Sitagliptin

Sitagliptin is used to treat type 2 diabetes. It is generally less preferred than metformin or sulfonylureas.{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=681|edition=76}} It is taken by mouth. It is also available as the fixed-dose combinations of sitagliptin/metformin (Janumet, Janumet XR) and sitagliptin/simvastatin (Juvisync).

Sitagliptin should not be used to treat type 1 diabetes. In December 2020, the US Food and Drug Administration (FDA) approved labeling changes stating that Januvia (sitagliptin), Janumet (sitagliptin and metformin hydrochloride), and Janumet XR (sitagliptin and metformin hydrochloride extended-release) are not proven to improve glycemic (blood sugar) control in children aged 10 to 17 with type 2 diabetes. The drugs are approved to improve blood sugar control in adults aged 18 and older with type 2 diabetes.{{cite web | title=Diabetes drug not proven to improve blood sugar in pediatric patients | website=U.S. Food and Drug Administration (FDA) | date=December 4, 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/new-studies-show-diabetes-drug-not-proven-improve-blood-sugar-control-pediatric-patients | access-date=December 5, 2020 | archive-date=December 4, 2020 | archive-url=https://web.archive.org/web/20201204222229/https://www.fda.gov/drugs/drug-safety-and-availability/new-studies-show-diabetes-drug-not-proven-improve-blood-sugar-control-pediatric-patients | url-status=live }} {{PD-notice}}

Adverse effects from sitagliptin are similar to placebo, except for rare nausea, common cold-like symptoms, and photosensitivity.{{cite web | url = http://www.rxlist.com/cgi/generic/januvia_ad.htm | title = Januvia Side Effects & Drug Interactions | year = 2007 | access-date = November 28, 2007 | publisher = RxList.com | url-status = dead | archive-url = https://web.archive.org/web/20071120121831/http://www.rxlist.com/cgi/generic/januvia_ad.htm | archive-date = November 20, 2007 }} It does not increase the risk of diarrhea.{{cite journal | vauthors = Zhao Q, Hong D, Zheng D, Xiao Y, Wu B | title = Risk of diarrhea in patients with type 2 diabetes mellitus treated with sitagliptin: a meta-analysis of 30 randomized clinical trials | journal = Drug Design, Development and Therapy | volume = 8 | pages = 2283–2294 | date = 2014 | pmid = 25419118 | pmc = 4234286 | doi = 10.2147/DDDT.S70945 | doi-access = free }} No significant difference exists in the occurrence of hypoglycemia between placebo and sitagliptin.{{cite journal | vauthors = Stricklin SM, Stoecker WV, Rader RK, Hood AF, Litt JZ, Schuman TP | title = Persistent edematous-plaque photosensitivity observed with sitagliptin phosphate (Januvia®) | journal = Dermatology Online Journal | volume = 18 | issue = 2 | pages = 9 | date = February 2012 | doi = 10.5070/D30D70K7B2 | pmid = 22398230 | url = https://escholarship.org/uc/item/0d70k7b2 | access-date = June 6, 2019 | url-status = live | archive-url = https://web.archive.org/web/20190408084349/https://escholarship.org/uc/item/0d70k7b2 | archive-date = April 8, 2019 }}{{cite web|url=https://www.ehealthme.com/ds/januvia/photosensitivity-reaction/|title=Januvia side effect: Photosensitivity reaction - eHealthMe|website=www.ehealthme.com|access-date=June 6, 2019|archive-date=June 7, 2019|archive-url=https://web.archive.org/web/20190607003203/https://www.ehealthme.com/ds/januvia/photosensitivity-reaction/|url-status=live}} In those taking sulphonylureas, the risk of low blood sugar is increased.{{cite journal | vauthors = Salvo F, Moore N, Arnaud M, Robinson P, Raschi E, De Ponti F, Bégaud B, Pariente A | display-authors = 6 | title = Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis | journal = BMJ | volume = 353 | pages = i2231 | date = May 2016 | pmid = 27142267 | pmc = 4854021 | doi = 10.1136/bmj.i2231 }}

The existence of rare case reports of kidney failure and hypersensitivity reactions is noted in the United States prescribing information, but a causative role for sitagliptin has not been established.

