Why do the TZD drugs (Avandia / Actos) have such a long onset of action?
The thiazolidenediones are a fairly new class of agents used to treat Type 2 Diabetes and have a mechanism of action unlike any of the other pharmacotherapeutic agents. These drugs do not directly lower blood glucose. They are synthetic ligands that are active in the nucleus of the cell where they bind to the nuclear peroxisome proliferator-actvated receptor-gamma and exert their action by activating transcription of genes that, among others, regulate adipocyte differentiation and adipogenesis as well as glucose and lipid metabolism. (Whew, that is quite a mouthful!) What this really means is that these drugs have their action in the nucleus of the cell where they promote the manufacturing of proteins which form the transfer substances that facilitate the transfer of glucose into the cells. The end result is to improve insulin resistance by making it easier for fat and muscle cells to remove glucose from the blood. When the glucose is removed from the blood, blood glucose levels will fall; thus these drugs are oral hypoglycemic (glucose lowering) drugs.
Because they have a unique mechanism of action and increase glucose disposal from the blood they work synergistically with other drugs with different mechanisms of action. As an example, the biguanides or metformin work mainly by decreasing the supply of glucose contributed to the blood from the liver while the TZDs increase the removal of glucose from the blood. The combination of both drugs together is greater than either drug alone. It takes some time for the activation of genes in the nucleus to result in increased glucose transmitter substances in fat and muscle cells which ultimately facilitates transfer of glucose into these cells and lowering of glucose levels in the blood. This process of improved glucose transport may take weeks or even months to be apparent. In studies, the maximum effect of the lowering of fasting blood glucose may take 8-12 weeks and so it may take 4 or 5 months before we see a significant reduction in A1c. The important thing is to realize that we have to be patient, it will take some time before we see significant glucose lowering. The fact that there is little or no immediate effect does not mean the drug is not working.
Dr. J. Robin Conway M.D. 3 Feb 2004