SGLT2 inhibitors are increasingly used with other therapeutic agents, increasing the need for simultaneous LC–MS/MS bioanalysis. However, it remains unclear how co-analytes affect analytical strategies compared with SGLT2 inhibitor-focused assays. To address this gap, analytical strategies in SGLT2 inhibitor-focused and combination-analyte LC–MS/MS assays were systematically compared. We identified 50 eligible studies, comprising 26 SGLT2 inhibitor-focused and 24 combination assays. Combination assays more frequently employed positive ESI and SPE, indicating selective adaptation of ionization and sample preparation for co-analytes. Chromatographic conditions also differed, with broader use of alternative stationary phases and more frequent isocratic elution in combination assays. Despite these differences, no consistent shift toward higher LLOQs or longer run times was observed. Overall, the inclusion of co-analytes was associated with selective changes in analytical strategy rather than a uniform increase in method complexity or loss of analytical performance. These findings suggest that simultaneous LC–MS/MS bioanalysis of SGLT2 inhibitors can often be achieved by adapting selected analytical conditions while maintaining adequate sensitivity and chromatographic performance. These findings may provide a practical basis for developing multi-analyte LC–MS/MS methods for SGLT2 inhibitors and co-administered drugs.