Pharmacogenetic Epidemiology of Statins in an Ageing Population

Abstract

Cardiovascular disease (CVD) is an important cause of morbidity and mortality worldwide. The increasing incidence and prevalence of CVD constitutes a considerable disease burden and major health challenge for prevention and treatment. CVD frequently co-exists with other diseases such as type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver diseases (NAFLD), which are both strongly related to the metabolic syndrome. The 3- hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors or statins are cholesterol-lowering drugs that are beneficial in the primary and secondary prevention of CVD. With an approximately 20-25% reduction of the risk of major cardiovascular endpoints, these drugs have definitely entered daily clinical practice, and their use is expected to increase even more with a widening of therapeutic indications. However, current pharmacotherapy may not be optimal for all patients, and some individuals may not respond adequately to statins. This inadequate response may consist of a lack of therapeutic effect or the occurrence of adverse drug reactions (ADRs), and can have several underlying reasons. Insight into why people do not respond adequately to statins might improve clinical practice, can partly avoid these events, and may finally lead to tailored drug therapy. Moreover, in 2013, the American guidelines on primary prevention of CVD lowered the threshold for the indication for statin treatment, and thereby widened the target population for these already frequently prescribed drugs. This might have implications for current clinical practice, since prescribers should not ignore the potential risk of overtreatment or unintended effects that may go with this increased use. In this thesis we focused on the pharmacogenetic epidemiology of statins in an ageing population. We describe genetic factors that modify the response to statins, whereby we discovered new genetic variation and validated previous findings from genome-wide research and other relevant literature on the pharmacogenetics of statins. Furthermore, we describe unintended effects of the use of statins in clinical practice, and methodological approaches to estimate statin effectiveness in observational studies. Overall, in this thesis we have provided more insight into the use of statins in an ageing population. Stalins are expected to be used even more frequently in clinical practice, i.e. through widening of the indication for statins, the aging population and the increasing prevalence of welfare diseases associated with dyslipidemia and an increased CVD risk. Future research should investigate the consequences of this increased use for daily clinical practice. Hopefully, there will be a future role for genotype-based clinical decision making, with statin therapy tailored to an individual's needs on the basis of patient's specific characteristics.