Several studies have demonstrated the decreased insulin resistance (IR) in persons with type 2 diabetes mellitus (T2DM) treated with glimepiride. Those suggest this might be associated with observed higher concentrations of adiponectin. We assessed if there is a difference in IR and metabolic syndrome components between glimepiride and glibenclamide treatment as well as adiponectin concentration in T2DM. Our research observed 20 T2DM patients treated with glibenclamid and 20 switched to glimepiride (n = 20) treatment for 24 weeks. Anthropometric measurements and laboratory analysis were performed at the beginning and at the end of treatment while IR was accessed by homeostasis model assessment of insulin resistance (HOMA-IR). The glimepiride group revealed better glycaemic control compared to glibenclamide group. Moreover, the adiponectin concentration increased (23.9 ± 17.3 to 29.1 ± 12.2 ng/mL, p = 0.087) whereas it decreased in the glibenclamide group (34.3 ± 22.6 to 20.3 ± 11.3 ng/mL, p = 0.011) following 24 weeks of treatment. The serum adiponectin and HOMA-IR were inversely correlated within the group of glibenclamide (r = –0.667, p = 0.009). The present study demonstrates that glimepiride might have beneficial effect on IR compared to glibenclamide, as suggested. However, this observation needs further study investigation among other formulations of SU.