Aim: Semaglutide has shown to be highly effective in the treatment of type 2 diabetes, beyond weight loss and reduction of cardiovascular risk. Aim of the current study is to compare the impact of subcutaneous and oral semaglutide on diabetic comorbidities and metabolic and anthropometric parameters. Materials and methods: Among 1500 patients on treatment with GLP-1 receptor agonists, we included 150 (90 M and 60 F) new users of oral and subcutaneous semaglutide, BMI (mean BMI 33.1±7.56 kg/m2) and age (mean age 60.3±11 years) matched. At baseline and after 12 months of semaglutide we evaluated BMI, WC, glycaemia, HbA1c, lipid panel, hepatic and renal function and diabetic macroangiopathic, including retinopathy, nephropathy and neuropathy and macroangiopathic complications. Results: All patients completed the study. The mean dose of subcutaneous semaglutide was 0.5 mg/day, while the mean dose of oral semaglutide was 7 mg/day. Of the total of patients, 100 patients were on combined treatment with metformin and semaglutide, 20 were treated with combined semaglutide, metformin and SGLT2 inhibitors, 15 were on combined insulin and semaglutide, 3 were on combined semaglutide, metformin and sulphanylureas. No significant differences were observed at baseline about diabetic complications and biochemical parameters between the two groups of patients. A significant decrease in BMI (p=0.037), fasting glycaemia (p<0.001), HbA1c (p<0.001), total cholesterol (p<0.001), LDL cholesterol (p=0.009), ALT (p=0.005) was found after 12 months of subcutaneous semaglutide compared to baseline. A significant decrease in fasting glycaemia (p<0.001), HbA1c (p<0.001) and total cholesterol (p=0.032) was found after 12 months of oral semaglutide compared to baseline. Comparing the changes (Δ) in the biochemical parameters after 12 months of treatment, injectable semaglutide resulted in a higher Δ_BMI (p=0.046), Δ_HbA1c (p=0.046), Δ total cholesterol (p=0.016) and Δ LDL cholesterol (p=0.049) than oral semaglutide. Interestingly, at multivariate analysis Δ_LDL cholesterol was correlated with Δ_BMI (p=0.026, β=0.366) and Δ_HbA1c (p=0.041, β=0.303). Conclusions: Subcutaneous semaglutide results in improvement in BMI, HbA1c and lipids at 12 months compared to oral semaglutide.