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Aims: To assess the comparative effects of glucagon-like peptide-1 receptor agonists (GLP-1RA), 4-dipeptidyl peptidase inhibitors (DPP-4I), and metformin treatment during one year on metabolic syndrome (MetS) components and severity in MetS patients. Methods: Prospective study (n = 6165 adults) within the frame of PREDIMED-Plus trial. The major end-point was changes on MetS components and severity after one- year treatment of GLP-1RA, DPP-4I, and metformin. Anthropometric measurements (weight, height and waist circumference), body mass index (BM), and blood pressure were registered. Blood samples were collected after overnight fasting. Plasma glucose, glycosylated hemoglobin (HbA1c), plasma triglycerides and cholesterol were measured. Dietary intakes as well as physical activity were assessed through validated questionnaires. Results: MetS parameters improved through time. The treated groups improved glycaemia compared with untreated (glycaemia ∆ untreated: −1.7 mg/dL(± 13.5); ∆ metformin: − 2.5(± 23.9) mg/dL; ∆ DPP-4I: − 4.5(± 42.6); mg/dL ∆ GLP-1RA: − 4.3(± 50.9) mg/dL; and HbA1c: ∆ untreated: 0.0(± 0.3) %; ∆ metformin: − 0.1(± 0.7) %; ∆ DPP-4I: − 0.1(± 1.0) %; ∆ GLP-1RA: − 0.2(± 1.2) %. Participants decreased BMI and waist circumference. GLP-1RA and DPP-4I participants registered the lowest decrease in BMI (∆ untreated: −0.8(± 1.6) kg/m2; ∆ metformin: − 0.8(± 1.5) kg/m2; ∆ DPP-4I: − 0.6(± 1.3) kg/m2; ∆ GLP-1RA: − 0.5(± 1.2) kg/m2. and their waist circumference (∆ untreated: −2.8(± 5.2) cm; ∆ metformin: − 2.6(± 15.2) cm; ∆ DPP-4I: − 2.1(± 4.8) cm; ∆ GLP-1RA: − 2.4(± 4.1) cm. Conclusion: In patients with MetS and healthy lifestyle intervention, those treated with GLP-1RA and DPP-4I obtained better glycemic profile. Anthropometric improvements were modest.