Effects of artificial sweeteners on coronary heart disease: A 2-way 2-sample Mendelian randomization study and mediation analysis

This study aims to investigate the causal relationship between intake of artificial sweeteners and coronary heart disease (CHD) and identify and quantify the role of insulin sensitivity index as a potential mediator. Using summary-level data from genome-wide association studies, a 2-sample Mendelian randomization (MR) analysis was conducted on genetically predicted artificial sweeteners (64,949 cases) and CHD (1,85,000 cases). In addition, we used a 2-step MR to quantitatively determine the proportion of the effect of genetically predicted intake of artificial sweeteners on CHD mediated by insulin sensitivity index. The MR analysis determined that a higher genetically predicted intake of artificial sweeteners (main MR analysis odds ratio: 1.320 per SD increase, 95% confidence interval: 1.044-1.668) increases the risk of CHD. There is no strong evidence suggesting that genetically predicted CHD has an impact on the risk of intake of artificial sweeteners (odds ratio: 0.996, 95% confidence interval: 0.990-1.002). The proportion of genetically predicted CHD mediated by insulin sensitivity index is 19.61%. In conclusion, our study identifies a causal relationship between intake of artificial sweeteners and CHD and that insulin sensitivity index can serve as its mediator. In clinical practice, excessive intake of artificial sweeteners should be avoided in CHD patients and susceptible individuals.