Diabetes Medicines in Liver Disease

Diabetes medicines in liver disease must achieve safe glycaemic control in a setting of impaired gluconeogenesis, reduced insulin clearance and unreliable HbA1c. Diabetes is common in metabolic dysfunction associated steatotic liver disease and develops in many patients with cirrhosis, where it increases the risk of decompensation and hepatocellular carcinoma.

Hypoglycaemia. Glycogen stores and gluconeogenesis are reduced in cirrhosis. Reduced hepatic insulin clearance prolongs insulin and sulphonylurea action.

HbA1c reliability. HbA1c underestimates glycaemia in anaemia, hypersplenism, haemolysis, bleeding and after transfusion. Use continuous glucose monitoring or capillary glucose profiles in advanced disease.

Steatotic liver disease. Some agents improve liver histology, notably pioglitazone and glucagon-like peptide 1 receptor agonists.

Compensated disease. - Metformin remains first line if kidney function is adequate and alcohol use has stopped. - Glucagon-like peptide 1 receptor agonists such as semaglutide are preferred when weight loss and steatohepatitis improvement are goals. - Pioglitazone improves steatohepatitis histology; weigh against weight gain, oedema and fracture risk. - Sodium glucose cotransporter 2 inhibitors are acceptable.

Decompensated disease. - Insulin is preferred. - Avoid metformin because of lactic acidosis risk. - Avoid pioglitazone because of fluid retention. - Use glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors only with specialist input, given malnutrition and volume depletion risks.

Other agents. - Dipeptidyl peptidase 4 inhibitors: sitagliptin and linagliptin are acceptable; avoid vildagliptin in hepatic impairment. - Sulphonylureas: avoid glibenclamide; gliclazide only at low dose in compensated disease. - Acarbose: avoid in cirrhosis.

Metformin. 500 mg orally once daily with food, increased weekly by 500 mg to a maximum of 2 g daily. Maximum 1 g daily if eGFR is 30 to 44 mL/min/1.73 m2; stop if under 30.

Gliclazide. 40 mg orally once daily with breakfast, increased slowly; usual maximum 320 mg daily, but use lower ceilings in liver disease. Avoid in severe hepatic impairment.

Pioglitazone. 15 mg orally once daily, increased to 30 mg; maximum 45 mg daily. Do not start if ALT exceeds 2.5 times the upper limit of normal.

Semaglutide. 0.25 mg subcutaneously once weekly for 4 weeks, then increase every 4 weeks to 0.5 mg and 1 mg (diabetes dosing), or to 2.4 mg weekly for weight management and steatohepatitis.

Sodium glucose cotransporter 2 inhibitors. Empagliflozin 10 mg or dapagliflozin 10 mg orally once daily. Withhold during acute illness, fasting or surgery.

Dipeptidyl peptidase 4 inhibitors. Sitagliptin 100 mg orally once daily; 50 mg if eGFR is 30 to 44, and 25 mg if under 30. Linagliptin 5 mg orally once daily with no kidney or liver adjustment.

Insulin in decompensated cirrhosis. Basal insulin such as glargine 0.1 units/kg subcutaneously once daily, increased by 2 units every 3 days to fasting glucose 6 to 10 mmol/L. Add prandial insulin for post-meal hyperglycaemia. Use lower targets only when hypoglycaemia risk is low.

Special groups. - Pregnancy: insulin is the agent of choice; metformin may be used; stop glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors before conception. - Breastfeeding: insulin and metformin are compatible. - Older adults: avoid sulphonylureas; relax targets. - Kidney impairment: often coexists; adjust metformin, sitagliptin and sulphonylureas.

Monitoring. Capillary glucose or continuous glucose monitoring in advanced disease. ALT before pioglitazone and when clinically indicated. Kidney function every 3 to 12 months on metformin and sodium glucose cotransporter 2 inhibitors.

Glycaemic targets. HbA1c around 53 mmol/mol (7%) in compensated disease if reliable. Relax targets in decompensated disease to avoid hypoglycaemia.

Stopping thresholds. - Metformin: stop in decompensation, active alcohol misuse, sepsis, acute kidney injury or lactate rise. - Pioglitazone: stop if ALT exceeds 3 times the upper limit of normal, jaundice develops, or oedema or heart failure appears. - Glucagon-like peptide 1 receptor agonists: stop for pancreatitis. - Sodium glucose cotransporter 2 inhibitors: stop for ketoacidosis or volume depletion.

Referral and escalation. Refer to diabetes and hepatology services for recurrent hypoglycaemia, decompensated disease or uncontrolled glycaemia.