TECOS

TECOS
IUPAC name	(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
Tradename	Tenelia, Kazano, Incresync
CAS number	760937-92-6
DrugBank	DB09280
ATC prefix	A10
ATC suffix	BH05
PubChem	11949646
ChemSpiderID	10130099
Molecular weight	426.37 g/mol
Bioavailability	High
Protein bound	78–81%
Metabolism	Hepatic (CYP3A4, flavin-containing monooxygenase 3)
Elimination half-life	~24 hours
Excretion	Renal (45%) and fecal (45%)

TECOS. It is an oral antidiabetic medication belonging to the dipeptidyl peptidase-4 inhibitor class, used in the management of type 2 diabetes mellitus. The drug is known for its potent and long-lasting inhibition of the DPP-4 enzyme, which enhances the body's own incretin system to improve glycemic control. It is marketed under various brand names including Tenelia and is often used in combination with other agents like metformin.

Overview

Approved for medical use in Japan in 2012, it represented a significant advancement in the DPP-4 inhibitor class available in the Asian market. Its development was spearheaded by the pharmaceutical company Mitsubishi Tanabe Pharma, and it has since been studied in various global populations. The medication is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, either as monotherapy or in combination with other agents like sulfonylureas. Its unique chemical structure, featuring a J-shaped conformation, contributes to its distinctive pharmacological profile.

Clinical trials

The pivotal trial demonstrating its cardiovascular safety was the large-scale, multinational TECOS trial, a randomized, double-blind, placebo-controlled study involving over 14,000 patients with type 2 diabetes and established cardiovascular disease. This study, published in The New England Journal of Medicine, was designed to assess cardiovascular outcomes and showed no increased risk of major adverse cardiovascular events compared to placebo. Other significant studies include the J-DOIT3 trial in Japan and various comparative effectiveness studies against agents like glimepiride. These trials consistently demonstrated its efficacy in reducing HbA1c levels with a low risk of hypoglycemia.

Mechanism of action

It works by selectively and competitively inhibiting the dipeptidyl peptidase-4 enzyme, which is responsible for the rapid degradation of the endogenous incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. By inhibiting DPP-4, it increases the concentration and activity of these hormones, leading to enhanced glucose-dependent insulin secretion from pancreatic beta cells and suppressed glucagon secretion from alpha cells. This mechanism is glucose-dependent, meaning it primarily acts in the presence of elevated blood glucose levels, which contributes to its favorable safety profile regarding hypoglycemia.

Pharmacokinetics

It is rapidly absorbed after oral administration, with peak plasma concentrations occurring within one to two hours, and it has a high absolute bioavailability. The drug is extensively metabolized in the liver, primarily by the cytochrome P450 enzyme CYP3A4 and also by flavin-containing monooxygenase 3, into several inactive metabolites. It has a long elimination half-life of approximately 24 hours, supporting once-daily dosing, and is eliminated almost equally via renal and fecal routes. Its pharmacokinetics are not significantly affected by food, age, gender, or mild to moderate hepatic impairment.

Adverse effects

Common adverse reactions reported in clinical trials include nasopharyngitis, constipation, and increased blood creatinine phosphokinase. Notably, it carries a low intrinsic risk of causing hypoglycemia when used as monotherapy. Like other members of its drug class, there have been post-marketing reports of serious adverse effects such as acute pancreatitis, severe arthralgia, and bullous pemphigoid, though a causal relationship is not always definitive. Prescribing information includes warnings about the potential for angioedema and advises monitoring for signs of pancreatitis.

Comparison with other DPP-4 inhibitors

Compared to other agents in its class like sitagliptin, saxagliptin, linagliptin, and alogliptin, it is noted for its particularly potent and long-lasting DPP-4 inhibition. While all DPP-4 inhibitors share a common mechanism, differences exist in their chemical structures, pharmacokinetic profiles, and routes of elimination; for instance, linagliptin is primarily non-renal, while it uses dual renal and hepatic pathways. Head-to-head studies, such as those against vildagliptin, have shown non-inferiority in glycemic efficacy, but it may offer a distinct advantage in certain patient subgroups due to its unique metabolism.

Category:Dipeptidyl peptidase-4 inhibitors Category:Antidiabetic drugs