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Sitagliptin - First In Class DPP4 Inhibitor for Type 2 Diabetes

Release time:2021/11/30 14:40:45
Author:Huateng Pharma

Sitagliptin, the first oral DPP-4 inhibitor to be marketed for treating Type 2 Diabetes

Sitagliptin is one of the most successful small molecule drugs in recent years. Sitagliptin succeeded in breaking $100 million in sales the year after its launch ($668 million in 2007) and $1 billion in the third year of its launch (nearly $1.4 billion in 2008). According to fiercepharma, sitagliptin and its combination reached $5.3 billion in sales in 2020, accounting for 60% of the global DPP-4 inhibitor market. Sitagliptin has been so successful because of the advantages in terms of efficacy and adverse effects on the one hand, and the successful development strategy of Merck on the other.

Sitagliptin, the first oral dipeptidyl peptidase IV (DPP-4) inhibitor to be marketed, was developed by Merck. In October 2006, Sitagliptin was approved by the US FDA for the treatment of type II diabetes, either alone or in combination with metformin and thiazolidinediones. After the launch of sitagliptin, Merck has also introduced metformin and sitagliptin tablets Janumet (2007), sitagliptin and simvastatin) tablets Juvisync (2011), sitagliptin and metformin HCl extended-release tablets Janumet XR (2012), and ertugliflozin and sitagliptin tablets Steglujan (2017) .

Mechanism of Action of DPP-4 Inhibitor

Dipeptidyl peptidase 4 (DPP-4) inhibitors, known as gliptins, are are a class of oral hypoglycemics for treating type 2 diabetes. 

Mechanism of Action of DPP4 Inhibitor, Image source: wikipedia

Glucagon increases blood glucose levels, and DPP-4 inhibitors help maintain glucose homeostasis. The mechanism of DPP-4 inhibitors is to increase incretin levels (mainly GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide) ), which inhibit glucagon release, in turn increasing insulin secretion, decreasing gastric emptying, and decreasing glucagon secretion.

GLP-1 is a hormone produced and secreted by intestinal enteroendocrine L cells and certain neurons upon food consumption, which decreases blood glucose by enhancing insulin secretion, reducing glucagon concentrations, and delaying gastric emptying. It has a half-life of fewer than 2 minutes due to rapidly degraded primarily by DPP-4, neutral endopeptidase 24.11 (NEP 24.11) and renal clearance. GIP is a inhibiting hormone produced and secreted by neuroendocrine K-cells. Its half-life is approximately approximately 7 and 5 minutes in healthy individuals and patients with type 2 diabetes, respectively

During a meal,, these incretins are released within minutes, and DPP-4 inactivates and catalyzes these hormones immediately. By inhibiting the DPP-4 enzyme, DPP-4 inhibitors slows their inactivation, thereby increasing the levels of GLP-1 and GIP, which in turn lower plasma glucose levels.

To date, there are 4 DPP-4 inhibitors approved by FDA, including sitagliptin (2006), saxagliptin (2009), linagliptin (2011), and alogliptin (2013). Vildagliptin (2007) has approval from the European Medicines Agency (EMA), but not by the FDA.

FDA Approved DPP-4 Inhibitors & EMA Approved DPP-4 Inhibitor

Huateng Pharma, as the leading pharmaceutical intermediates in China, can provide sitagliptin intermediates for your R&D research. We have helped clients by scaling up its pharmaceutical intermediates through the development of innovative processes and optimizing the production process thus it making it cost-efficient. 

[1] Capuano A, Sportiello L, Maiorino MI, Rossi F, Giugliano D, Esposito K. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy--focus on alogliptin. Drug Des Devel Ther. 2013;7:989-1001.
[2] Kasina SVSK, Baradhi KM. Dipeptidyl Peptidase IV (DPP IV) Inhibitors. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542331/

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