Metformin

  Child-Pugh A + B Child-Pugh C
Safety Safe Additional risks known
Dose No dose adjustment necessary Use 50% of the normal dose
Explanation

In Child-Pugh A and B cirrhosis, there is enough evidence that metformin could be safely used and the pharmacokinetics of metformin are not altered. Metformin can therefore be used in these patients, provided that there are no risk factors for lactic acidosis (renal impairment and active alcohol consumption). In Child-Pugh C cirrhosis, a more than doubled exposure to metformin was predicted and several case-reports of lactic acidosis show that patients are very fragile. There is no convincing evidence that the reduced lactate clearance due to cirrhosis does not increase the risk of metformin-associated lactic acidosis. Therefore, if possible, a safer alternative should be used (“additional risks known”) and otherwise use half of the normal dose.

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

Summary of literature

Considerations

Four studies (evidence level 3) with in total 679 patients with cirrhosis (n=26 CTP A/B, n=3 CTP C; rest severity unknown) demonstrated that metformin was safely used in patients with cirrhosis. Based on the pharmacokinetics of metformin and on a pharmacokinetic modelling study (level 4), the exposure to metformin in Child-Pugh A and B cirrhosis does not alter to a clinical relevantly extent. Therefore, in Child-Pugh A and B it is classified as “safe” and no dose adjustment is advised. 

In Child-Pugh C however, a more than doubled exposure to metformin was predicted. There were five case-reports (level 4) of lactic acidosis in patients with cirrhosis, in some risk factors were present. A few demonstrate that in advanced cirrhosis, the patients are very fragile and a provoking factor like shock or an infection could lead to lactic acidosis. Furthermore, we have very little evidence that it was safely used in Child-Pugh C, and there are safer alternatives. Due to these risks, it is classified as “additional risks known”. Based on the results of the modelling study, it is advised to use half of the normal dose.

Pharmacokinetic data

The bioavailability of metformin is approximately 50-60% and the plasma protein binding is negligible. Metformin is a hydrophilic base that is cationized at physiological pH. Metformin is excreted unchanged in the urine. A physiologically based pharmacokinetic model predicted that the exposure to metformin almost doubled in patients with Child-Pugh B cirrhosis and more than doubled in Child-Pugh C cirrhosis. The authors explain that these predicted increases probably result from decreased renal function and a decreased uptake into the liver and biliary secretion of metformin mediated by OCT1.

Safety data

Lactic acidosis is an important but rare side effect of metformin. Due to cirrhosis, lactate clearance can be reduced, which is possibly a risk for lactate accumulation and acidosis. Many studies in patients with Child-Pugh A and B cirrhosis show that metformin can be safely used without occurrence of lactic acidosis. A large retrospective cohort study determined the risk of lactic acidosis in patients with type 2 diabetes. In total, 443 patients with hepatic dysfunction (mostly cirrhosis, severity not mentioned) were included. None of the patients treated with metformin developed lactic acidosis and hepatic dysfunction did not significantly increase the risk of acidosis.

There are five case reports published of lactic acidosis occurring in patients with cirrhosis on metformin. Two patients (Child-Pugh B) were admitted for nausea, vomiting and breathlessness with high lactate levels. One had a history of alcohol abuse and used 500 mg metformin daily, he developed renal insufficiency in the hospital. This patient recovered after hemofiltration. The other patient used metformin 1000 mg daily and was diagnosed with bacterial peritonitis and high lactate levels at admission. While in hospital, renal insufficiency emerged and septic shock was suspected. Treatment with antibiotics was unsuccessful and the patient died.

In the three other case reports there were also other risk factors for lactic acidosis involved. Two patients were known for alcohol abuse with one also suffering from acute renal impairment. In the last case report, an overdose of metformin was suspected, though the patient also had end-stage renal disease.


Last update: 28-03-19

Changes: classification of metformin in Child-Pugh C cirrhosis changed from “safe” to “additional risks known” based on new literature.