| Systematic (IUPAC) name | |
|---|---|
| (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine | |
| Clinical data | |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a606023 |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. | B(US) |
| Legal status | POM (UK) ℞-only (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | 87% |
| Protein binding | 38% |
| Metabolism | Hepatic (CYP3A4- and CYP2C8-mediated) |
| Half-life | 8 to 14 h[1] |
| Excretion | Renal (80%)[1] |
| Identifiers | |
| CAS number | 486460-32-6 |
| ATC code | A10BH01 |
| PubChem | CID 4369359 |
| DrugBank | DB01261 |
| ChemSpider | 3571948 |
| UNII | QFP0P1DV7Z |
| ChEBI | CHEBI:40237 |
| ChEMBL | CHEMBL1422 |
| Chemical data | |
| Formula | C16H15F6N5O |
| Mol. mass | 407.314 g/mol |
| SMILES | eMolecules & PubChem |
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Sitagliptin(INN; previously identified as MK-0431 and marketed as sitagliptin phosphate under the trade name Januvia) is an oral antihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. It was developed, and is marketed, by Merck & Co. This enzyme-inhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of diabetes mellitus type 2.[2] The benefit of this medicine is its fewer side effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values. While safety is its advantage, efficacy is often challenged as it is often recommended to be combined with other agents like metformin. Exenatide (Byetta) also works by its effect on the incretin system.
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In clinical trials, adverse effects were as common with sitagliptin (whether used alone or with metformin or pioglitazone) as they were with placebo, except for extremely rare nausea and common cold-like symptoms.[3] There is no significant difference in the occurrence of hypoglycemia between placebo and sitagliptin.[3]
There have been several postmarketing reports of pancreatitis (some fatal) in people treated with sitagliptin,[4] and the U.S. package insert carries a warning to this effect,[5] although the causal link between sitagliptin and pancreatitis has not yet been fully substantiated.[2]
The DPP-4 enzyme is known to be involved in the suppression of certain malignancies, particularly in limiting the tissue invasion of these tumours. Inhibiting the DPP-4 enzymes may allow some cancers to progress.[6][7] A study of DPP-4 inhibition in human nonsmall cell lung cancer (NSCLC) concluded "DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells.[8]
The hypothetical risk of cancer activation with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market (saxagliptin and vildagliptin) in addition to sitagliptin.
Sitagliptin was approved by the U.S. Food and Drug Administration (FDA) on October 17, 2006,[9] and is marketed in the US as Januvia by Merck & Co. On April 2, 2007, the FDA approved an oral combination of sitagliptin and metformin marketed in the US as Janumet.
Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones released in response to a meal.[10] By preventing GLP-1 and GIP inactivation, they are able to increase the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes, thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia) which is seen with some other oral hypoglycemic agents.
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