|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||B (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Metabolism||Hepatic (CYP3A4- and CYP2C8-mediated)|
|Half-life||8 to 14 h1|
|Mol. mass||407.314 g/mol|
| (what is this?)
Sitagliptin (INN; previously identified as MK-0431 and marketed as the phosphate salt 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.
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, including photosensitivity.3 There is no significant difference in the occurrence of hypoglycemia between placebo and sitagliptin.345
There have been several postmarketing reports of pancreatitis (some fatal) in people treated with sitagliptin and other DPP-4 inhibitors,6 and the U.S. package insert carries a warning to this effect,7 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.89 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.10
The hypothetical risk of cancer activation with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market (saxagliptin, linagliptin, alogliptin and vildagliptin) in addition to sitagliptin.
One study with lab rats published 2009 concluded that some possible risks of pancreatitis, or pancreatic cancer from sitagliptin may be reduced when it is used with metformin. However, while DDP-4 inhibitors show an increase in such risk factors, as of 2009, there is no reported increase in pancreatic cancer in individuals taking DDP-4 inhibitors.11
Sitagliptin was approved by the U.S. Food and Drug Administration (FDA) on October 17, 2006,12 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. On October 7, 2011, the FDA approved an oral combination of sitagliptin and simvastatin marketed in the US as Juvisync.13 Marketed in Pakistan with brand name Trevia (Sitagliptin) & Treviamet (Sitagliptin + Metformin) by Getz Pharma. In India, Glenmark Pharmaceuticals launched a similar moelcule in the name of ZITA & ZITAMET
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.14 By preventing GLP-1 and GIP inactivation, they are able to increase the secretion of insulin and suppress the release of glucagon by the alpha cells of 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.
Sitagliptin has been shown to lower HbA1c level by about 0.7% points versus placebo. It is slightly less effective than metformin when used as a monotherapy. It does not cause weight gain and has less hypoglycemia compared to sulfonylureas. Sitagliptin is recommended as a second line drug (in combination with other drugs) after the combination of diet/exercise and metformin fails.15
- Herman GA; Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA (December 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.
- National Prescribing Service (August 2010). "Sitagliptin for Type 2 Diabetes". Retrieved 27 August, 2010.
- "Januvia Side Effects & Drug Interactions". RxList.com. 2007. Retrieved 2007-11-28.
- Olansky L (2010). "Do incretin-based therapies cause acute pancreatitis?". J Diabetes Sci Technol 4 (1): 228–9. PMC 2825646. PMID 20167189.
- "Januvia for type 2 diabetes". Merck & Co. Retrieved 2010-07-31.
- Pro B, Dang NH (October 2004). "CD26/dipeptidyl peptidase IV and its role in cancer". Histol. Histopathol. 19 (4): 1345–51. PMID 15375776.
- Wesley UV; McGroarty M, Homoyouni A (February 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.
- Wesley UV, Tiwari S, Houghton AN (May 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.
- Aleksey V. Matveyenko, Sarah Dry, Heather I. Cox, Artemis Moshtaghian1, Tatyana Gurlo, Ryan Galasso, Alexandra E. Butler and Peter C. Butler, Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes - Interactions With Metformin Diabetes July 2009 vol. 58 no. 7 1604-1615
- "FDA Approves New Treatment for Diabetes" (Press release). U.S. Food and Drug Administration (FDA). October 17, 2006. Retrieved 2006-10-17.
- "FDA Approves Combination Therapy Juvisync" (Press release). U.S. Food and Drug Administration (FDA). October 7, 2011. Retrieved 2013-11-17.
- 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.
- Gadsby, Roger (2009). "Efﬁcacy and Safety of Sitagliptin in the Treatment of Type 2 Diabetes" (pdf). Clinical Medicine: Therapeutics (1): 53–62.
- 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
- Januvia lawsuit
- Januvia Recall