Will genetic studies deliver the next generation of cardioprotective therapies?

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Abstract

More than 20 years have passed since the seminal report that simvastatin reduced cardiovascular event rates in survivors of myocardial infarction. This was followed by a large number of clinical trials that reinforced the importance of lipid lowering, with statins becoming the cornerstone for cardiovascular prevention. However, the finding that many cardiovascular events continue to occur despite statin therapy highlights the need to develop additional approaches that will complement statin therapy and result in more effective reduction of cardiovascular risk. The evolving paradigm of pathological events promoting the formation, progression and rupture of atherosclerotic plaque have provided important insights with the potential to inform what are the next targets for therapeutic modulation. These studies have emphasised the importance of atherogenic lipoproteins and inflammatory pathways in promoting atherosclerosis and a potentially protective role for high-density lipoproteins (HDL). The finding that circulating biomarkers related to these factors associate with the residual clinical risk observed in statin-treated patients provided further support for the development of new therapies. However, the disappointing results of clinical trials of fibrates, HDL raising agents and anti-inflammatory therapies have failed to produce new agents in clinical practice. In the current issue of the journal, Gregson and colleagues report their investigation of the relationship of loss of function variants in lipoprotein-associated phospholipase A2 (Lp-PLA2) and cardiovascular risk in more than 300,000 individuals from a range of observational studies. They reported that loss of function variants were associated with a 45% reduction in LpPLA2 activity per inherited allele, but no reduction in cardiovascular risk. This paralleled their observations that the chemical Lp-PLA2 inhibitor, darapladib, reduced activity by 65%, yet similarly produced no cardiovascular benefit in two large clinical outcomes trials. They concluded that Lp-PLA2 is unlikely to be a causal risk factor for atherosclerosis and questioned whether chemical inhibition would be a viable anti-atherosclerotic strategy. The rationale for clinical development was based on pathology observations that implicated Lp-PLA2 in atherosclerosis. Lp-PLA2 is present within unstable plaques and plays an important role in the generation of bioactive products of arachidonic acid metabolism that promote a range of inflammatory and oxidative pathways. Development of darapladib as a chemical LpPLA2 inhibitor received early enthusiasm on the basis of favourable effects on a porcine model of atherosclerosis and in an early intravascular imaging study in patients with coronary disease demonstrating a protective influence on expansion of the necrotic core, a secondary endpoint. These data were supported by observational data from the same authors as the present genetic study that circulating Lp-PLA2 levels were as strongly associated with coronary heart disease as LDL-C. This latter finding in particular persuaded the drug developer to conduct two large clinical outcomes studies of darapladib in patients with stable and unstable ischaemic syndromes. However, the inability of darapladib to reduce cardiovascular events in both studies suggests that the inhibition of Lp-PLA2 is unlikely to be cardioprotective. The findings of Gregson and colleagues reinforce the trial data and further dampen enthusiasm for Lp-PLA2 inhibition as a causal factor in atherosclerosis. The alignment of the genetic invalidation of Lp-PLA2 with the lack of efficacy of darapladib in outcome trials raises the intriguing question regarding the utility of genetic analyses in drug development. Advances in