Antisense oligonucleotides (ASOs) have emerged as a new therapeutic modality for the treatment of both rare and common human diseases. A significant proportion of the patient population that may benefit from ASO therapy may also have common diseases, such as diabetes mellitus. The potential influence of prevalent diseases on the effectiveness of ASO drugs in silencing their target mRNAs remains largely unexplored. The current study utilized in vitro cell models to determine the impact on the FDA-approved ASO drug-mediated target reduction by cellular glucose levels.