Sitagliptin
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| Non-proprietary name | Sitagliptin | ||||||||||||||||||
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( R ) -3-Amino-1- {3- (trifluoromethyl) -5,6,7,8-tetrahydro [1,2,4] triazol [4,3- a ] pyrazin-7-yl} -4- (2,4,5-trifluorophenyl) butan-1-one |
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| Molecular formula | C 16 H 15 F 6 N 5 O | ||||||||||||||||||
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| Molar mass | 407.31 g mol −1 | ||||||||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||||||||
Sitagliptin is an orally active drug used to treat type 2 diabetes mellitus . It belongs to the active ingredient group of inhibitors of dipeptidyl peptidase 4 (also called gliptins ), which, in addition to incretin mimetics, are based on the effect of glucagon-like peptide 1 (GLP-1). Sitagliptin was developed by MSD Sharp & Dohme .
Scientific basis
Mechanism of action
The effect of sitagliptin is based on the inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4), which is responsible for the breakdown of the hormone glucagon-like peptide 1 (GLP-1). Since the GLP-1 produced by the L cells of the intestinal mucosa stimulates the release of the blood sugar-lowering hormone insulin and reduces the secretion of the insulin counterpart glucagon , an inhibition of dipeptidyl peptidase 4 by sitagliptin leads to a lowering of the blood sugar level in diabetic patients. The effect of GLP-1 in the context of the insulin response is known as the incretin effect .
Pharmacokinetics
The maximum plasma concentration after ingestion of 100 milligrams of sitagliptin is reached after one to four hours in adults. The plasma half-life is around twelve hours. A value of 87 percent was determined for the absolute bioavailability after oral intake. The binding to plasma proteins is low at around 38 percent, the total volume of distribution is 198 liters. Most of the substance, 79 percent, is excreted unchanged in the urine ; only a small part is chemically changed through metabolic reactions. The cytochrome P450 enzymes CYP3A4 and CYP2C8 are mainly responsible for metabolism .
chemistry
The IUPAC name of sitagliptin is ( R ) -7- [3-amino-1-oxo-4- (2,4,5-trifluorophenyl) butyl] -5,6,7,8-tetrahydro-3- (trifluoromethyl ) -1,2,4-triazolo [4,3-a] pyrazine. The solid is in monohydrate form as phosphate and is a white, crystalline and non- hygroscopic powder. The molecular formula of the compound is C 16 H 15 F 6 N 5 O · H 3 PO 4 · H 2 O, the molar mass is 523.32 g / mol. Sitagliptin is soluble in water , slightly soluble in methanol , very slightly soluble in ethanol , acetone and acetonitrile and insoluble in isopropanol .
The US President's Green Presidential Award 2010 went to MSD Sharp & Dohme and Codexis for the improved green synthesis of sitagliptin. Sitagliptin exhibits difficult stereoselective transamination of an enamine in synthesis . In the chemical synthesis, a crystallization step and a necessary hydrogenation at 250 psi (≈17 bar) must be carried out using a rhodium catalyst. In the enzymatically catalyzed reaction, this enamine reduction is resolved by transamination of a ketone that is more easily accessible. Using protein modeling, an optimized transaminase was developed that was 25,000 times more efficient than the wild type and stereoselectively biotransformed the ( R ) -enantiomer of sitagliptin. It was possible to increase productivity by 56%, yield by more than 10% and reduce the amount of waste by 20%.
Therapeutic use
Sitagliptin is used to treat non-insulin-dependent type 2 diabetes mellitus and is generally taken once a day in adults in a single dose of 25 to 100 milligrams, depending on kidney function. It is not primarily used for the short-term treatment of hyperglycaemia or for targeted use before meals, but rather to improve the body's own insulin response during long-term treatment.
Admission status
Sitagliptin was approved by the US Food and Drug Administration (FDA) in October 2006 both for monotherapy and for use in combination with metformin or glitazone . In March 2007, the European Commission granted marketing authorization in the European Union (EU), where sitagliptin is approved for oral use in combination with metformin or a thiazolidine ( insulin sensitizer ), and since 2008 in combination in the case of metformin intolerance with a sulfonylurea . As the only DPP-4 inhibitor to date, sitagliptin is also approved in monotherapy (in the case of metformin intolerance), in triple combinations with metformin and thiazolidine or sulfonylurea, and in combination with insulin (with and without metformin).
Sitagliptin was the first in a new class of drugs called dipeptidyl peptidase inhibitors, or DPP-4 inhibitors . Other substances from this group are vildagliptin , saxagliptin and alogliptin . A hoped-for protective effect on the cardiovascular system has not yet been shown. In contrast to the sulfonylureas and glitazones, however, there were no indications of cardiac risks. DPP-4 inhibitors are the second group of active substances alongside incretin mimetics , which are based on the incretin effect.
