These medications do not cause weight gain and provide critical mortality benefit by addressing the primary cause of death in MASLD patients. 4

Alternative Approaches for Specific Populations

Normal-Weight MASLD Patients

• For patients with normal BMI (<25 kg/m² non-Asian, <23 kg/m² Asian), focus on diet quality improvement and exercise to reduce liver fat without weight loss targets. 1
• Implement Mediterranean dietary patterns emphasizing vegetables, fruits, low-fat dairy, nuts, olive oil, legumes, and unprocessed fish/poultry while avoiding ultra-processed foods. 1, 2
• Prescribe structured exercise programs targeting >150 minutes/week of moderate-intensity OR 75 minutes/week of vigorous-intensity physical activity. 1, 2, 4

MASLD with Cirrhosis and Sarcopenia

• In compensated cirrhosis with sarcopenia or decompensated cirrhosis, implement high-protein diet (1.2-1.5 g/kg/day) with late-evening snacks to prevent muscle wasting, avoiding weight loss interventions. 1
• Weight reduction is contraindicated in decompensated cirrhosis or when significant sarcopenia is present. 1

Medications to Avoid or Use Cautiously

GLP-1 Receptor Agonists and SGLT2 Inhibitors

• While these medications improve MASLD histology and cardiovascular outcomes, they inherently cause weight loss (GLP-1 agonists: 10-15% body weight; SGLT2 inhibitors: 2-3% body weight), making them unsuitable when weight maintenance is desired. 2, 4, 3, 6, 7
• These should be reserved for patients with concurrent type 2 diabetes or obesity where weight loss is therapeutically beneficial. 2, 4

Critical Clinical Considerations

Common Pitfall: Clinicians often assume all MASLD patients require weight loss, but normal-weight MASLD patients (15-20% of cases) and those with sarcopenia require different therapeutic approaches focusing on metabolic improvement without weight reduction. 1

Stopping Rules: For resmetirom and other MASH-targeted therapies, early predictors of non-response need definition, though current guidelines do not establish clear stopping rules for non-responders. 1

Multidisciplinary Approach: Given the bidirectional connections between MASLD and cardiometabolic comorbidities, coordinate care with endocrinology for diabetes management, cardiology for cardiovascular risk, and nutrition for dietary optimization. 1, 2, 4