Metformin

  Child-Pugh A + B + C
Safety Safe
Dose No dose adjustment necessary
Explanation

Due to the renal clearance of metformin, the pharmacokinetics will not be affected by liver cirrhosis. There is much experience with metformin, also in patients with cirrhosis. Metformin can therefore be used safely in these patients, provided that there are no risk factors for lactic acidosis. These risk factors include renal impairment and alcohol consumption.

Information about the safety classification and the recommended actions can be found here.

Summary of literature

Considerations

Due to renal clearance, the pharmacokinetics of metformin will be virtually unaffected by liver cirrhosis. The literature also shows in six safety studies (evidence level 2-5) that metformin is being used in cirrhotic patients (n=248). Lactic acidosis only occurred when other risk factors were present. Metformin is evaluated as safe in cirrhosis. No dose was mentioned in any of the clinical trials. Theoretically, there is no reason to believe that metformin accumulates in impaired liver function because it is not hepatically cleared. Therefore, no dose adjustment is recommended.

 

Pharmacokinetic data

The bioavailability of metformin is approximately 50-60% and plasma protein binding is negligible. Metformin is a hydrophilic base that is cationized at physiological pH. As a result, metformin does not pass the hepatocyte membrane substantially and is also not metabolised in the liver. Metformin is excreted unchanged in the urine. A liver function disorder like cirrhosis will theoretically not affect the pharmacokinetics of metformin. However, there is no pharmacokinetic study that confirm this.

 

Safety data

The major risk with metformin is lactic acidosis. Due to cirrhosis, lactate clearance can be reduced, with risk the accumulation of lactate and lactic acidosis. Many studies prove that metformin, even in patients with cirrhosis, can be safely used without this side effect. This was also true in patients with severe cirrhosis (Child-Pugh C), although not much research has been done in these patients (n=3).
There are two case reports of a fatal lactic acidosis in metformin use. In both case reports there were also other risk factors involved. Both patients were known for alcohol abuse and one patient had acute renal impairment. Therefore, in order to minimize the risk of lactic acidosis, it is important that metformin is not used in patients with other risk factors for lactic acidosis. These are a decreased kidney function or alcohol consumption, see also the Dutch General Practitioners guideline on Diabetes.