Comments on Mendelian randomization analysis
In a recent Mendelian randomization (MR) study, Xiao,et al 20 provided genetic and real-world evidences about the protective role of PDE5 inhibition against ischemic heart disease (IHD), and found the potential of these drugs to be repurposed for IHD (CAD and AMI) prevention and treatment. Overall, this study on MR analysis is indeed a good job. However, further investigation, especially large-scale clinical trials are needed to enhance its strength, since the dose-response effects of PDE5i from more data on IHD prevention may provide additional information.
These excellent data in this study supported the protective role of PDE5i on IHD and other cardiovascular outcomes by a MR analysis, which offered the possibility of assessing causal relationships between genetically predicted risk factors and acquired CVD. It is an optimal study method to assess cardiovascular outcomes associated with risk factors of interest. It’s believed that this study would be a new example and an influential MR study, since it revealed the protective role of PDE5 inhibition against IHD, and it is also pivotal for the development of PDE5i due to lowering CVD risk in high-risk individuals.
In fact, there are indeed the opportunities and challenges of MR studies for CAD, since MR analysis has tremendous potential for identifying therapeutic targets that are likely to be causal for CAD.21 And MR has been increasingly used not only to predict the efficacy and safety of existing and novel drugs targeting risk factors of CVD but also to develop the repurposing potential of available PDE5i.22
As we know, there are the potential causal associations of lifestyle factors with risk of CVD, particularly CAD and ischaemic stroke, however, some MR studies indicated inconsistent results. On the one hand, this phenomenon is probably a gap between single and comprehensive risk factors; On the other hand, limitations of MR analysis are that “genetic variants have life-long effects, whereas trials assess the impact of short-term interventions”. Herein, “MR studies may not reflect real-world practice, and trial endpoints often differ from outcomes in MR analyses”.
However, in this study, Xiao, et al 20 added “a real-world study”. Obviously, it enhanced the strengthen of this study. At the same time, sensitivity analysis is one of the key steps for a reliable and powerful MR study. Since MR analysis may help to evaluate the repurposing potential of available PDE5i, no doubt, this study is an excellent example. Of course, clinical trials are required to further investigate the efficacy of PDE5i on preventing IHD at both the population and the specific individual levels.