Author + information
- Emmanuel E. Egom, MD, PhD∗ ()
- ↵∗Jewish General Hospital and Lady Davis Research Institute, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1E2, Canada
The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial (1), which demonstrated that the addition of the PCSK9 inhibitor evolocumab to statin therapy significantly reduced the risk of atherosclerotic cardiovascular disease (ASCVD) events, has aroused much enthusiasm among advocates of the over-simplistic low-density lipoprotein (LDL)-cholesterol hypothesis and among the firm believers of the concept of “lower is better.” This will undoubtedly rekindle arguments in favor of targets for LDL-cholesterol levels.
Interestingly, in a recent issue of the Journal, Pastori et al. (2) demonstrated that plasma PCSK9 levels are associated with an increased risk of ASCVD events, independent of their effect on LDL-cholesterol. This observation raises the intriguing question of whether the observed cardiovascular benefit of the PCSK9 inhibitor evolocumab in the FOURIER trial might have been due, at least in part, to other potential mechanisms independent of its LDL–cholesterol-lowering effects. In fact, evidence suggesting some potential pleiotropic effects of PCSK9 inhibitors are rapidly accumulating (3,4).
Although these observations (1,2) make a valuable contribution to this field, the question of whether raised LDL-cholesterol actually is causative or simply the indication of an underlying inflammation-based complex vascular disorder (ASCVD) is still unresolved, the latter being supported by the recent finding showing anti-inflammatory therapy targeting interleukin-1β may lead to a significantly lower rate of recurrent ASCVD events, independent of lipid level lowering (5).
If LDL-cholesterol was critical as a mechanism for ASCVD development (i.e., the essential ingredient): 1) ASCVD would occur only when LDL-cholesterol was high; 2) there should be a strong and close relationship between LDL-cholesterol and ASCVD events; 3) other cardiovascular prevention strategies would not be required in individuals with low or reduced LDL-cholesterol; and 4) cardiovascular prevention strategies at the time of elevated LDL-cholesterol would successfully prevent the occurrence of ASCVD events.
If, on the other hand, LDL-cholesterol was just a marker for the presence of ASCVD (i.e., an “innocent bystander”): 1) the risk of ASCVD would relate but not closely to the levels of LDL-cholesterol; 2) even low level would be a powerful marker of ASCVD; 3) successful lowering of LDL-cholesterol should not abolish ASCVD events; and 4) ASCVD would occur when other comorbidity mechanisms were present but LDL-cholesterol was normal.
Current data, therefore, support the concept that LDL-cholesterol is not an essential ingredient but probably just a marker for ASCVD and therefore may be used only to assess patients’ adherence, as well as the response, to maximal tolerated doses of LDL–cholesterol-lowering agents with proven pleiotropic effects.
Please note: Dr. Egom has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation