In a patient with metabolic‑dysfunction‑associated steatotic liver disease on metformin who is experiencing significant loss of appetite and weight, does metformin cause anorexia, and how should the medication be managed?

Metformin-Induced Anorexia and Weight Loss in MASLD

Yes, metformin directly causes anorexia and weight loss through GDF15-mediated appetite suppression, and in a patient with MASLD experiencing significant loss of appetite and weight, metformin should be discontinued or dose-reduced immediately to prevent further nutritional compromise and potential sarcopenia.

Mechanism of Metformin-Induced Anorexia

Metformin induces anorexia through a well-established GDF15 pathway. Recent mechanistic evidence demonstrates that metformin administration increases GDF15 expression in the kidneys, leading to elevated circulating GDF15 levels that directly suppress appetite and reduce food intake 1. In patients with type 2 diabetes receiving metformin for 8 weeks, GDF15 was significantly upregulated and this correlated with reduced body mass 1.

• GDF15 functions as a potent anorectic factor with anti-inflammatory properties, and is already elevated in patients with MASLD compared to healthy controls 2
• In MASLD specifically, hepatocytes contribute to increased GDF15 levels due to stress-induced signaling, which metformin further amplifies 1
• This mechanism explains why metformin produces durable weight loss primarily through decreased food intake rather than increased energy expenditure 3

Clinical Significance of Weight Loss in MASLD

The magnitude of metformin-induced weight loss is independently associated with baseline BMI, with higher BMI patients experiencing more pronounced weight loss 4. However, this becomes problematic when:

• Patients develop significant anorexia leading to unintentional weight loss beyond therapeutic targets
• Weight loss occurs too rapidly, risking sarcopenia in patients with underlying liver disease 1
• Nutritional status becomes compromised in the context of chronic liver disease where protein requirements are elevated 1

Management Algorithm

Immediate Assessment

Discontinue or reduce metformin dose by 50% immediately in patients with MASLD experiencing significant appetite loss and unintentional weight loss 5. Then assess:

• Severity of weight loss: If >10% body weight loss over 3-6 months with ongoing anorexia, stop metformin entirely
• Nutritional status: Evaluate for sarcopenia or sarcopenic obesity, which requires high-protein intake (1.2-1.5 g/kg/day) 1
• Liver disease stage: In compensated cirrhosis, adapt dietary recommendations to severity and presence of sarcopenia 1

Metformin's Role in MASLD

Metformin is not recommended as a specific treatment for liver disease in MASLD/NASH 1. The evidence is clear:

• Metformin has no significant effect on liver histology despite improving aminotransferases 1
• 6-12 months of metformin plus lifestyle intervention did not improve liver histology compared to lifestyle intervention alone 1
• The 2024 EASL-EASD-EASO guidelines state there is insufficient evidence to recommend metformin as MASH-targeted therapy, though it remains safe for diabetes management 1

Alternative Approach

If diabetes control requires pharmacotherapy, consider switching to:

• GLP-1 receptor agonists: These provide substantial weight loss with potential hepatic histological benefit, though extensively documented benefits are still emerging 1
• Pioglitazone: Despite weight gain concerns (2.5 kg average), it significantly improves liver histology in NASH with diabetes 1
• Lifestyle modification alone: Weight loss of 5-10% through diet and exercise consistently reduces liver fat by 40% on average 1

Monitoring After Discontinuation

• Recheck liver enzymes at 3-6 months, expecting stabilization with appropriate nutritional intervention 5
• Monitor eGFR as metformin discontinuation removes the need for renal monitoring every 3-6 months if eGFR <60 mL/min/1.73 m² 5
• Assess nutritional recovery: Ensure adequate protein intake and resolution of anorexia before considering any weight-loss promoting medications

Critical Pitfalls to Avoid

Do not continue metformin simply because liver enzymes are elevated. While metformin is safe with elevated transaminases and does not cause hepatotoxicity 5, 6, its continuation in the face of significant anorexia prioritizes glycemic control over quality of life and nutritional status.

Do not assume weight loss from metformin is always beneficial in MASLD. Although weight loss improves steatosis, the mechanism matters—GDF15-mediated anorexia leading to inadequate protein intake can worsen sarcopenia, which is particularly detrimental in liver disease 1.

Do not overlook that metformin's weight loss is dose-dependent and cumulative. The average weight loss is 2 kg over 16 weeks, but this continues gradually with ongoing therapy 4. In patients with significant appetite suppression, this trajectory accelerates.