This head-to-head trial aims to establish comparative effectiveness between the SGLT2 inhibitor empagliflozin and the sulfonylurea glimepiride, used as second-line therapy in patients with T2DM in whom metformin and diet/exercise has failed, with regard to glycemic control, beta-cell function, diabetes-associated comorbidities such as obesity and hypertension, and safety, including macro- and renal microvascular complications, over 4 years. Here, SLC5A2 is linked to diabetes mellitus.