Sitagliptin

Overview
Sitagliptin, previously identified as MK-0431, is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. This enzyme-inhibiting drug is to be used either alone (monotherapy) or in combination with either metformin or a thiazolidinedione for the control of type 2 diabetes mellitus. Potential benefits of this medicine include a lower incidence of side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose. Another potential advantages of sitagliptin is that it can be administered orally as a pill - it does not require subqutaneous injection.

Adverse effects
In clinical trials, adverse effects were as common with sitagliptin (whether used alone or with metformin or pioglitazone) as they were with placebo, except for nausea and common cold-like symptoms, which were more common with sitagliptin. There is no significant difference in the occurrence of hypoglycemia between placebo and sitagliptin.

History
Sitagliptin was approved by the U.S. Food and Drug Administration (FDA) on October 17, 2006 and is marketed in the US as Januvia by Merck & Co. On April 2, 2007, the FDA approved an oral combination of sitagliptin and metformin marketed in the US as Janumet.

Mechanism
The drug works to competitively inhibit a protein/enzyme, dipeptidyl peptidase 4 (DPP-4), that results in an increased amount of active incretins (GLP-1 and GIP), reduced amount of release of glucagon (diminishes its release) and increased release of insulin (increases its synthesis and release) to restore blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia) which is seen with some other oral hypoglycemic agents.

Sitagliptin works by inhibiting the inactivation of the incretins GLP-1 and GIP by DPP-4. By preventing GLP-1 and GIP inactivation, GLP-1 and GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. Sitagliptin incorporates a beta amino acid moiety that allows for a more favorable fit into the active site of DPP-4. The trifluorophenyl moiety also fits into a hydrophobic region of the active site.