A novel ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was established for simultaneous determination of three hypoglycemic drugs namely; sitagliptin (STG), vildagliptin (VLG) and metformin (MET) in the presence of their degradation products and STG related impurities. Chromatographic separation was accomplished on a Hypersil gold 50 mm  2.1 mm (1.9 mm) column, using acetonitrile and 0.2% formic acid aqueous solution as the mobile phase with a gradient elution. Electrospray ionization (ESI) source was operated in the positive ion mode. The selected reaction monitoring (SRM) mode on a triple quadrupole mass spectrometer was used to quantify the drugs utilizing the transitions of 408.12 / 235.24 (m/z), 304.33 / 154.32 (m/z), 130.12 / 71.32 (m/z) and 255.75 / 166.15 (m/z), for STG, VLG, MET and diphenhydramine (IS), respectively. The method has displayed a lower limit of detection of 1.50 ng mL À1 , 1.50 ng mL À1 and 3.00 ng mL À1 for STG, VLG and MET, respectively. The drugs were subjected to forced degradation where it was concluded that STG, VLG and MET were highly susceptible for alkaline stress conditions. In addition, the study of the degradation kinetics of the drugs has proved that the degradation follows a pseudo-first-order reaction.The proposed method was effectively applied for the analysis of laboratory prepared mixtures as well as combined pharmaceutical formulations. No significant difference was found regarding accuracy and precision upon statistical comparison of the obtained results with those of the reported method.Validation was conducted in compliance with the ICH guidelines proving the method to be selective, linear, precise and accurate. The simplicity and sensitivity of this method allows its use in the quality control of the cited drugs. Scheme 1 The proposed structures and pathways of the main degradation products of STG produced under (a) alkaline degradation and (b) acid degradation. 60476 | RSC Adv., 2015, 5, 60467-60481 This journal is