Separating the direct effects of risk factors for atherosclerotic cardiovascular disease from those mediated by type 2 diabetes

BackgroundType 2 diabetes and atherosclerotic cardiovascular disease share several risk factors. However, it is unclear whether the effect of these risk factors on liability to atherosclerotic cardiovascular disease is independent of their effect on liability to type 2 diabetes. MethodsWe performed univariate Mendelian randomization to quantify the effects of continuous risk factors from the IEU OpenGWAS database on liability to three outcomes: type 2 diabetes, coronary artery disease, and peripheral artery disease, as well as the effects of liability to type 2 diabetes on the risk factors. We also performed two-step Mendelian randomization for mediation to estimate the mediating pathways between the risk factors, liability to type 2 diabetes, and liability to the atherosclerotic cardiovascular disease outcomes where possible. ResultsWe found evidence for 53 risk factors as causes of liability to coronary artery disease, including eight which were causes of liability to type 2 diabetes only and four which were consequences only. Except for fasting insulin and hip circumference, the direct and total effects from the two-step Mendelian randomization were similar. This suggests that the combination of these risk factors with liability to type 2 diabetes was unlikely to alter liability to coronary artery disease beyond their individual effects. We also found 13 risk factors that were causes of liability peripheral artery disease, including six which were causes of liability to type 2 diabetes only and four which were consequences only. Again, the direct and total effects were similar for these ten risk factors apart from fasting insulin. ConclusionsMost risk factors were likely to affect liability to atherosclerotic cardiovascular disease independently of their relationship with liability to type 2 diabetes. Control of modifiable risk factors therefore remains important for reducing atherosclerotic cardiovascular disease risk regardless of patient liability to type 2 diabetes. RESEARCH IN CONTEXTO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIType 2 diabetes, coronary artery disease and peripheral artery disease, share several risk factors C_LIO_LIType 2 diabetes is also one of the strongest independent risk factors for both coronary and peripheral artery disease C_LI What is the key question?O_LIWhich risk factors for atherosclerotic cardiovascular disease are mediated by liability to type 2 diabetes and which are independent? C_LI What are the new findings?O_LIAmong 108 risk factors in this study, there was evidence to support: 10 risk factors as causes, 23 risk factors as consequences, and 34 risk factors as both causes and consequences of liability to type 2 diabetes C_LIO_LIIn addition, we found evidence for 53 risk factors as causes of liability to coronary artery disease and 42 risk factors as causes of liability to peripheral artery disease C_LIO_LIUsing two-step Mendelian randomization for mediation, we found most risk factors for atherosclerotic cardiovascular disease were likely to act independently of liability to type 2 diabetes C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur findings support continued control of modifiable risk factors as this is likely to reduce atherosclerotic cardiovascular disease, regardless of patient liability to type 2 diabetes C_LI