Dipeptidylpeptidase-4 inhibitors

Key examples

• Sitagliptin
• Linagliptin
• Saxagliptin

Common indications

Type 2 diabetes:

1. In combination with metformin (and/or other hypoglycaemic agents) where blood glucose is not adequately controlled on a single agent.
2. As a single agent to control blood glucose and reduce complications where metformin is contraindicated or not tolerated.

Mechanisms of action

• The incretins (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) are released by the intestine throughout the day, but particularly in response to food. They promote insulin secretion and suppress glucagon release, lowering blood glucose. The incretins are rapidly inactivated by hydrolysis by the enzyme dipeptidylpeptidase-4 (DPP-4).
• DPP-4 inhibitors (‘gliptins’) therefore lower blood glucose by preventing incretin degradation and increasing plasma concentrations of their active forms.
• The actions of the incretins are glucose dependent, occurring when blood glucose is elevated, so they do not stimulate insulin secretion at normal blood glucose concentrations or suppress glucagon release in response to hypoglycaemia. This means that DPP-4 inhibitors are less likely to cause hypoglycaemia than sulphonylureas, which stimulate insulin secretion irrespective of blood glucose.

Important adverse effects

• DPP-4 inhibitors are generally well tolerated.
• Patients may experience GI upset, headache, nasopharyngitis or peripheral oedema.
• Hypoglycaemia can occur, particularly where DPP-4 inhibitors are prescribed in combination with other drugs that cause hypoglycaemia such as sulphonylureas or insulin.
• All the DPP-4 inhibitors are associated with a small risk of acute pancreatitis, affecting 0.1–1% people taking the drugs. This should be suspected in patients experiencing persistent abdominal pain and usually resolves on stopping the drug.

Warnings

• DPP-4 inhibitors are contraindicated in people with a history of hypersensitivity to the drug class and should not be used in the treatment of type 1 diabetes or ketoacidosis.
• As there is animal evidence of reproductive toxicity and insufficient human data to ascertain safety, they should not be used during pregnancy or breastfeeding.
• They should be used with caution in the elderly (>80 years) and people with a history of pancreatitis. 
• Many of the DPP-4 inhibitors are renally excreted, so a dose reduction may be required for patients with moderate-to-severe renal impairment.

Important interactions

• Risk of hypoglycaemia is increased by co-prescription of other antidiabetic drugs, including sulphonylureas and insulin, and by alcohol. 
• β-blockers may mask symptoms of hypoglycaemia.
• The efficacy of DPP-4 inhibitors is reduced by drugs that elevate blood glucose, e.g. prednisolone, thiazide and loop diuretics.