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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Kinetics-effect relations of insulin-releasing drugs in patients with type 2 diabetes: brief overview.

Sulfonylureas and glinides have similar mechanisms of action but differ in receptor affinity and binding sites and in absorption and elimination rates. This promotes differences in potency, rate of onset, and duration of action. While prominent in single-dose studies, these differences have less importance during long-term sulfonylurea treatment: at ordinary dosages, rapid- and short-acting (glipizide) and slow- and long-acting (glyburide) sulfonylureas maintained continuously effective plasma levels and similar 24-h glucose control. Moreover, there was no difference in patient outcome between the first-generation sulfonylurea chlorpropamide and the second-generation glyburide in the U.K. Prospective Diabetes Study. However, the risk of long-lasting and hence dangerous hypoglycemia is higher with these two long-acting sulfonylureas. Conversely, this risk should be low with the short-acting glinides, but seemingly at the expense of less effective glucose control. The most important kinetics-effect relations are that hyperglycemia delays sulfonylurea absorption and that the sulfonylurea dose-response curve is bell shaped; continuous sulfonylurea exposure over a certain level (e.g., 10 mg glipizide) impairs rather than improves insulin and glucose responses to sulfonylurea (downregulation). Accordingly, a vicious circle may be established: unrelenting hyperglycemia may promote sulfonylurea dose increase, which increases hyperglycemia, promoting further dose increase and eventually therapeutic failure.[1]


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