Several postmarketing reports of pancreatitis (some fatal) have been made in people treated with sitagliptin and other DPP-4 inhibitors,{{cite journal | vauthors = Olansky L | title = Do incretin-based therapies cause acute pancreatitis? | journal = Journal of Diabetes Science and Technology | volume = 4 | issue = 1 | pages = 228–229 | date = January 2010 | pmid = 20167189 | pmc = 2825646 | doi = 10.1177/193229681000400129 }}{{cite web | title=FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes | website=U.S. Food and Drug Administration (FDA) | date=June 21, 2019 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-investigating-reports-possible-increased-risk-pancreatitis-and-pre | access-date=May 10, 2022 | archive-date=May 10, 2022 | archive-url=https://web.archive.org/web/20220510021433/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-investigating-reports-possible-increased-risk-pancreatitis-and-pre | url-status=live }} and the US FDA package insert carries a warning to this effect, although the causal link between sitagliptin and pancreatitis has not yet been fully substantiated.{{cite web |title=Sitagliptin for Type 2 Diabetes |author=National Prescribing Service |date=August 2010 |access-date=August 27, 2010 |url=http://www.nps.org.au/consumers/publications/medicine_update/issues/sitagliptin |url-status=dead |archive-url=https://web.archive.org/web/20100718022620/http://www.nps.org.au/consumers/publications/medicine_update/issues/sitagliptin |archive-date=July 18, 2010 }} One study with lab rats published in 2009 concluded that some of the possible risks of pancreatitis or pancreatic cancer may be reduced when it is used with metformin. However, while DPP-4 inhibitors showed an increase in such risk factors, as of 2009, no increase in pancreatic cancer has been reported in individuals taking DPP-4 inhibitors.{{cite journal | vauthors = Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, Butler AE, Butler PC | display-authors = 6 | title = Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin | journal = Diabetes | volume = 58 | issue = 7 | pages = 1604–1615 | date = July 2009 | pmid = 19403868 | pmc = 2699878 | doi = 10.2337/db09-0058 }}

In 2015, the US Food and Drug Administration (FDA) added a new warning and precaution about the risk of "severe and disabling" joint pain to the labels of all DPP-4 inhibitor medicines.{{cite web|title=DPP-4 Inhibitors for Type 2 Diabetes: Drug Safety Communication—May Cause Severe Joint Pain|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-dpp-4-inhibitors-type-2-diabetes-may-cause-severe-joint-pain|website=U.S. Food and Drug Administration (FDA)|access-date=September 1, 2015|date=August 28, 2015|archive-date=December 13, 2019|archive-url=https://web.archive.org/web/20191213203243/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-dpp-4-inhibitors-type-2-diabetes-may-cause-severe-joint-pain|url-status=live}}

{{see also|Dipeptidyl peptidase-4 inhibitors}}

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.{{cite journal | vauthors = Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA | display-authors = 6 | title = Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects | journal = Journal of Clinical Pharmacology | volume = 46 | issue = 8 | pages = 876–886 | date = August 2006 | pmid = 16855072 | doi = 10.1177/0091270006289850 | s2cid = 45849328 }} By preventing breakdown of GLP-1 and GIP, they are able to increase the secretion of insulin and suppress the release of glucagon by the alpha cells of the pancreas.{{medcn|date=May 2022}} This drives blood glucose levels towards normal.{{medcn|date=May 2022}} 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.{{medcn|date=May 2022}}

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.{{cite journal| vauthors = Gadsby R |title=Efficacy and Safety of Sitagliptin in the Treatment of Type 2 Diabetes|journal=Clinical Medicine: Therapeutics |year=2009 |volume=1 |issue=1 |pages=53–62 |doi=10.4137/CMT.S2313 | doi-access = free }}

{{see also|Development of dipeptidyl peptidase-4 inhibitors}}

Sitagliptin was approved by the US Food and Drug Administration (FDA) in October 2006,{{cite press release | title = FDA Approves New Treatment for Diabetes | publisher = U.S. Food and Drug Administration (FDA) | date = October 17, 2006 | url = https://www.fda.gov/bbs/topics/NEWS/2006/NEW01492.html | archive-url = https://web.archive.org/web/20090228075200/https://www.fda.gov/bbs/topics/NEWS/2006/NEW01492.html | archive-date = February 28, 2009 | url-status = dead | access-date = October 17, 2006 }} and is sold under the brand name Januvia.{{cite web | title=Drug Approval Package: Januvia (Sitagliptin Phosphate) NDA #021995 | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000TOC.cfm | access-date=September 27, 2024}} In April 2007, the FDA approved an oral combination of sitagliptin/metformin sold under the brand name Janumet.{{cite web | title=Drug Approval Package: Janumet (Sitagliptin/Metformin Hydrochloride) NDA #022044 | website=U.S. Food and Drug Administration (FDA) | date=July 8, 2008 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044TOC.cfm | access-date=September 27, 2024}} In October 2011, the FDA approved an oral combination of sitagliptin/simvastatin sold under the brand name Juvisync.{{cite web | title=Drug Approval Package: Juvisync (sitagliptin and simvastatin fixed-dose combination) Tablets NDA #202343 | website=U.S. Food and Drug Administration (FDA) | date=July 13, 2012 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202343Orig1s000TOC.cfm | access-date=September 27, 2024}}{{cite press release | title = FDA Approves Combination Therapy Juvisync | publisher = U.S. Food and Drug Administration (FDA) | date = October 7, 2011 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm274748.htm | archive-url = https://web.archive.org/web/20140824195440/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm274748.htm | archive-date = August 24, 2014 | url-status = dead | access-date = November 17, 2013 }} The extended release version of sitagliptin/metformin was approved in February 2012.{{cite web | title=Drug Approval Package: Janumet XR (sitagliptin/metformin hydrochloride) NDA #202270 | website=U.S. Food and Drug Administration (FDA) | date=September 3, 2013 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202270_janumet_xr_toc.cfm | access-date=September 27, 2024}}

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