Metformin – a biguanide – is one of the cornerstones of pharmacotherapy for T2DM, along with exercise and diet. It has a number of actions that improve glucose tolerance. Unlike sulphonylureas, metformin does not cause hypoglycaemia or weight gain and is therefore preferred as the first-line treatment – particularly in overweight patients.
Gastrointestinal upset i.e., nausea, anorexia, diarrhoea (intolerable in 20% of patients)
GLP-1 agonists
GLP-1 agonists are commonly used as an adjunct to metformin or as an alternative. They are typically given as a subcutaneous injection and are very expensive. GLP-1 agonists have been approved for weight loss. They are therefore an attractive choice for diabetic patients who are obese. They have a few, but severe adverse effects.
Mechanism of action
Mimics GLP-1 → increased insulin secretion and reduced glucagon secretion
Indications
BMI > 35 with a specific psychological or medical condition associated with obesity
BMI < 35 for whom insulin therapy would have significant occupational implications
Contraindications
MEN-2 syndrome
Personal history or family history of medullary thyroid cancer
Adverse effects
Acute pancreatitis
DPP-4 inhibitors
DPP-4 inhibitors are commonly used as adjuncts to metformin or as alternatives. They have a similar mechanism to GLP-1 agonists but are weight-neutral. They have very few adverse effects.
Mechanism of action
Inhibition of DPP-4 enzymes → reduced degradation of incretins (GLP-1 and GIP) → increased insulin synthesis and reduced glucagon release
Sulfonylureas have fallen out of favour (due to weight gain and hypoglycemia). They still may be an appropriate monotherapy for patients in whom metformin is contraindicated.
Mechanism of action
Bind to ATP-dependent K+ channels → increased insulin release
Adverse effects
Weight gain
Hypoglycemia (especially with long-acting preparations)
Thiazolidinediones have fallen out of favour due to their propensity to cause water retention. They may still be an appropriate monotherapy for patients in whom metformin is contraindicated.
Mechanism of action
Agonism at PPAR-gamma receptor → increase peripheral insulin sensitivity