Abstract
Gaudet D, Alexander V, Baker B, et al.
N Engl J Med 2015; 373: 438–447.
Raised plasma triglyceride levels are associated with an increased risk of cardiovascular disease and pancreatitis. As such, reducing triglyceride levels is presumed to be clinically advantageous, although outcome evidence for this is so far lacking. Triglycerides are partially regulated by apolipoproteins, such as apolipoprotein C-III (APOC3) which itself inhibits lipoprotein lipase and hepatic lipase. Therefore, reduction of APOC3 levels represents one potential method to reduce plasma triglyceride levels.
In this phase 2 study of 57 patients, APOC3 levels were markedly reduced (by up to 80%) in a dose-dependent manner using an antisense oligonucleotide to APOC3 (ISIS 304801). Furthermore, fasting triglyceride levels were also significantly reduced in patients treated with ISIS 304801. While the degree of triglyceride level reduction was considered to be of clinical significance, it is unfortunate that postprandial triglyceride measurements were not also reported, given the significant contribution postprandial lipaemia is believed to make to triglyceride-related pathologies.
In addition, APOC3 reduction also resulted in raised low density lipoprotein (LDL) cholesterol levels, which may need to be managed by further treatment. Clinically, this may be feasible since individuals on fibrate therapy during the study showed less pronounced increases in LDL cholesterol than those without additional therapies.