Roles of Cardiometabolic Factors in Mediating the Causal Effect of Type 2 Diabetes on Cardiovascular Diseases: A Two-Step, Two-Sample Multivariable Mendelian Randomization Study

Objective: The objective of this study is to investigate the roles of cardiometabolic factors (including blood pressure, blood lipids, thyroid function, body mass, and insulin sensitivity) in mediating the causal effect of type 2 diabetes (T2DM) on cardiovascular disease (CVD) outcomes. Design: Two-step, two-sample multivariable Mendelian randomization (MVMR) study. Setting: International genome-wide association study (GWAS) consortia data. Exposure: Type 2 diabetes, blood pressure: systolic blood pressure (SBP), diastolic blood pressure (DBP); blood lipids: low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglycerides (TG); thyroid function: hyperthyroidism, hypothyroidism; body mass index (BMI), waist-hip-ratio (WHR), and insulin sensitivity. Main Outcomes: Cardiovascular disease includes coronary heart disease (CHD), myocardial infarction (MI), and stroke. Methods: Summary-level data for exposures and main outcomes were extracted from GWAS consortia. We used two-sample MR to illustrate the causal effect of T2DM on CVD subtypes and regression-based MVMR to quantify the possible mediation effects of cardiometabolic factors on CVD. Results: Each additional unit of log odds of T2DM increased 16% risk of CHD [odds ratio (OR): 1.16, 95% CI: 1.12–1.21], 15% risk of myocardial infarction (MI) (OR: 1.15, 95% CI: 1.10–1.20), and 10% risk of stroke (OR: 1.10, 95% CI: 1.06–1.13). In mediation analysis, SBP, DBP, and TG were found as main mediators, while the mediation effects of other cardiometabolic factors were not significant. The proportion of total effect of T2DM on CHD mediated by SBP, DBP, and TG was 16% (95% CI: 8–24%), 7% (95% CI: 1–13%) and 10% (95% CI: 2–18%), respectively. Mediation effect of SBP and DBP on MI and stroke, TG on MI was also prominent, while mediation effect of TG on stroke was not significant. The combined mediation effect of all the three mediators accounted for 29%, 26%, and 13% of the total effect of T2DM on CHD, MI, and stroke, respectively. Conclusion: Systolic blood pressure, DBP, and TG mediate a substantial proportion of the causal effect of T2DM on CVD and thus interventions on these factors might reduce the considerable excess risk of CVD among patients with T2DM.