From the Guidelines
Metformin is generally not considered hepatotoxic and is actually the preferred first-line medication for type 2 diabetes in patients with liver disease, including those with non-alcoholic fatty liver disease (NAFLD). While rare cases of liver injury have been reported with metformin use, these instances are extremely uncommon compared to the millions of patients who take the medication safely 1. Metformin works primarily by reducing glucose production in the liver and improving insulin sensitivity, which can actually have beneficial effects on liver health by reducing fat accumulation in liver cells. The medication is typically started at 500 mg once or twice daily and can be gradually increased to a maximum of 2000-2500 mg daily, divided into two or three doses. Unlike many other diabetes medications, metformin does not require dose adjustment in patients with mild to moderate liver disease, though it should be used cautiously in severe liver impairment. Regular liver function monitoring is still recommended when starting any new medication, but metformin's safety profile regarding liver health is well-established, making it a preferred option for diabetic patients with underlying liver conditions.
Some key points to consider when using metformin in patients with liver disease include:
- Metformin can be used in adults with compensated cirrhosis and preserved renal function, but should not be used in adults with decompensated cirrhosis, especially when there is concomitant renal impairment, because of the risk of lactic acidosis 1.
- Metformin improves ALT but not histological steatosis, however, observational data suggest a potential protective effect against HCC 1.
- The risk of metformin-associated lactic acidosis is increased in individuals with renal impairment and hepatic decompensation, especially when both are present 1.
- Metformin may cause lactic acidosis through impairment of oxidative phosphorylation, and the risk is increased in individuals with renal impairment and hepatic decompensation 1.
Overall, the benefits of metformin in patients with type 2 diabetes and liver disease outweigh the risks, and it is a preferred first-line medication for these patients. However, regular monitoring of liver function and renal function is recommended to minimize the risk of adverse effects.
From the FDA Drug Label
Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.
Metformin may be hepatotoxic as there have been reports of liver injury, including cholestatic, hepatocellular, and mixed hepatocellular liver injury, in the postmarketing experience with metformin 2.
- Key points:
- Hepatocellular liver injury has been reported
- Cholestatic liver injury has been reported
- Mixed hepatocellular liver injury has been reported However, these reactions are reported voluntarily from a population of uncertain size, making it difficult to estimate their frequency or establish a causal relationship to drug exposure.
From the Research
Metformin Hepatotoxicity
- Metformin is not considered intrinsically hepatotoxic, and it may be beneficial in patients with nonalcoholic fatty liver disease 3.
- The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis, but little evidence supports this warning 4.
- A case report of metformin-induced hepatotoxicity was documented, where a 61-year-old obese man presented with jaundice, nausea, fatigue, and an unintentional weight loss 2 weeks following initiation of metformin 5.
- Another case report described a 63-year-old female with alcoholic liver disease on metformin who developed metformin-associated lactic acidosis complicated by acute decompensated liver failure, renal failure, and shock 6.
Risk Factors for Hepatotoxicity
- Patients with cirrhosis, particularly those with encephalopathy, may have arterial hypoxemia, which heightens the risk of developing lactic acidosis 3.
- Chronic liver disease patients with type 2 diabetes mellitus (T2DM) were associated with higher plasma lactate concentrations 4.
- CLD patients with cirrhosis had higher lactate concentrations than those without cirrhosis 4.