Studies of Statins, Cholesterol and the Risk of Cardiovascular Disease

Abstract

Statins have been shown to substantially reduce the risk of cardiovascular disease and mortality over the past two decades. However there remain questions around their initiation, biological mechanisms, efficacy and safety, particularly in certain population subgroups. The aim of this thesis was to investigate some of the major uncertainties. Patient level meta-analyses were performed using data from 27 randomised statin trials to explore the effects of statins by gender and by age. The accuracy of common cardiovascular risk calculators used to guide the initiation of statin therapy was also investigated. A meta-analysis of trials with extended follow-up examined whether earlier statin treatment confers long-term legacy benefits. And an approach to serial aortic plaque imaging using optical coherence tomography (OCT) in a cholesterol fed rabbit model +/- statin therapy was developed, to explore plaque changes and guide methods for ongoing anti-atherosclerotic research. We found statins have similar, significant proportional vascular and mortality benefits in women compared to men, and are effective across all risk levels. Efficacy and safety in those age >75 years without heart failure or dialysis is also similar to younger adults, but there remains insufficient evidence in the primary prevention setting. Newer UK and US risk calculators perform better than the Framingham calculator, but persisting inaccuracies require clinical consideration. In long term trial follow up, there appear to be legacy effects from prior statin therapy for at least five years which would support an earlier approach to lipid lowering. Serial OCT imaging of rabbit atherosclerotic plaque is feasible, with preliminary findings that statins significantly slow plaque progression. More accurately characterising which individuals should commence statin, or potentially newer lipid lowering therapies, based on risk/benefit profiles will be the major ongoing focus in this area.