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

Abstract

ObjectiveThe 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.DesignTwo-step, two-sample multivariable Mendelian randomization (MVMR) study.SettingInternational genome-wide association study (GWAS) consortia data.ExposureType 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 OutcomesCardiovascular disease includes coronary heart disease (CHD), myocardial infarction (MI), and stroke.MethodsSummary-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.ResultsEach 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.ConclusionSystolic 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.

Assessment of the causal association between celiac disease and cardiovascular diseases

“…Compared with conventional observational studies, the possibility of residual confounding and reverse causation is greatly reduced in MR. Being a valuable tool for casual inference, MR has been widely used in the cardiovascular disease field ( 28 , 29 ). We investigated the association of CD with 10 cardiovascular diseases using a two-sample MR design.…”

Proportion of participants with type 2 diabetes achieving a metabolic composite endpoint with once‐weekly semaglutide treatment versus comparators: Post hoc pooled analysis from SUSTAIN 1‐5, 7‐10 and SUSTAIN China

“…Understanding the potential roles of cardiometabolic risk factors in mediating causal effect of T2D on CV disease may help identify treatment targets required to reduce T2D disease progression and CV risk. 3 Several prospective studies, ranging from a duration of 7 months to 19 years, have observed that the proportions of patients with T2D who achieve composite metabolic targets are usually very low, ranging from approximately 5% to 25%, with the higher proportions observed in the United States and the lower proportions in China. [9][10][11] More specifically, a registry study in the United States reported that 10 However, it should be emphasized that only 7.1% of participants were receiving sodiumglucose cotransporter-2 inhibitors or GLP-1RAs.…”

“…The association between diabetes and cardiovascular (CV) health is well known, and the interrelated risk factors of hypertension, elevated fasting glucose, dyslipidaemia, abdominal obesity and elevated triglycerides, collectively known as cardiometabolic disorders, 1 are leading causes of long‐term diabetes complications 2,3 . Adiposity and dysglycaemia are the two main metabolic drivers for cardiometabolic‐based chronic diseases, as applied to the CV endpoints of coronary heart disease, heart failure and atrial fibrillation 4 …”

“…The association between diabetes and cardiovascular (CV) health is well known, and the interrelated risk factors of hypertension, elevated fasting glucose, dyslipidaemia, abdominal obesity and elevated triglycerides, collectively known as cardiometabolic disorders, 1 are leading causes of long-term diabetes complications. 2,3 Adiposity and dysglycaemia are the two main metabolic drivers for cardiometabolic-based chronic diseases, as applied to the CV endpoints of coronary heart disease, heart failure and atrial fibrillation. 4 The multiple benefits of comprehensive treatment, which includes targeting of metabolic risk factors for the management of both diabetes and CV risk, have long been established, with the STENO-2 trial showing that multifactorial intervention reduced the risk of CV and microvascular events by about 50% in patients with T2D and microalbuminuria.…”

Bidirectional relationship between type 2 diabetes mellitus and coronary artery disease: Prospective cohort study and genetic analyses

“…[3,4] Multiple pleiotropic loci (e.g., CDKN2B-AS1, [5,6] TCF7L2, [6][7][8] HNF1A, [6,7] ALDH2, [5] FTO, [6] CCDC92, [7] APOE, [7] and MASP1 [8] ) are also reported to independently affect both diseases. Mendelian randomization (MR), which uses genetic variants as instrumental variables (IVs) to estimate exposure-outcome causal relationships, has consistently identified a causal association (effect sizes ranging from 1.09 to 1.63) between genetically determined T2DM and CAD [3,7,[9][10][11][12][13][14] (a detailed summarization is shown in Supplementary Figure 1, http://links. lww.com/CM9/B771).…”