Background: The dual agonism of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) becomes a groundbreaking treatment for type 2 diabetes (T2D) that achieves robust glycemic control and maintains body weight. It also induces potential risk reduction in diabetic retinopathy (DR), Alzheimer disease (AD), and heart diseases including coronary artery disease (CAD) in treated T2D patients. To date, the molecular basis underpinning the remarkable causal treatment effects and synergy of the dual agonism of GLP-1R and GIPR on risk reduction in T2D, CAD, DR and AD has not been systematically investigated. Methods: To elucidate the treatment effects and potential synergy of dual GLP-1R/GIPR agonism on risk reduction in T2D, CAD, DR and AD while minimizing the impact of confounders, we used a robust cis-Mendelian randomization (cis-MR) with a principal component-based generalized method of moments (PC-GMM) where blood-based glycated hemoglobin (HbA1c), high- and low-density lipoprotein cholesterol (HDL-c, LDL-c), and BMI were used as mediating biomarkers. Results: Our cis-MR analyses confirmed a synergistic causal protective effect of dual GLP-1R/GIPR agonism on T2D via HbA1c reduction [OR = 0.17; 95% CI = (0.11, 0.26); p = 3.68 × 10-17] which is more significant than either GLP-1R agonism or GIPR agonism alone. Similarly, the causal protective effect of dual GLP-1R/GIPR agonism via HbA1c reduction was also significant for DR [OR = 0.20; 95% CI = (0.11, 0.36); p = 9.22 × 10-8]. Further, our multivariate cis-MR (or cis-MVMR) analyses revealed that after adjusting for HbA1c, a synergistic protective effect on DR via a reduction in LDL-c is significant in dual GLP-1R/GIPR agonism [OR = 0.57; 95% CI = (0.29, 0.94)], while the protective effect on DR of LDL-c reduction is non-significant in either GLP-1R agonism or GIPR agonism alone. Also, after adjusting for HbA1c, the multivariate cis-MR results showed significant protective effects on AD via a reduction in LDL-c in GLP-1R/GIPR agonism [OR = 0.44; 95% CI = (0.25, 0.81)]. Importantly, the multivariate cis-MR results also revealed that dual GLP-1R/GIPR agonism has significant protective effects on CAD via both a reduction in BMI [OR = 0.46; 95% CI = (0.28, 0.75)] and an improvement in HDL [OR = 0.59; 95% CI = (0.39, 0.90)]. This is in support of the hypothesis that dual GLP-1R/GIPR agonism has a synergistic protective effect on CAD that is stronger than that of GLP-1R agonism alone, which yielded a non-significant causal effect for both HDL and BMI, and GIPR agonism alone also yielded a non-significant causal effect for HDL when adjusted for BMI. Conclusions: These novel findings have significant implications for repurposing dual incretin agonism in terms of diabetic drugs to serve as a unifying, precision prevention strategy against CAD, DR and AD as leading drivers of mortality and morbidity in diabetic patients.
