Design, Optimization, and Biological Evaluation of First-in-Class Triple Inhibitors of SGLT1, SGLT2, and DPP4 for Type 2 Diabetes Mellitus

(72 nM, 6.7 nM, 0.8 nM) induced glucosuria in nondiabetic rats. Following oral glucose challenge in Zucker diabetic rats, they demonstrated statistically superior plasma glycemic control versus SGLT2-selective inhibitor dapagliflozin and conferred a prolonged increase in active GLP-1 relative to the SGLT1/2 inhibitor sotagliflozin, implying synergistic SGLT1 and DPP4 inhibition. These results support triple-targeted inhibitors as multitarget, multiorgan drug candidates for improved glycemic control and cardiorenal benefits.