Sitagliptin

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Sitagliptin
Sitagliptin.svg
Sitagliptin 3D.png
Clinical data
Pronunciation /sɪtəˈɡlɪptɪn/ ⓘ
Trade names Januvia, Zituvio, others
AHFS/Drugs.com Monograph
MedlinePlus a606023
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 87%
Protein binding 38%
Metabolism Liver (CYP3A4- and CYP2C8-mediated)
Elimination half-life 8 to 14 h [7]
Excretion Kidney (80%) [7]
Identifiers
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.217.948 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H15F6N5O
Molar mass 407.320 g·mol−1
3D model (JSmol)
  • Fc1cc(c(F)cc1F)C[C@@H](N)CC(=O)N3Cc2nnc(n2CC3)C(F)(F)F
  • 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 Yes check.svgY
  • Key:MFFMDFFZMYYVKS-SECBINFHSA-N Yes check.svgY
   (verify)

Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. [8] In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. [9] It is taken by mouth. [8] It is also available in the fixed-dose combination medication sitagliptin/metformin (Janumet, Janumet XR). [8]

Contents

Common side effects include headaches, swelling of the legs, and upper respiratory tract infections. [8] Serious side effects may include angioedema, low blood sugar, kidney problems, pancreatitis, and joint pain. [8] Whether use in pregnancy or breastfeeding is safe is unclear. [10] It is in the dipeptidyl peptidase-4 (DPP-4) inhibitor class and works by increasing the production of insulin and decreasing the production of glucagon by the pancreas. [8]

Sitagliptin was developed by Merck & Co. and approved for medical use in the United States in 2006. [8] In 2022, it was the 86th most commonly prescribed medication in the United States, with more than 7 million prescriptions. [11] [12] It is available as a generic medication. [13] [14] [15]

Medical uses

Sitagliptin is used to treat type 2 diabetes. [8] It is generally less preferred than metformin or sulfonylureas. [9] It is taken by mouth. [8] It is also available as the fixed-dose combinations of sitagliptin/metformin (Janumet, Janumet XR) [8] and sitagliptin/simvastatin (Juvisync). [16]

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. [17] The drugs are approved to improve blood sugar control in adults aged 18 and older with type 2 diabetes. [17]

Adverse effects

Adverse effects from sitagliptin are similar to placebo, except for rare nausea, common cold-like symptoms, and photosensitivity. [18] It does not increase the risk of diarrhea. [19] No significant difference exists in the occurrence of hypoglycemia between placebo and sitagliptin. [18] [20] [21] In those taking sulphonylureas, the risk of low blood sugar is increased. [22]

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. [2]

Several postmarketing reports of pancreatitis (some fatal) have been made in people treated with sitagliptin and other DPP-4 inhibitors, [23] [24] and the US FDA package insert carries a warning to this effect, [2] although the causal link between sitagliptin and pancreatitis has not yet been fully substantiated. [25] 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. [26]

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. [27]

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. [28] 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.[ medical citation needed ] This drives blood glucose levels towards normal.[ medical citation needed ] 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.[ medical citation needed ]

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. [29]

History

Sitagliptin was approved by the US Food and Drug Administration (FDA) in October 2006, [30] and is sold under the brand name Januvia. [31] In April 2007, the FDA approved an oral combination of sitagliptin/metformin sold under the brand name Janumet. [32] In October 2011, the FDA approved an oral combination of sitagliptin/simvastatin sold under the brand name Juvisync. [33] [16] The extended release version of sitagliptin/metformin was approved in February 2012. [34]

Related Research Articles

<span class="mw-page-title-main">Metformin</span> Medication used to treat diabetes

Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of Type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, and is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics. It has also been shown to inhibit inflammation, and is not associated with weight gain. Metformin is taken orally.

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

<span class="mw-page-title-main">Incretin</span> Group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.

<span class="mw-page-title-main">Vildagliptin</span> Chemical compound

Vildagliptin, sold under the brand name Galvus and others, is an oral anti-hyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas.

<span class="mw-page-title-main">Dipeptidyl peptidase-4 inhibitor</span> Enzyme blocker and diabetes treatment drug

Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.

<span class="mw-page-title-main">Saxagliptin</span> Chemical compound

Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug.

<span class="mw-page-title-main">Alogliptin</span> Anti-diabetic drug

Alogliptin, sold under the brand names Nesina and Vipidia, is an oral anti-diabetic drug in the DPP-4 inhibitor (gliptin) class. Like other members of the gliptin class, it causes little or no weight gain, exhibits relatively little risk of hypoglycemia, and has relatively modest glucose-lowering activity. Alogliptin and other gliptins are commonly used in combination with metformin in people whose diabetes cannot adequately be controlled with metformin alone.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand name Victoza among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

Dipeptidyl peptidase-4 inhibitors are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4). They are used in the treatment of type 2 diabetes mellitus. Inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins that play an important role in insulin secretion and blood glucose control regulation. Type 2 diabetes mellitus is a chronic metabolic disease that results from inability of the β-cells in the pancreas to secrete sufficient amounts of insulin to meet the body's needs. Insulin resistance and increased hepatic glucose production can also play a role by increasing the body's demand for insulin. Current treatments, other than insulin supplementation, are sometimes not sufficient to achieve control and may cause undesirable side effects, such as weight gain and hypoglycemia. In recent years, new drugs have been developed, based on continuing research into the mechanism of insulin production and regulation of the metabolism of sugar in the body. The enzyme DPP-4 has been found to play a significant role.

