: The efficacy and safety of the following new treatment agents were analyzed: once weekly semaglutide (OWSem) and the empagliflozine (Empa). This was done with patients with type 2 diabetes mellitus (T2DM) at the Clinical Hospital in Shtip, R.N. Macedonia.: One-hundred-twenty-one diabetic patients were treated for the first time with OWSema or Empa and were retrospectively analyzed. Glycemic control, serum creatinine, decrease in weight, co-morbidities, and hospitalization during treatment were recorded.: Among the 61 patients treated with OWSema and 60 patients treated with Empa, there were not any statistically significant differences in age, sex, BMI, duration of diabetes, and a number of patients treated with insulin. Both agents (OWSema and Empa) achieved statistically significant HbA1c reduction after 6, 12, and 18 months (9.2; vs. 7.6; 6.7; 6.6, and 9.3; vs. 7.5; 7.2, 7.5%, respectively) treatment. There were not any differences in the value of creatinine between the visits in both groups. During the period of 2 years, 3 patients (5%) from the Empa group died, all with multiple comorbidities. One patient from Empa group was hospitalized because of acute pulmonary edema and two from the OWSema group because of TIA and acute coronary syndrome. The median decrease in weight was more pronounced in the OWSema group (6.0 vs. 4.0kg). Five patients stopped the treatment with Empa because of a simple urinary infection, and one stopped the OWSema because of GIT intolerance. Eight patients did not tolerate the dose of 1mg, and they therefore continued with 0.5mg of OWSema.: Once weekly treatment with semaglutide and empagliflozine achieves a great reduction in HbA1c, and as such are safe for treatment of T2DM.