Khomtchouk, Bohdan B.Sun, PatrickMaggio, Zane A.Ditmarsch, MarcKastelein, John J. P.Davidson, Michael H.2024-09-202024-09-202024-06-19Khomtchouk BB, Sun P, Maggio ZA, Ditmarsch M, Kastelein JJP, Davidson MH. CETP and SGLT2 inhibitor combination therapy increases glycemic control: a 2x2 factorial Mendelian randomization analysis. Front Endocrinol (Lausanne). 2024;15:1359780. Published 2024 Jun 19. doi:10.3389/fendo.2024.1359780https://hdl.handle.net/1805/43476Introduction: Cholesteryl ester transfer protein (CETP) inhibitors, initially developed for treating hyperlipidemia, have shown promise in reducing the risk of new-onset diabetes during clinical trials. This positions CETP inhibitors as potential candidates for repurposing in metabolic disease treatment. Given their oral administration, they could complement existing oral medications like sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying the need for injectable therapies such as insulin. Methods: We conducted a 2x2 factorial Mendelian Randomization analysis involving 233,765 participants from the UK Biobank. This study aimed to evaluate whether simultaneous genetic inhibition of CETP and SGLT2 enhances glycemic control compared to inhibiting each separately. Results: Our findings indicate that dual genetic inhibition of CETP and SGLT2 significantly reduces glycated hemoglobin levels compared to controls and single-agent inhibition. Additionally, the combined inhibition is linked to a lower incidence of diabetes compared to both the control group and SGLT2 inhibition alone. Discussion: These results suggest that combining CETP and SGLT2 inhibitor therapies may offer superior glycemic control over SGLT2 inhibitors alone. Future clinical trials should investigate the potential of repurposing CETP inhibitors for metabolic disease treatment, providing an oral therapeutic option that could benefit high-risk patients before they require injectable therapies like insulin or glucagon-like peptide-1 (GLP-1) receptor agonists.en-USAttribution 4.0 InternationalMendelian randomizationCETPSGLT2Glycemic controlDiabetesEpidemiologyCombination therapyCardioinformaticsArticle