<span class="mw-page-title-main">Canagliflozin</span> Chemical compound

Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Sitagliptin/metformin, sold under the brand name Janumet among others, is a fixed-dose combination anti-diabetic medication used to treat type 2 diabetes. It may be used in those whose blood sugar is not controlled with metformin and a sulfonylurea. It is taken by mouth.

<span class="mw-page-title-main">Sitagliptin/simvastatin</span> Combination drug

Sitagliptin/simvastatin, sold under the brand name Juvisync, is a fixed-dose combination anti-diabetic medication used to treat type 2 diabetes and hypercholesterolemia. It contains sitagliptin and simvastatin. Sitagliptin is a dipeptidyl peptidase-4 inhibitor and simvastatin is an HMG-CoA reductase inhibitor. These two disorders commonly occur in people at the same time, and have been typically treated with administration of these medications separately. The combination was approved in 2011, and sold under the brand name Juvisync by Merck. Juvisync was later removed from the market in 2013, due to business reasons.

<span class="mw-page-title-main">Gemigliptin</span> Chemical compound

Gemigliptin (rINN), sold under the brand name Zemiglo, is an oral anti-hyperglycemic agent of the dipeptidyl peptidase-4 inhibitor class of drugs. Glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors.

<span class="mw-page-title-main">Omarigliptin</span> Chemical compound

Omarigliptin (MK-3102) is a potent, long-acting oral antidiabetic drug of the DPP-4 inhibitor class used for once-weekly treatment of type 2 diabetes and currently under development by Merck & Co. It inhibits DPP-4 to increase incretin levels, which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying and decreases blood glucose levels.

<span class="mw-page-title-main">Ertugliflozin</span> Chemical compound

Ertugliflozin, sold under the brand name Steglatro, is a medication for the treatment of type 2 diabetes.

Empagliflozin/metformin, sold under the brand name Synjardy among others, is a fixed-dose combination anti-diabetic medication used to treat type 2 diabetes. It contains empagliflozin and metformin hydrochloride. It is taken by mouth.

Empagliflozin/linagliptin/metformin, sold under the brand name Trijardy XR, is a fixed-dose combination medication used for the treatment of type 2 diabetes. It is a combination of empagliflozin, linagliptin, and metformin. Empagliflozin/linagliptin/metformin was approved for use in the United States in January 2020.

Dapagliflozin/metformin, sold under the brand name Xigduo Xr among others, is a fixed-dose combination anti-diabetic medication used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is a combination of dapagliflozin and metformin and is taken by mouth. Dapagliflozin/metformin was approved for use in the European Union in January 2014, in the United States in February 2014, and in Australia in July 2014.

Canagliflozin/metformin, sold under the brand name Vokanamet among others, is a fixed-dose combination anti-diabetic medication used for the treatment of type 2 diabetes. It is used in combination with diet and exercise. It is taken by mouth.

