Association of metformin use on metabolic acidosis in diabetic patients with chronic hepatitis B‐related cirrhosis and renal impairment

Abstract

Background and Aims Metformin is an oral anti‐hyperglycemic recommended by the American Diabetes Association (ADA) as a preferred initial pharmacologic agent for type 2 diabetes. Metabolic acidosis is a rare yet severe side effect of it. We examined the association of metformin use and dosage on the risk of metabolic acidosis in diabetic patients with different degrees of chronic hepatitis B (CHB)‐related cirrhosis and chronic kidney disease (CKD). Methods Metabolic acidosis was defined by blood pH ≤7.35, together with lactate >5 mmol/L or arterial bicarbonate ≤18 mmol/L or venous bicarbonate ≤21 mmol/L, and/or diagnosis codes. Child‐Pugh class and CKD stage were included in the model as time‐dependent covariates. Age, gender, comorbidities, and use of relevant medications were adjusted as covariates. Maximum daily dose of metformin was classified into ≤1000 mg and >1000 mg. Results We identified 4431 diabetic patients with CHB‐related cirrhosis between 2000 and 2017 from a territory‐wide database in Hong Kong. The risk of metabolic acidosis increased with Child‐Pugh class B and C cirrhosis regardless of CKD stage (adjusted subdistribution hazard ratio [aSHR] ranged from 3.50 to 86.16). Metformin use was associated with a higher risk in patients with Child‐Pugh class B or C cirrhosis and stage 3A CKD or above (aSHR ranged from 1.55 to 2.46). In stage 4/5 CKD, a daily dose of metformin ≤1000 mg was still associated with a higher risk of metabolic acidosis regardless of the severity of cirrhosis (aSHR ranged from 2.45 to 3.92). Conclusion In conclusion, patients with Child‐Pugh class B cirrhosis or above were at a higher risk of metabolic acidosis. Metformin further increased the risk in patients with Child‐Pugh class B cirrhosis or above and stage 3A CKD or above. Dose adjustment in stage 4/5 CKD did not reduce the risk of metabolic acidosis.

Diabetes and cirrhosis: Current concepts on diagnosis and management

“…Decreased hepatic lactate clearance and the frequent risk of cardiorenal complications place patients with cirrhosis at an increased risk of metformin-associated lactic acidosis. The biguanide should be used with caution, or best avoided, in people with Child-Pugh class B cirrhosis and stage eGFR <60 mL/min/1.73 m 2 ,151 while contraindicated in decompensated liver disease independent of renal function. Of note, some studies have shown improved outcomes of patients with NASH 152–154.…”

EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

“…Metformin may cause lactic acidosis through impairment of oxidative phosphorylation [478]. The risk of metformin-associated lactic acidosis is increased in individuals with renal impairment and hepatic decompensation, especially when both are present [479].…”