Sodium-dependent glucose transporters (SGLTs) exploit the sodium ion concentration gradient to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are drug targets for the treatment of type 2 diabetes (T2DM). Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 (hSGLT1/2) in complex with inhibitors by combining computational and functional studies. The binding poses recapitulate hSGLT1 mutagenesis studies and suggest a partial closure of the outer gate upon inhibitor binding. The models also reveal the location of a putative non-conserved Na+ binding site in hSGLT1, and disruption of the site reduces the Na+ transport stoichiometry to the value in hSGLT2 and increases affinity for the aglycon tails. Our work reveals that inhibitor subtype selectivity arises from two factors: Na+-mediated control of outer gate closure and non-conserved residues in the extracellular loop EL5.