References

  1. ↑ "Product monograph brand safety updates". Health Canada. February 2024. Retrieved March 24, 2024.
  2. 1 2 3 "Januvia- sitagliptin tablet, film coated". DailyMed. Archived from the original on October 27, 2021. Retrieved October 15, 2021.
  3. ↑ "Zituvio- sitagliptin tablet". DailyMed. November 1, 2023. Retrieved December 25, 2023.
  4. ↑ "Zituvio- sitagliptin tablet". DailyMed. November 1, 2023. Retrieved December 25, 2023.
  5. ↑ "Januvia EPAR". European Medicines Agency. September 17, 2018. Archived from the original on October 23, 2021. Retrieved October 15, 2021.
  6. ↑ "Xelevia EPAR". European Medicines Agency (EMA). March 21, 2007. Retrieved October 19, 2024.
  7. 1 2 Herman GA, Stevens C, van Dyck K, Bergman A, Yi B, De Smet M, et al. (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". Clinical Pharmacology and Therapeutics. 78 (6): 675–688. doi:10.1016/j.clpt.2005.09.002. PMID   16338283. S2CID   20935646.{{cite journal}}: CS1 maint: overridden setting (link)
  8. 1 2 3 4 5 6 7 8 9 10 "Sitagliptin Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on March 4, 2016. Retrieved March 3, 2019.
  9. 1 2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 681. ISBN   9780857113382.
  10. ↑ "Sitagliptin Pregnancy and Breastfeeding Warnings". Drugs.com. Archived from the original on March 6, 2019. Retrieved March 3, 2019.
  11. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on August 30, 2024. Retrieved August 30, 2024.
  12. ↑ "Sitagliptin Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved August 30, 2024.
  13. ↑ "Generic Januvia Availability". Drugs.com. Retrieved December 1, 2023.
  14. ↑ "JAMP Pharma Group receives Health Canada approval for PrJAMP Sitagliptin, a new generic alternative for the treatment of type 2 diabetes" (Press release). JAMP Pharma. January 6, 2023. Retrieved June 19, 2023– via Newswire.
  15. ↑ "Sitagliptin SUN EPAR". European Medicines Agency (EMA). December 9, 2021. Retrieved September 27, 2024.
  16. 1 2 "FDA Approves Combination Therapy Juvisync" (Press release). U.S. Food and Drug Administration (FDA). October 7, 2011. Archived from the original on August 24, 2014. Retrieved November 17, 2013.
  17. 1 2 "Diabetes drug not proven to improve blood sugar in pediatric patients". U.S. Food and Drug Administration (FDA). December 4, 2020. Archived from the original on December 4, 2020. Retrieved December 5, 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  18. 1 2 "Januvia Side Effects & Drug Interactions". RxList.com. 2007. Archived from the original on November 20, 2007. Retrieved November 28, 2007.
  19. ↑ Zhao Q, Hong D, Zheng D, Xiao Y, Wu B (2014). "Risk of diarrhea in patients with type 2 diabetes mellitus treated with sitagliptin: a meta-analysis of 30 randomized clinical trials". Drug Design, Development and Therapy. 8: 2283–2294. doi: 10.2147/DDDT.S70945 . PMC   4234286 . PMID   25419118.
  20. ↑ Stricklin SM, Stoecker WV, Rader RK, Hood AF, Litt JZ, Schuman TP (February 2012). "Persistent edematous-plaque photosensitivity observed with sitagliptin phosphate (Januvia®)". Dermatology Online Journal. 18 (2): 9. doi:10.5070/D30D70K7B2. PMID   22398230. Archived from the original on April 8, 2019. Retrieved June 6, 2019.
  21. ↑ "Januvia side effect: Photosensitivity reaction - eHealthMe". www.ehealthme.com. Archived from the original on June 7, 2019. Retrieved June 6, 2019.
  22. ↑ Salvo F, Moore N, Arnaud M, Robinson P, Raschi E, De Ponti F, et al. (May 2016). "Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis". BMJ. 353: i2231. doi:10.1136/bmj.i2231. PMC   4854021 . PMID   27142267.{{cite journal}}: CS1 maint: overridden setting (link)
  23. ↑ Olansky L (January 2010). "Do incretin-based therapies cause acute pancreatitis?". Journal of Diabetes Science and Technology. 4 (1): 228–229. doi:10.1177/193229681000400129. PMC   2825646 . PMID   20167189.
  24. ↑ "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". U.S. Food and Drug Administration (FDA). June 21, 2019. Archived from the original on May 10, 2022. Retrieved May 10, 2022.
  25. ↑ National Prescribing Service (August 2010). "Sitagliptin for Type 2 Diabetes". Archived from the original on July 18, 2010. Retrieved August 27, 2010.
  26. ↑ Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, et al. (July 2009). "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. 58 (7): 1604–1615. doi:10.2337/db09-0058. PMC   2699878 . PMID   19403868.{{cite journal}}: CS1 maint: overridden setting (link)
  27. ↑ "DPP-4 Inhibitors for Type 2 Diabetes: Drug Safety Communication—May Cause Severe Joint Pain". U.S. Food and Drug Administration (FDA). August 28, 2015. Archived from the original on December 13, 2019. Retrieved September 1, 2015.
  28. ↑ Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, et al. (August 2006). "Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects". Journal of Clinical Pharmacology. 46 (8): 876–886. doi:10.1177/0091270006289850. PMID   16855072. S2CID   45849328.{{cite journal}}: CS1 maint: overridden setting (link)
  29. ↑ Gadsby R (2009). "Efficacy and Safety of Sitagliptin in the Treatment of Type 2 Diabetes". Clinical Medicine: Therapeutics. 1 (1): 53–62. doi: 10.4137/CMT.S2313 .
  30. ↑ "FDA Approves New Treatment for Diabetes" (Press release). U.S. Food and Drug Administration (FDA). October 17, 2006. Archived from the original on February 28, 2009. Retrieved October 17, 2006.
  31. ↑ "Drug Approval Package: Januvia (Sitagliptin Phosphate) NDA #021995". U.S. Food and Drug Administration (FDA). Retrieved September 27, 2024.
  32. ↑ "Drug Approval Package: Janumet (Sitagliptin/Metformin Hydrochloride) NDA #022044". U.S. Food and Drug Administration (FDA). July 8, 2008. Retrieved September 27, 2024.
  33. ↑ "Drug Approval Package: Juvisync (sitagliptin and simvastatin fixed-dose combination) Tablets NDA #202343". U.S. Food and Drug Administration (FDA). July 13, 2012. Retrieved September 27, 2024.
  34. ↑ "Drug Approval Package: Janumet XR (sitagliptin/metformin hydrochloride) NDA #202270". U.S. Food and Drug Administration (FDA). September 3, 2013. Retrieved September 27, 2024.
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