Metformin Use in MASH (Metabolic Dysfunction-Associated Steatohepatitis)
Metformin is safe to use in patients with MASH but should not be prescribed as a MASH-targeted therapy, as there is insufficient evidence that it reduces liver damage, fibrosis, or liver-related outcomes. 1
Primary Indication and Safety Profile
Metformin should be used for its approved indications—type 2 diabetes, heart failure, and chronic kidney disease—not for treating MASH itself. 1
The 2024 EASL-EASD-EASO guidelines explicitly state that metformin is safe to use in MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) and MASH, but lacks robust evidence as a liver-directed therapy. 1
Disease Stage-Specific Recommendations
Non-Cirrhotic MASH (F0-F3 Fibrosis)
Metformin can be used safely in patients with non-cirrhotic MASH when indicated for diabetes management. 1
For MASH-targeted therapy in this population, GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) or coagonists (tirzepatide) are preferred over metformin. 1
If locally approved, resmetirom is the recommended MASH-targeted therapy for F2-F3 fibrosis. 1
Compensated Cirrhosis (F4)
Metformin can be used in adults with compensated cirrhosis and preserved renal function (GFR >30 mL/min), but should NOT be used in decompensated cirrhosis, especially with concomitant renal impairment, due to the risk of lactic acidosis. 1
The critical GFR threshold is 30 mL/min per 1.73 m²—metformin should be discontinued below this level. 1
Decompensated Cirrhosis
Metformin is contraindicated in decompensated cirrhosis due to the high risk of metformin-associated lactic acidosis (MALA), which has a mortality rate approaching 50%. 1, 2
Insulin becomes the preferred glucose-lowering agent in decompensated cirrhosis. 1
Critical Safety Considerations
Lactic Acidosis Risk
The primary toxicity concern with metformin in advanced liver disease is lactic acidosis, not hypoglycemia. 3
Metformin does not cause hypoglycemia when used alone, as it decreases hepatic glucose output rather than stimulating insulin release. 3, 4
MALA typically requires both elevated plasma metformin concentrations (from renal impairment) AND a secondary event that disrupts lactate production or clearance (cirrhosis, sepsis, hypoperfusion). 2
Renal Function Monitoring
Metformin should be temporarily discontinued during serious intercurrent illness that increases AKI risk in patients with GFR <60 mL/min per 1.73 m². 1
The KDIGO guidelines recommend: continue metformin with GFR ≥45 mL/min; review use with GFR 30-44 mL/min; discontinue with GFR <30 mL/min. 1
Special Populations
In patients with mitochondrial diseases (including MELAS syndrome), metformin should be used with extreme caution or avoided, as it can trigger clinical manifestations by inhibiting mitochondrial function. 5
A case report documented late-onset MELAS syndrome unmasked by metformin use, with symptoms improving after metformin discontinuation. 5
Preferred Alternatives in MASH
When metformin cannot be used or is insufficient:
GLP-1 receptor agonists are safe in MASH (including Child-Pugh class A cirrhosis) and improve cardiometabolic outcomes. 1
SGLT2 inhibitors can be used in Child-Pugh class A and B cirrhosis. 1
Sulfonylureas should be avoided in hepatic decompensation due to hypoglycemia risk. 1
Common Pitfalls to Avoid
Do not prescribe metformin expecting direct liver histological improvement—it is not a MASH-targeted therapy. 1
Do not continue metformin in patients who develop decompensated cirrhosis, even if renal function is preserved. 1
Do not overlook gastrointestinal adverse events (diarrhea, nausea), which occur commonly and may require dose titration or switching to extended-release formulations. 6
Do not forget to check vitamin B12 levels with long-term use (>4 years), as deficiency is associated with prolonged metformin therapy. 4