Effective management of type 2 diabetes mellitus (T2DM) requires lifestyle changes and suitable medications to enhance quality of life and prevent complications. Choosing the right treatment involves considering the patient's clinical profile, drug efficacy, side effects, and cost. This study compares the safety and efficacy of sitagliptin, glimepiride, and metformin in T2DM patients. A prospective cross-sectional study was conducted at the Diabetes Center of Layla Qasim, Erbil, Iraq, including 143 diabetic patients. They were divided into three groups: group A received glimepiride (N=50), group B metformin (N=48), and group C sitagliptin (N=45). Drug costs, therapeutic outcomes, and side effects were analyzed. Patients aged 30 to 78 participated, with a female-to-male ratio of 83:60. All groups showed significantly improved HbA1c levels (P=0.001). Total cholesterol (TC) and LDL levels were also significantly different (P=0.047 and P=0.010, respectively). Sitagliptin significantly increased triglycerides (TG) and HDL-C. Gastrointestinal side effects were prominent in the metformin group. When selecting medication for T2DM, factors like age, HbA1c, glucose levels, obesity, metabolic syndrome, insulin secretion, and hypoglycemia risk should be considered. Both sitagliptin and glimepiride were well tolerated, with minimal hypoglycemia risk and no significant weight differences between groups. Glimepiride is an effective, safe, and weight-neutral adjunct to metformin, offering extrapancreatic benefits and remains a viable second-line treatment option for T2DM patients
