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Sitagliptin

Clinical data
AHFS/Drugs.com	Monograph
MedlinePlus	a606023
License data	EU EMA: by INN US FDA: Sitagliptin
Routes of administration	Oral
ATC code	A10BH01 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	87%
Protein binding	38%
Metabolism	Hepatic (CYP3A4- and CYP2C8-mediated)
Elimination half-life	8 to 14 h
Excretion	Renal (80%)
Identifiers
IUPAC name (R)-4-oxo-4-triazolopyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine
CAS Number	486460-32-6
PubChem CID	4369359
DrugBank	DB01261
ChemSpider	3571948
UNII	QFP0P1DV7Z
ChEBI	CHEBI:40237
ChEMBL	ChEMBL1422
CompTox Dashboard (EPA)	DTXSID70197572
ECHA InfoCard	100.217.948
Chemical and physical data
Formula	C16H15F6N5O
Molar mass	407.314 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES Fc1cc(c(F)cc1F)C(N)CC(=O)N3Cc2nnc(n2CC3)C(F)(F)F
InChI InChI=1S/C16H15F6N5O/c17-10-6-12(19)11(18)4-8(10)3-9(23)5-14(28)26-1-2-27-13(7-26)24-25-15(27)16(20,21)22/h4,6,9H,1-3,5,7,23H2/t9-/m1/s1 Key:MFFMDFFZMYYVKS-SECBINFHSA-N
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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. 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.

Adverse effects

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. There is no significant difference in the occurrence of hypoglycemia between placebo and sitagliptin.

There have been several postmarketing reports of pancreatitis (some fatal) in people treated with sitagliptin, and the U.S. package insert carries a warning to this effect, although the causal link between sitagliptin and pancreatitis has not yet been fully substantiated.

Cancer risk of DPP-4 inhibitors

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. 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.

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.

History

Sitagliptin was approved by the U.S. Food and Drug Administration (FDA) on October 17, 2006, 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.

Mechanism of action

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. 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.

See also

• Dipeptidyl peptidase-4
• Development of dipeptidyl peptidase-4 inhibitors

References

1. ^ Herman GA (2005). "Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses". Clin Pharmacol Ther. 78 (6): 675–88. doi:10.1016/j.clpt.2005.09.002. PMID 16338283. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
2. ^ National Prescribing Service (August 2010). "Sitagliptin for Type 2 Diabetes". Retrieved 27 August, 2010. {{cite web}}: Check date values in: |accessdate= (help)
3. ^ "Januvia Side Effects & Drug Interactions". RxList.com. 2007. Retrieved 2007-11-28.
4. Olansky L (2010). "Do incretin-based therapies cause acute pancreatitis?". J Diabetes Sci Technol. 4 (1): 228–9. PMC 2825646. PMID 20167189.
5. "Januvia for type 2 diabetes". Merck & Co. Retrieved 2010-07-31.
6. Pro B, Dang NH (2004). "CD26/dipeptidyl peptidase IV and its role in cancer". Histol. Histopathol. 19 (4): 1345–51. PMID 15375776. {{cite journal}}: Unknown parameter |month= ignored (help)
7. Wesley UV (2005). "Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway". Cancer Res. 65 (4): 1325–34. doi:10.1158/0008-5472.CAN-04-1852. PMID 15735018. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
8. Wesley UV, Tiwari S, Houghton AN (2004). "Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells". Int J Cancer. 109 (6): 855–66. doi:10.1002/ijc.20091. PMID 15027119. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
9. "FDA Approves New Treatment for Diabetes" (Press release). U.S. Food and Drug Administration (FDA). October 17, 2006. Retrieved 2006-10-17.
10. Herman G, Bergman A, Liu F, Stevens C, Wang A, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan A, Lasseter K, Dilzer S, Blum R, Wagner J (2006). "Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects". J Clin Pharmacol. 46 (8): 876–86. doi:10.1177/0091270006289850. PMID 16855072.{{cite journal}}: CS1 maint: multiple names: authors list (link)

External links

• Official website
• Januvia Prescribing Information Merck & Co.
• Sitagliptin Pharmacokinetics – PubPK
• Merck Announces FDA Acceptance of New Drug Application for JANUVIA - Merck press release.
• The race to get DPP-4 inhibitors to market - Forbes.com
• Merck's March Madness - Forbes.com
• Banting and Best Diabetes Centre at UT sitagliptin – Sitagliptin
• Banting and Best Diabetes Centre at UT dpp4 – About DPP-4
• U.S. National Library of Medicine: Drug Information Portal - Sitagliptin

• Amides
• Anti-diabetic drugs
• Dipeptidyl peptidase-4 inhibitors
• Organofluorides