Importance:Cholesteryl ester transfer protein (CETP) inhibition has been associated with decreased risk of new-onset diabetes in past clinical trials exploring their efficacy in cardiovascular disease and can potentially be repurposed to treat metabolic disease. Notably, as an oral drug it can potentially be used to supplement existing oral drugs such as sodium-glucose cotransporter 2 (SGLT2) inhibitors before patients are required to take injectable drugs such as insulin.Objective:To identify whether CETP inhibitors could be used as an oral add-on to SGLT2 inhibition to improve glycemic control.Design, Setting, and Participants:2×2 factorial Mendelian Randomization (MR) is performed on the general population of UK Biobank participants with European ancestry.Exposures:Previously constructed genetic scores for CETP and SGLT2 function are combined in a 2×2 factorial framework to characterize the associations between joint CETP and SGLT2 inhibition compared to either alone.Main Outcomes and Measures:Glycated hemoglobin and type-2 diabetes incidence.Results:Data on 233,765 UK Biobank participants suggests that individuals with genetic inhibition of both CETP and SGLT2 have significantly lower glycated hemoglobin levels (mmol/mol) than control (Effect size: −0.136; 95% CI: −0.190 to −0.081; p-value: 1.09E-06), SGLT2 inhibition alone (Effect size: −0.082; 95% CI: −0.140 to −0.024; p-value: 0.00558), and CETP inhibition alone (Effect size: −0.08479; 95% CI: −0.136 to −0.033; p-value: 0.00118). Furthermore, joint CETP and SGLT2 inhibition is associated with decreased incidence of diabetes (log-odds ratio) compared to control (Effect size: −0.068; 95% CI: −0.115 to −0.021; p-value: 4.44E-03) and SGLT2 inhibition alone (Effect size: −0.062; 95% CI: −0.112 to −0.012; p-value: 0.0149).Conclusions and Relevance:Our results suggest that CETP and SGLT2 inhibitor therapy may improve glycemic control over SGLT2 inhibitors alone. Future clinical trials can explore whether CETP inhibitors can be repurposed to treat metabolic disease and provide an oral therapeutic option to benefit high-risk patients before escalation to injectable drugs such as insulin or glucagon-like peptide 1 (GLP1) receptor agonists.