The Lipid Hypothesis: From Resins to Proprotein Convertase Subtilisin/Kexin Type-9 Inhibitors

The validity of the lipid hypothesis has been debated recently in both, the media and the medical press. In this chapter we review the relevant evidence to evaluate whether it is still applicable in cardiovascular prevention. After a brief description of developments leading to the lipid hypothesis we consider prospective epidemiological studies, paying particular attention to the Framingham Heart Study as it was conceived at a time when lipid lowering therapy was unavailable. We also present the predictive factors of the other commonly used cardiovascular risk scoring models. All the algorithms show cholesterol (total or low density lipoprotein – cholesterol) and high density lipoproteins to predict cardiovascular disease. Our own data from the Whickham Study where subjects were recruited in the pre-statin era also show total cholesterol to be significantly associated with coronary heart disease. We then discuss intervention randomised controlled studies using agents that lower low density lipoprotein – cholesterol (resins, statins, ezetimibe and Proprotein convertase subtilisin/kexin type 9 inhibitors) paying particular attention to studies not demonstrating reduction in cardiovascular outcomes. Apart from patients with heart failure and possibly on dialysis the lipid hypothesis appears to be true. This is reinforced by a meta-analysis carried out by the Cholesterol Treatment Trialists’ Collaboration. We do not feel that outcomes from cohort studies consisting of patients subject to multiple guideline driven treatments can be used as good quality evidence against the lipid hypothesis. We do acknowledge that more research is required regarding heterogeneity and describe a non-invasive way in which atherogenesis of the individual may be measured. We would like future randomised controlled trials to incorporate study of disease mechanism(s) within the study design.

Keywords: Cardiovascular disease, Cardiovascular disease prediction, Coronary heart disease, Ezetimibe, Framingham Heart Study, Lipid hypothesis, LDLcholesterol, Peak systolic velocity, Proprotein convertase subtilisin/kexin type 9 inhibitors, Randomised Controlled Trials, Statins, Total cholesterol, Whickham study.