Metformin

Mechanism of Action and Pharmacokinetic Considerations

Metformin acts on the intestine, liver and skeletal muscle to reduce hyperglycaemia. 

• Intestine: delays intestinal glucose absorption 
• Liver: inhibits gluconeogenesis and glycogenolysis, reducing hepatic glucose production.
• Skeletal muscle: increases glucose uptake and enhances glycogenesis 
• Cellular effect: increases the transport capacity of membrane glucose transporters 

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Fig 1: mechanism of action of metformin

The t ½ of metformin (standard release) is approximately 6.5 hours. Metformin is eliminated unchanged by the kidneys via renal clearance, so dose adjustment (or avoidance) is required in patients with renal impairment.

Contraindications 

• CrCl <30ml/min
• Acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis)
• Acute alteration of renal function in conditions such as dehydration & shock
• Hepatic insufficiency
• Diabetic pre-coma
• Disease which may cause tissue hypoxia (e.g., acute and unstable heart failure, respiratory failure, recent MI)

Cautions

A dose reduction is required in patients with CrCl <60ml/min. Furthermore, there is risk of

lactic acidosis with metformin therapy (very rare). 

• Increased likelihood with worsening of renal function/sepsis, leading to accumulation of metformin. 
• Alcohol intake increases the risk. 
• Symptoms include: acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma
• Lab findings: ↓ pH (<7.35), ↑ lactate (>5 mmol/L), ↑ anion gap, ↑ lactate/pyruvate ratio

Adverse effects

• No hypoglycaemia risk (does not stimulate insulin secretion).
• Very common: Gastrointestinal upset (diarrhoea, nausea, abdominal discomfort).
  • Improve tolerance by slow dose titration, taking with food, or switching to modified-release formulation.
• Common: Vitamin B12 deficiency (dose-dependent), taste disturbance.

Interactions

• Nephrotoxic agents (NSAIDs, ACE inhibitors, ARBs, diuretics, iodinated contrast agents): may worsen renal function.
• Metformin is a substrate of cation transporters OCT1 and OCT2:
  • Inhibitors of OCT1 (e.g., verapamil) ↓ efficacy of metformin 
  • Inducers of OCT1 (e.g., rifampicin) ↑ GI absorption and efficacy of metformin Inhibitors of OCT2 (e.g., cimetidine, trimethoprim) ↓ renal elimination of metformin therefore ↑ efficacy 
• Beta blockers – mask signs of hypoglycaemia such as tremor (interaction is applicable to all antidiabetic agents)
• Topiramate: may increase plasma metformin concentration.

Some drugs also increase or decrease the glucose lowering effects of metformin: 

References

1. Metformin—mode of action and clinical implications for diabetes and cancer | Nature Reviews Endocrinology
2. Metformin | Prescribing information | Diabetes – type 2 | CKS | NICE
3. Metformin 500 mg film coated Tablets – Summary of Product Characteristics (SmPC) – (emc)