CETP and SGLT2 inhibitor combination therapy improves glycemic control

ImportanceCholesteryl 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. ObjectiveTo identify whether CETP inhibitors could be used as an oral add-on to SGLT2 inhibition to improve glycemic control. Design, Setting, and Participants2x2 factorial Mendelian Randomization (MR) is performed on the general population of UK Biobank participants with European ancestry. ExposuresPreviously constructed genetic scores for CETP and SGLT2 function are combined in a 2x2 factorial framework to characterize the associations between joint CETP and SGLT2 inhibition compared to either alone. Main Outcomes and MeasuresGlycated hemoglobin and type-2 diabetes incidence. ResultsData 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 RelevanceOur 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. Key Points QuestionDoes combined genetic CETP and SGLT2 inhibition confer decreased glycated hemoglobin or diabetes incidence compared to SGLT2 inhibition alone? FindingsIn this cohort study, a 2x2 factorial Mendelian randomization analysis on the UK Biobank reveals that combined genetic CETP and SGLT2 inhibition is associated with decreased glycated hemoglobin and diabetes risk compared to both control and SGLT2 inhibition alone. MeaningOur findings suggest that CETP inhibitors, which are currently in clinical trials to treat cardiovascular disease, can be repurposed to treat metabolic disease in a combination therapy approach with SGLT2 inhibitors.