Sitagliptin

Key points

• The primary enzyme responsible for sitagliptin’s limited metabolism is CYP3A4, with a contribution from CYP2C8. Sitagliptin is also a substrate of P-glycoprotein.
• After a single oral dose in healthy volunteers the apparent terminal half-life was 12.4 hours, with peak plasma concentrations reached one to four hours after the dose.
• Taken with metformin and rosiglitazone, the overall incidence of hypoglycaemia was 2.2% on added sitagliptin against 0% on added placebo through week 18, rising to 3.9% against 1% by week 54.
• Sitagliptin has not been studied in people with a history of pancreatitis, and the label says it is unknown whether they face an increased risk of developing it.

How it works

Sitagliptin is a DPP-4 inhibitor which is believed to act in type 2 diabetes by slowing the inactivation of incretin hormones. Those hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are released by the intestine through the day and rise after a meal, and are rapidly inactivated by the enzyme DPP-4. By slowing that inactivation, sitagliptin increases concentrations of the active intact hormones and prolongs their action. The label describes the incretins as part of an endogenous system involved in the physiologic regulation of glucose homeostasis.

Safety specific to sitagliptin

Pancreatitis. The label records postmarketing reports of acute pancreatitis, including fatal and non-fatal haemorrhagic or necrotising pancreatitis, in people taking sitagliptin. It says that after starting sitagliptin, patients should be observed carefully for signs and symptoms of pancreatitis, and that if pancreatitis is suspected sitagliptin should promptly be discontinued.

Low blood sugar when combined with insulin or a sulphonylurea. When sitagliptin was used with insulin or an insulin secretagogue such as a sulphonylurea, the label records that the incidence of hypoglycaemia was increased over placebo used in the same combination. It notes that a lower dose of the sulphonylurea or insulin may therefore be required. This matters because sitagliptin is commonly taken as part of a combination.

Serious hypersensitivity reactions. The label records postmarketing reports of serious hypersensitivity reactions, including anaphylaxis, angioedema and exfoliative skin conditions such as Stevens-Johnson syndrome. Onset occurred within the first three months of treatment, with some reports after the first dose. A serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema, is a contraindication to taking it again.

Kidney function. There have been postmarketing reports of worsening renal function, including acute renal failure sometimes requiring dialysis. The label notes a subset of these reports involved people with renal impairment, some of whom were prescribed inappropriate doses.

The label also records postmarketing reports of severe and disabling arthralgia in people taking DPP-4 inhibitors, with time to onset varying from one day to years and relief on stopping, and cases of bullous pemphigoid requiring hospitalisation. On heart failure, the label reports an association observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class, not for sitagliptin itself, and advises weighing risks and benefits in people already at risk.

When to seek urgent care

The label directs that patients be told to report blisters or erosions developing while taking sitagliptin. Signs and symptoms of pancreatitis warrant prompt medical attention, since the label instructs that the medicine be stopped promptly if pancreatitis is suspected.

Further reading

• SITAGLIPTIN tablet, film coated
• Sitagliptin: MedlinePlus Drug Information