Sitagliptin
Sitagliptin is an oral dipeptidyl peptidase-4 inhibitor used in adults with type 2 diabetes. It improves glycaemic control by extending the half-life of endogenous incretin hormones, with a low intrinsic risk of hypoglycaemia.
- Chemical formula
- C16H15F6N5O
- CAS number
- 486460-32-6
- ATC code
- A10BH01
- Molecular weight
- 407.31 g/mol
- Drug class
- DPP-4 inhibitor
- Also known as
- MK-0431, Sitagliptina
What is it?
Sitagliptin is a small-molecule, orally active inhibitor of dipeptidyl peptidase-4 developed by Merck and approved in 2006 as the first medication of its class. The drug is supplied as the phosphate monohydrate salt in tablets of various strengths and as a fixed-dose combination with metformin. It introduced a new pharmacological strategy in type 2 diabetes by selectively targeting the enzyme that degrades endogenous incretins, rather than directly stimulating insulin or insulin signalling.
Mechanism of action
Sitagliptin reversibly inhibits DPP-4, the serine protease responsible for rapid degradation of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Higher concentrations of these incretins enhance glucose-dependent insulin secretion from pancreatic beta cells and suppress inappropriate glucagon release, with no effect when glucose levels are normal. The drug is highly selective for DPP-4 over related peptidases, which contributes to its tolerability profile.
Pharmacokinetics
After oral administration, sitagliptin is absorbed rapidly, with peak plasma concentrations reached within one to four hours and absolute bioavailability of about 87%. Plasma protein binding is around 38%. The drug is excreted predominantly unchanged in urine through active tubular secretion, and the terminal half-life is approximately twelve hours. Renal impairment requires dose reduction, while moderate hepatic impairment does not. Drug interactions through cytochrome P450 enzymes are limited.
Indications
Sitagliptin is approved in adults with type 2 diabetes mellitus, alone or in combination with other antidiabetic agents, to improve glycaemic control. It is often used when metformin is insufficient, contraindicated or not tolerated, and is also available in fixed-dose combinations with metformin and with selected SGLT2 inhibitors. According to international guidelines, the choice between sitagliptin, GLP-1 receptor agonists or other classes depends on glycaemic targets, weight, comorbidities and risk of hypoglycaemia.
Safety profile
Sitagliptin is generally well tolerated. The most frequent adverse effects are nasopharyngitis, headache and upper respiratory tract symptoms. Acute pancreatitis has been reported and prompts caution in patients with previous pancreatitis. Severe joint pain and bullous pemphigoid have been described in rare cases. The drug has a low intrinsic risk of hypoglycaemia, but combination with insulin or sulfonylureas may require dose adjustments. According to the prescribing information, hypersensitivity reactions and severe renal impairment require specific evaluation by the prescriber.
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Frequently asked questions
How is sitagliptin different from GLP-1 receptor agonists? ▾
Sitagliptin is an oral DPP-4 inhibitor that prolongs the action of endogenous GLP-1 and GIP, while GLP-1 receptor agonists are injectable or oral peptides that directly activate the GLP-1 receptor at much higher levels than physiological. As a result, GLP-1 receptor agonists generally produce greater HbA1c reduction and meaningful weight loss, while DPP-4 inhibitors are weight-neutral and convenient. Tolerability profiles also differ in their gastrointestinal effects.
Can sitagliptin cause hypoglycaemia? ▾
Sitagliptin amplifies the action of incretins only when glucose levels are elevated, so it has a very low intrinsic risk of hypoglycaemia in monotherapy. Hypoglycaemia is more likely when sitagliptin is combined with insulin or sulfonylureas, in which case dose reduction of these companion agents may be required, under medical supervision according to the prescribing information.
Is dose adjustment needed in kidney disease? ▾
Yes. Because sitagliptin is excreted predominantly unchanged in urine, the prescribing information recommends dose reduction in moderate to severe renal impairment, with the specific cut-offs based on estimated glomerular filtration rate. Patients on dialysis can usually receive sitagliptin at a reduced dose. Renal function should be assessed before treatment and periodically during therapy.
Does sitagliptin cause weight gain? ▾
Sitagliptin is generally weight-neutral in clinical trials, with no consistent weight gain or loss. This contrasts with sulfonylureas and insulin, which often cause modest weight increase, and with GLP-1 receptor agonists and SGLT2 inhibitors, which usually reduce weight. Adults with type 2 diabetes who require both glycaemic control and weight reduction may be offered other classes after evaluation by the prescriber.
What are the main contraindications for sitagliptin? ▾
Known hypersensitivity to sitagliptin, including serious skin reactions such as Stevens-Johnson syndrome, is a formal contraindication. Caution is required in patients with previous pancreatitis, severe renal impairment (with mandatory dose adjustment), and during pregnancy and breastfeeding where data are limited. According to the prescribing information, the medical history and current medication list must be reviewed by a clinician before any prescription.
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