Mipomersen is a 20-nucleotide, second-generation, antisense oligonucleotide that inhibits human apolipoprotein B (apo B)–1003 production by binding to and preventing translation of apo B messenger RNA. As apo B–100 is an essential structural component of VLDL, intermediate-density lipoprotein (IDL), LDL, and lipoprotein(a), decreased hepatic production of apo B by mipomersen should lead to reduced circulating concentrations of all of these atherogenic lipoprotein particles (1). However, Reyes-Soffer et al., in a stable isotope study of 17 healthy volunteers without hyperlipidemia and presumably on a restricted fat diet, reported that mipomersen 200 mg weekly for 7 weeks, although reducing VLDL and its apo B and triglyceride content, did not reduce the production rates of VLDL apo B but surprisingly increased its clearance (2). The study did, however, find modest reductions in IDL- and LDL apo B–associated production and postulated that these lipoproteins were decreased independently and directly rather than being a consequence of reduced VLDL production. The authors postulated that, due to the partial inhibition of apo B synthesis by mipomersen, compensation occurred by increasing the proportion of newly synthesized apo B directed to VLDL production, which in turn helped maintain hepatic lipid homeostasis (2). In addition, there was increased loading of triglyceride onto VLDL …