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THE PHARMA REVIEW (APRIL - MAY, 2008)

Sitagliptin: A Promising Hope for the Pharmacotherapy of Type-2 Diabetes Mellitus

Dr. Pavan Malhotra, Dr. O.P. Gupta, Dr. Archana Parihar and Dr. Shakti Bala

Abstract: Diabetes mellitus is a syndrome of disordered metabolism associated with hyperglycaemia due to either deficiency of insulin secretion, decreased release or reduction in biological effectiveness of insulin due to development of resistance by insulin receptors. Diabetes is the fifth leading cause of death in the developed world. The drugs available to treat type 2 diabetes are not able to provide adequate glycaemic control. The patient suffers from associated complications, progressive exhaustion or failure of beta cells; most patients require increasing doses of oral hypoglycaemic agents or shift to insulin treatment.

The drugs developed and used over the years for the management of this disorder are the oral hypoglycaemics which include sulfonyl-ureas, glinides and insulin sensitizers like glitazones. A new group of drugs recently developed that act by enhancing the action of incretin hormones by inhibiting the enzyme dipeptidyl peptidaseIV (DPP-4) have been named “GLIPTINS”. Sitagliptin phosphate, the prototype of these drugs has been recently approved by the Food and Drug Administration, USA, for the treatment of type 2 diabetes mellitus.

Development of Sitagliptin

During early 20th century, experiments were taken up to find the endogenous entities that could release insulin. In 1932, J. LA Bowne extracted a polypeptide from the epithelium of upper gut which on testing was found to cause hypoglycaemia and coined the term incretins for such entites. In mid sixties it was observed that the release of insulin after intrajejunal glucose administration was double that of equitable amount of glucose administered intravenously. By 1969, the existence of entero-insular axis for blood glucose regulation gained significance.

Advances made in understanding the endogenous glucoregulatory mechanism led to the identification of two polypeptide hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), that are released by the gut and have been named as incretins as per the term already coined by Bowne for such entities. These hormones serve the feed forward mechanism to keep the check on the rise of blood glucose subsequent to ingestion of the food. Released from gut, these are carried by circulation to the pancreas and cause the release of insulin and decrease the glucagon secretion. As the blood glucose level approaches normal, the above activated process gets diminished to prevent an overshoot to hypoglycaemia which occurs with some known hypoglycaemic agents. The increase of insulin and decrease of glucagon by the incretins is mediated in glucose-dependant manner.

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