70 New Age Therapeutics in Type 2 Diabetes New Age Therapeutics in Type 2 Diabetes CHAPTER 10 Current Status of Sulphonylureas after CAROLINA and CARMELINA Trial - Maximum Glycemic Efficacy with Cardiac Safety Dr. Nandakrishna B Dr. Siddharth Gosavi Dr. Sudha Vidyasagar Introduction Sulfonylureas (SU) are one of the most used antidiabetic medications mainly due to their cost- effectiveness and reduced frequency of dosing. They have a therapeutic effect in patients with adequate β cell function. SU were frst discovered in 1942 by Janbon who observed that some sulfonamides generated hypoglycemia in experimental animals. Carbutamide was the frst sulfonylurea which was discovered and used to treat diabetes, but was subsequently withdrawn from the market because of damage to the bone marrow. By the 1960s several SU became available; they were classifed into 2 generations. Gliclazide, Glipizide, Glibenclamide and Glimepiride are second-generation sulfonylureas, currently used, while frst-generation drugs (such as Tolbutamide and Chlorpropamide) are no longer used due to their adverse cardiovascular profle. Second generation drugs are as effective as frst-generation drugs to lower the blood glucose concentrations, but there are differences in absorption, metabolism and dosing [1] . Mechanism of Action SU lower the glycemic levels in blood by markedly stimulating the release of insulin from pancreatic beta cells. The potassium ATP channel plays a major role in regulation of insulin secretion from pancreatic β cells. When the sulfonylurea acts, it leads to inhibition of the potassium ATP channels thereby increasing calcium infux and insulin release. There is a formation of new insulin granules which is possible only if β-cell function is preserved. Therefore, at all blood glucose concentrations, there is more insulin generated due to the increased response of beta cells to glucose and amino acids. SU are also responsible for decreasing the hepatic clearance of insulin. This appears mainly after the increase of insulin secretion has taken place. It is important to realize that the release of insulin induced by sulfonylureas is independent of glucose levels, and this can increase the risk of hypoglycemia [2,3] . In the frst month of treatment, the levels of insulin and insulin response to glucose rise rapidly, resulting in lower glycemic levels. Baseline and stimulated insulin levels become lower during this period compared to those measured at the beginning of treatment; however, blood glucose values remain unchanged. Chronic intake of sulfonylureas leads to the down-regulation of the receptor