Indication and therapeutic benefit
Sitagliptin is used to treat diabetes mellitus in patients who cannot get enough blood sugar through diet and exercise alone and metformin is unsuitable. Sitagliptin for the treatment of type 2 diabetes can be considered as an alternative to insulin therapy if other oral antidiabetic agents fail in monotherapy or combination therapy. Antidiabetic sitagliptin monotherapy, primarily for newly discovered diabetes or secondarily for failure of other oral antidiabetic drugs, is approved in the USA, but not in Europe.
Clinical studies have shown that the effect of GLP-1 is dependent on the blood sugar level. Since the effect of sitagliptin takes place via the GLP-1, there is practically no risk of hypoglycaemia in the event of an overdose when treating with sitagliptin, in contrast to some previously approved oral antidiabetic drugs . Compared to the incretin mimetic exenatide , sitagliptin has the advantage for patients that it does not have to be injected, but can be taken in tablet form .
The body weight reduction observed with exenatide has not been demonstrated for sitagliptin. On the other hand, treatment with sitagliptin does not lead to weight gain, a common side effect of some other oral antidiabetic drugs. In addition, some studies have shown that dipeptidyl peptidase inhibitors such as incretin mimetics have positive effects on the insulin-producing beta cells in the islets of Langerhans in the pancreas and may protect them from loss of function or delay it. However, the actual clinical relevance of this observation is unclear.
Studies with hard clinical endpoints that demonstrate a long-term protective effect of the drug are currently not available.
The IQWiG came to a positive result ("additional benefit") in the dossier assessment of gliptins in accordance with the Medicinal Market Reform Act (AMNOG) .
Side effects, contraindications and interactions
Contraindications are renal failure , pregnancy and breastfeeding. Common side effects (1–10% of those treated) included headache and hypoglycaemia , the latter in combination with sulfonylureas (4.7% –13.8%) and insulin (9.6%). Occasionally (1–10% of the treated population) dizziness, constipation and pruritus have been reported. There are other side effects such as skin and musculoskeletal disorders, but the frequency is not known. For the cardiac glycoside digoxin , there was a slight increase in the plasma level with simultaneous administration with sitagliptin, for which, however, no adjustment of the dosage of both drugs is normally recommended. Individual cases of acute pancreatitis have been described.
Trade names
Januvia (D, A, CH), Tesavel (A), Xelevia (D, A, CH)
With metformin : Efficib (A), Janumet (D, A, CH), Velmetia (D, A, CH)
Web links
- Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Sitagliptin
- MedlinePlus Drug Information: sitagliptin (English)
- Technical information in USA for Januvia ® 2014 (PDF) (English; 148 kB)
literature
- DJ Drucker & MA Nauck (2006): The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. In: Lancet. Vol. 368, pp. 1696-1705. PMID 17098089 doi: 10.1016 / S0140-6736 (06) 69705-5 .
- Richard Daikeler, Götz Use, Sylke Waibel: Diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 158 f.
Individual evidence
- ↑ Registration dossier for (3R) -3-amino-1- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] - 4- (2,4,5-trifluorophenyl) butan-1-one ( GHS section ) from the European Chemicals Agency (ECHA), accessed on July 12, 2020.
- ↑ EPA information dated August 10, 2011 .
- ↑ Sitagliptin approved in combination with sulfonylurea . In: DAZ.online . March 20, 2008 ( deutsche-apotheker-zeitung.de [accessed on May 12, 2017]).
- ↑ a b c Fachinformation Januvia (R), February 2016
- ^ Specialist information Galvus, version June 2010.
- ↑ technical information Onglyza, Version February 2011.
- ↑ William B. White, Christopher P. Cannon, Simon R. Heller, Steven E. Nissen, Richard M. Bergenstal, George L. Bakris, Alfonso T. Perez, Penny R. Fleck, Cyrus R. Mehta, Stuart Kupfer, Craig Wilson, William C. Cushman, Faiez Zannad: Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. In: New England Journal of Medicine. 2013, p. 130902030035004, doi: 10.1056 / NEJMoa1305889 .
- ↑ Benjamin M. Scirica, Deepak L. Bhatt, Eugene Braunwald, P. Gabriel Steg, Jaime Davidson, Boaz Hirshberg, Peter Ohman, Robert Frederich, Stephen D. Wiviott, Elaine B. Hoffman, Matthew A. Cavender, Jacob A. Udell , Nihar R. Desai, Ofri Mozenson, Darren K. McGuire, Kausik K. Ray, Lawrence A. Leiter, Itamar Raz: Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. In: New England Journal of Medicine. 2013, p. 130902030035004, doi: 10.1056 / NEJMoa1307684 .
- ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 158 f.
- ↑ Gliptine: IQWiG evaluates subsequently submitted manufacturer data . IQWiG press release of October 1, 2013.
- ↑ FDA Safety Information of September 28, 2009 .
