There are concerns about the adverse effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on cardiac function. We investigated the effects of gemigliptin on cardiac function and compared the effects of gemigliptin and glimepiride in patients with type 2 diabetes (T2D). Sixty T2D patients being treated with metformin were assigned to a gemigliptin group (50 mg daily) or glimepiride group (2 mg daily) for 24 weeks. The preadjudicated extension period was up to 52 weeks. Glucose metabolism parameters and cardiac biomarkers were measured. Echocardiography was used to evaluate cardiac functions. Glycated hemoglobin level decreased significantly from 8.1% ± 0.6% to 6.8% ± 0.6% in the gemigliptin group and from 8.1% ± 0.6% to 7.0% ± 0.7% in the glimepiride group, without a between-group difference. Gemigliptin reduced insulin resistance, high sensitivity C-reactive protein and low-density lipoprotein cholesterol levels, and blood pressure, and increased adiponectin level compared with glimepiride therapy. Gemigliptin induced favorable changes in body composition. Left ventricular end diastolic volume decreased in the gemigliptin group but increased in the glimepiride group, with a borderline between-group difference. Cardiac biomarkers did not change significantly in either group. At 52 weeks, the HbA1c levels in both groups increased slightly; 7.3% ± 0.8% in the gemigliptin group vs 7.7% ± 1.3% in the glimepiride group, without a between-group difference. Gemigliptin had a comparable glucose-lowering efficacy without deleterious effects on cardiac functions or on biomarkers reflective of myocardial injury or heart failure during the 24-week observation period. However, larger, longer-term studies are needed to confirm these findings. ClinicalTrials.gov NCT05663736 This article is protected by copyright. All rights reserved.