Sitagliptin - Diabetic Medications

What is sitagliptin?

Sitagliptin is an orally active drug for the treatment of (diabetes mellitus type 2). It belongs to a group of medicines inhibitors of dipeptidyl peptidase-4 (also called Gliptine) based next to the Inkretinmimetika on the effect of glucagon-like peptide-1 (GLP-1). Sitagliptin was developed by MSD Sharp Dohme.

Scientific Basis

Mechanism of Action
Effects of sitagliptin based on the inhibition of the enzyme dipeptidyl peptidase 4, which is the degradation of the hormone glucagon-like peptide-1 (GLP-1) responsible. Since the formed by the L-cells of the intestinal mucosa GLP-1 stimulates the release of glucose-lowering hormone insulin and reduces the secretion of insulin-antagonist, glucagon, leads an inhibition of dipeptidyl peptidase 4 by sitagliptin to reduce blood sugar levels in diabetic patients. The effect of the GLP-1 as part of the insulin response is called incretin effect.

The maximum plasma concentration after ingestion of 100 mg sitagliptin is reached after one to four hours. The plasma half-life is approximately twelve hours. For the absolute bioavailability after oral intake, a value of 87 percent was determined. Binding to plasma proteins is low at around 38 percent, the total volume of distribution is 198 liters. The largest with 79 percent of the substance is excreted unchanged in the urine, only a small part is changed chemically over Metabolisierungsreaktionen. Mainly responsible for the metabolism are the cytochrome P450 enzymes CYP3A4 and CYP2C8.

The IUPAC name of sitagliptin is(R)-7-[3-Amino-1-oxo-4-(2,4,5-trifluorphenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluormethyl)-1,2,4-triazol[4,3-a]pyrazin. The solid is present as phosphate monohydrate and in front is a white, crystalline and non-hygroscopic powder. The empirical formula of the compound is C16H15F6N5O · H3PO4 · H2O, 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 Green Presidential Award 2010 of the US President was the company MSD Sharp Dohme and Codexis for the enhanced green synthesis of sitagliptin Sitagliptin has awarded a difficult stereoselective transamination of an enamine in the synthesis. In the chemical synthesis, a crystallization step and at 250 psi required for hydrogenation using a rhodium catalyst must be carried out (≈17 bar). In the enzymatically catalyzed reaction, this is achieved by a transamination Enaminreduktion a ketone, which is easily accessible. Optimized transaminase was designed by protein modeling, which was by a factor of 25,000 more efficiently than the wild-type and stereoselectively biotransformed the R-enantiomer of sitagliptin. So the productivity by 56%, increased the yield by more than 10% and the amount of waste was reduced by 20%.

Therapeutic use

Sitagliptin is mellitus type 2 is used for the treatment of non-insulin-dependent diabetes and taken in a single dose of 100 milligrams usually once daily. It is not primarily used for short-term treatment of hyperglycemia or the specific use before meals, but to improve the body's insulin response at a longer-term treatment.

Approval status
Sitagliptin was (FDA) approved in October 2006 by the US Food and Drug Administration Food and Drug Administration for both a 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 use in combination with metformin or a thiazolidinedione (insulin sensitizers). As the only DPP-4 inhibitor sitagliptin is also in monotherapy (metformin intolerance), in triple combination with metformin and thiazolidinedione or sulfonylurea and combination with insulin (with or without metformin) approved.

Sitagliptin was the first substance of a new class of drugs known as dipeptidyl peptidase inhibitors or DPP-4 inhibitors. Other substances in this group are vildagliptin, saxagliptin and Alogliptin. A hoped-protective effect on the cardiovascular system has not yet been shown. However, evidence of cardiac risks were not found in contrast to the sulfonylureas and glitazones. DPP-4 inhibitors are the second group of active substances in addition to the Inkretinmimetika based on the incretin effect.

Therapeutic benefit
Sitagliptin for the treatment of type 2 diabetes comes as an alternative to insulin therapy be considered if other oral antidiabetic agents fail in mono- or combination therapy. An antidiabetic sitagliptin monotherapy, primarily at a newly discovered diabetes or secondary to failure of other oral antidiabetic agents is, although approved in the US but not in Europe.

In clinical studies showed that the effect of GLP-1 is dependent on blood sugar levels. Since the effect of sitagliptin on GLP-1 takes place, is when treated with sitagliptin in contrast to some previously approved orally administered antidiabetic drugs virtually no risk of hypoglycaemia in overdose. Compared with the incretin mimetic exenatide, sitagliptin has the advantage for the patient, that it must not be injected, but can be taken in tablet form.

The observed for exenatide reduction in body weight could not be shown for sitagliptin. On the other hand, it is also not to weight gain, a common side effect of some other oral antidiabetic agents when treated with sitagliptin. In addition, some studies have provided evidence that the dipeptidyl peptidase inhibitors such as the incretin mimetics have positive effects on the insulin-producing beta cells in the islets of Langerhans of the pancreas and may protect them from a loss of function or delay this. The actual clinical relevance of this observation is unclear.

Studies with hard clinical endpoints, demonstrating a long-term protective effect of the drug, currently are not available.

In the dossier according to the Gliptine pharmaceutical market Restructuring Act (AMNOG) IQWiG is a positive outcome ("value added") came.

Side effects, contraindications and interactions

Contraindications include renal insufficiency, pregnancy and lactation. Side effects include headaches, colds and infections of the upper respiratory tract in patients treated with sitagliptin occurred slightly more frequently than with placebo. For the cardiac glycoside digoxin, a slight increase in plasma levels when coadministered with sitagliptin, for however normally no adjustment of dosage of both drugs is recommended showed. There are described isolated cases of acute pancreatitis.

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