We demonstrated previously that the HDL-raising effect of various classical lipid-lowering drugs was caused by a reduction in plasma cholesteryl ester transfer protein (CETP) that mediates the net transfer of cholesteryl esters from HDL to (V)LDL. In APOE*3-Leiden.CETP mice, a well-established animal model for human-like lipoprotein metabolism, statins (6), fibrates (7), and niacin (8) decrease the hepatic lipid content (i.e., both TG and cholesterol), resulting in a decreased hepatic CETP expression accompanied by decreased plasma CETP levels and a consequently increased plasma HDL. Recently, we showed that a similar mechanism may account for the HDL-raising effect of pioglitazone in humans. In patients with type 2 diabetes mellitus, pioglitazone decreased hepatic TG content (9), accompanied by a decrease in plasma CETP concentration and increase in HDL level (10). In contrast, metformin did not affect either hepatic TG, plasma CETP, or HDL levels (10).