Using Genetic Variants in the Targets of Lipid Lowering Therapies to Inform Drug Discovery and Development: Current and Future Treatment Options.

Mendelian randomization studies and "human knock-out" studies of rare loss-of-function coding variants suggest that plasma levels of low-density lipoprotein-cholesterol LDL-C, triglycerides (TGs), and lipoprotein(a) (Lp(a)) are causally associated with the risk of cardiovascular disease, and, therefore, therapies directed against these targets should reduce the risk of cardiovascular events. However, several therapies directed against these targets have failed to reduce the risk of cardiovascular events in large-scale randomized trials, thus suggesting that causality is not sufficient evidence to establish genetic target validation. Instead, the critical question that needs to be answered to improve drug discovery and development is how much a causal biomarker needs to be changed to produce a clinically meaningful benefit in a short-term trial. This review describes how to use naturally randomized genetic evidence to accurately anticipate the results of randomized trials evaluating current and future lipid lowering therapies, inform the design of randomized trials, and transform the drug discovery and development process.