Sitagliptin

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 or in combination with metformin or a thiazolidinedione for control of type 2 diabetes mellitus. The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values.

One of the big advantages of sitagliptin is that it can be taken as a pill - it does not need to be injected.

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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.^[2] There is no significant difference in the occurrence of hypoglycemia between placebo and sitagliptin.^[2]

History

Sitagliptin was approved by the U.S. Food and Drug Administration (FDA) on October 17, 2006^[3] 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.^[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.

See also

• Dipeptidyl peptidase-4

References