Type 2 Diabetes, Metabolic Traits, and Risk of Heart Failure: A Mendelian Randomization Study

<b>Objective</b> <p>The aim of this study was to use Mendelian randomization (MR) techniques to estimate the causal relationships between genetic liability to type 2 diabetes, glycaemic traits and risk of HF.</p> <p><b>Research Design and Methods</b></p> <p>Summary-level data were obtained from genome-wide association studies (GWAS) of type 2 diabetes, insulin resistance (IR), glycated haemoglobin, fasting insulin and glucose and HF. MR was conducted using the inverse variance weighted (IVW) method. Sensitivity analyses included MR-Egger, weighted median and mode methods, and multivariable MR conditioning on potential mediators.</p> <p><b>Results</b></p> <p>Genetic liability to type 2 diabetes was causally related to higher risk of HF (OR: 1.13 per 1 log-unit higher risk of type 2 diabetes; 95% CI 1.11-1.14, p<0.001), however sensitivity analysis revealed evidence of directional pleiotropy. The relationship between type 2 diabetes and HF was attenuated when adjusted for coronary disease, body mass index, LDL-cholesterol and blood pressure. Genetically-instrumented higher IR was associated with higher risk of HF (OR 1.19 per 1 log-unit higher risk of IR; 95% CI 1.00-1.41, p=0.041). There were no notable associations identified between fasting insulin, glucose or glycated haemoglobin and risk of HF. Genetic liability to HF was causally linked to higher risk of type 2 diabetes (OR 1.49; 95% CI 1.01-2.19, p=0.042) though again with evidence of pleiotropy.</p> <p><b>Conclusions</b></p> These findings suggest a causal role of type 2 diabetes and IR in HF aetiology, though both the presence of bidirectional effects and directional pleiotropy highlight potential sources of bias that need to be considered.