Evogliptin (Suganon) is an orally bioavailable, selective dipeptidyl peptidase-4 (DPP-4; CD26 antigen) inhibitor being developed by Dong-A ST for the treatment of type 2 diabetes mellitus. Evogliptin was approved in South Korea on 2 October 2015 for blood glucose lowering in patients with type 2 diabetes mellitus inadequately controlled by diet and exercise alone or by metformin plus diet and exercise. In July 2015, Dong-A ST signed a licensing out agreement for evogliptin with Geropharm for Russia, Ukraine and Kazakhstan markets. In April 2015, Dong-A ST signed a licensing agreement with Eurofarma Laboratorios of Brazil for 17 Latin America countries including Mexico. Evogliptin is a potent DPP-4 inhibitor with a 50 % inhibitory concentration (IC50) against soluble human DPP-4 of 0.98 nmol/L and an IC50 of 1.26 nmol/L against membrane-bound human DPP-4. It displayed 6000-fold higher potency for human DPP-4 than for human DPP-8 and DPP-9, and 20,000-fold greater potency for DPP-4 than for DPP-1, DPP-2 and other closely-related enzymes. Evogliptin is effective in improving glycosylated hemoglobin (HbA1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and β-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents. Evogliptin was generally well tolerated in clinical trials.

Gemigliptin, an orally active, CD26 antigen (dipeptidyl peptidase IV or DPP IV) antagonist, was developed by LG Life Sciences (Seoul, Korea) and was approved by the Ministry of Food and Drug safety in June 2012 for the treatment of Type 2 diabetes mellitus. Zemiglo is the brand name of gemigliptin. The company also signed licensing agreement with multinational pharmaceutical companies including Sanofi (Paris, France), and at present gemigliptin is approved in India, Columbia, Costa Rica, Panama, Ecuador and a few other countries. Registration studies are currently ongoing in several countries including Russia, Mexico and Thailand. Various studies have proven the efficacy and safety of gemigliptin for the treatment of T2DM, both as monotherapy as well as in combination with other anti-diabetic drugs. Gemigliptin binds to the S1, S2, and S2 extensive subsites of the DPP-4 enzyme. The piperidinone group of gemigliptin binds to the S1 subsite, where the upside F atom on the piperidin ring forms a hydrogen bond with the side chain of Tyr631 and the downside F atom makes a hydrophobic interaction with the side chain of Tyr666 and Tyr662. In addition, the key interaction occurs between the CF3 groups on the pyrimidino piperidine and the S2 extensive subsite of the DPP-4 substrate, which enhances the potency of the drug and increases its selectivity as well. Gemigliptin is a reversible and competitive inhibitor of DPP-4 enzyme with a Ki value of 7.25 ± 0.67 nM. It acts as a long-acting DPP-4 inhibitor which inhibits DPP-4 in a dose-dependent manner. In addition, it showed at least >23,000 fold selectivity for proteases such as DPP-8, DPP-9, and fibroblast activating protein – α. By preventing degradation of GLP-1 by DPP-4 inhibition, it increases insulin secretion, reduces glucagon secretion, decreases HbA1c, and prevents β-cell damage. Gemigliptin has also been investigated for the treatment of cancer and cisplatin adverse reaction.

Vildagliptin, previously identified as LAF237, is a new oral anti-hyperglycemic agent (anti-diabetic drug) of the new 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 glucaon release by the alpha cells of the islets of Langerhans in the pancreas. It is currently in clinical trials in the U.S. and has been shown to reduce hyperglycemia in type 2 diabetes mellitus. While the drug is still not approved for use in the US, it was approved in Feb 2008 by European Medicines Agency for use within the EU and is listed on the Australian PBS with certain restrictions. Vildagliptin is marketed under the trade names Galvus, Zomelis.

Saxagliptin is an orally active hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. FDA approved on July 31, 2009. Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor antidiabetic for the treatment of type 2 diabetes. DPP-4 inhibitors are a class of compounds that work by affecting the action of natural hormones in the body called incretins. Incretins decrease blood sugar by increasing consumption of sugar by the body, mainly through increasing insulin production in the pancreas, and by reducing production of sugar by the liver. [Bristol-Myers Squibb Press Release] DPP-4 is a membrane associated peptidase which is found in many tissues, lymphocytes and plasma. DPP-4 has two main mechanisms of action, an enzymatic function and another mechanism where DPP-4 binds adenosine deaminase, which conveys intracellular signals via dimerization when activated. Saxagliptin forms a reversible, histidine-assisted covalent bond between its nitrile group and the S630 hydroxyl oxygen on DPP-4. The inhibition of DPP-4 increases levels active of glucagon like peptide 1 (GLP-1), which inhibits glucagon production from pancreatic alpha cells and increases production of insulin from pancreatic beta cells.

Pioglitazone (brand name Actos) is a prescription drug of the thiazolidinedione class with hypoglycemic action used in the treatment of type 2 diabetes. Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. It modulates the transcription of the genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. As a result, pioglitazone reduces insulin resistance in the liver and peripheral tissues, decreases gluconeogenesis in the liver, and reduces the quantity of glucose and glycated hemoglobin in the bloodstream. Pioglitazone is used to lower blood glucose levels in the treatment of diabetes mellitus type 2 (T2DM) either alone or in combination with a sulfonylurea, metformin, or insulin. Pioglitazone cannot be used in patients with a known hypersensitivity to pioglitazone, other thiazolidinediones or any of components of its pharmaceutical forms. It is ineffective and possibly harmful to diabetes mellitus type 1 and diabetic ketoacidosis. Pioglitazone can cause fluid retention and peripheral edema. As a result, it may precipitate congestive heart failure (which worsens with fluid overload in those at risk). It may cause anemia. Mild weight gain is common due to increase in subcutaneous adipose tissue. In studies, patients on pioglitazone had an increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.

Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. It is FDA approved for the treatment of as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Inhibitors of CYP2C8 (e.g., gemfibrozil) may increase rosiglitazone levels; inducers of CYP2C8 (e.g., rifampin) may decrease rosiglitazone levels. Common adverse reactions include edema, weight gain, and headache.