Metformin

Metformin is considered the first-line hypoglycaemic agent for the treatment of type 2 diabetes mellitus.

Metformin has been one of most prescribed medications worldwide over the last decade.

The typical starting dose for adults is 500 mg daily, which can be increased to a maximum dose of 2 g daily. The most common adverse-effect is gastrointestinal upset (i.e. nausea, abdominal pain, diarrhoea), although rarely metformin can result in lactic acidosis.

Derived from galegine, which is a natural protein found in the plant Galega officinalis.

Metformin was first synthesised around the 1920s and then used clinically in the 1950s. It is now used worldwide in the treatment of diabetes mellitus.

Metformin is considered the first-line hypoglycaemic agent for the treatment of type 2 diabetes mellitus. It can be used in combination with other hypoglycaemic agents and with insulin.

Indications include:

• Treatment of type 2 diabetes mellitus – Monotherapy or in combination with other anti-diabetic agents
• Polycystic ovarian syndrome (PCOS) – to help reduce symptoms of hyperandrogenism (unlicensed indication)

Metformin reduces hepatic glucose production and acts systemically to increase glucose uptake.

Metformin is a biguanide, which is a compound formed by two guanidine molecules. Despite its global use, the exact mechanism of action remains incompletely understood.

Metformin has multiple sites of action. Metformin reduces hepatic glucose production and acts systemically to increase glucose uptake. Metformin does not affect insulin secretion.

Liver

Suppression of hepatic gluconeogenesis

Within the liver, metformin inhibits the mitochondrial electron transport chain. This leads to activation of the enzyme AMP-activated protein kinase (AMPK). Through other downstream mechanisms, this enhances insulin sensitivity and reduces hepatic glucose output.

Metformin also acts through AMPK-independent pathways by inhibition of the enzyme fructose-1,6-bisphosphatase, which is required for gluconeogenesis. However, risk of hypoglycaemia is minimal as some gluconeogenic activity remains.

Intestine

Increased utilisation of glucose by enterocytes and secretion of GLP-1

Within the intestine, metformin leads to increased utilisation of glucose by enterocytes and increases secretion of glucagon-like peptide-1 (GLP-1).

GLP-1 is important in glucose homeostasis through numerous mechanisms, including:

• Increased insulin secretion
• Decreased glucagon secretion
• Decreased hepatic glucose output
• Increased insulin sensitivity

The general starting dose for adults in 500 mg daily, which can be increased to a maximum of 2g daily.

Metformin should not be used in patients with significant renal impairment (eGFR < 30).

Commonly metformin can cause gastrointestinal upset (i.e. nausea, abdominal pain, diarrhoea). The most serious and well recognised adverse effect, albeit rare, is lactic acidosis.

Common adverse effects:

• Gastrointestinal upset  – nausea, anorexia, abdominal pain, diarrhoea
• Lactic acidosis – metformin inhibits pyruvate metabolism leading to lactate accumulation. More common in the presence of renal impairment.

Absolute contraindications include acute metabolic acidosis.

Metformin should not be used in patients with acute metabolic acidosis (i.e. DKA, lactate acidosis). In addition, metformin should be used with caution in the elderly, particularly those with poor renal function (see below).

Acute metabolic acidosis

In the presence of patients presenting acute with metabolic acidosis, metformin is usually suspended until resolved.

Renal impairment

Metformin should not be used in patients with an estimated glomerular filtration rate (eGFR –  mL/minute/1.73 m2) or calculated creatinine clearance (CrCl – ml/min) < 30.

Pregnancy

Metformin can be used in diabetes but should be guided by a specialist diabetologist/endocrinologist