Abstract Background Contrast-Induced Acute Kidney Injury (CI-AKI) is a complication of patients undergoing percutaneous coronary intervention (PCI) associated with high morbidity and mortality and higher incidence is in patients with type II diabetes mellitus. Recently several randomized controlled trials have shown a clear benefit of new anti-diabetic drugs (GLP-1 analogues, DPP-4 inhibitors and SGLT-2 inhibitors) in the prevention of kidney damage but no study has evaluated their possible role in the prevention of CI-AKI in patients undergoing percutaneous coronary intervention. Methods The study enrolled 408 patients undergoing PCI and divided them into three groups: 136 with type 2 diabetes mellitus treated with new-antidiabetic drugs, 136 with type 2 diabetes mellitus treated with standard-antidiabetic therapy, and 136 non-diabetic patients. Patients were evaluated for serum creatinine (measured at the time of hospitalization, 24-hour and 48-hour post-PCI), glomerular filtration rate (eGFR) estimated using the Cockcroft-Gault equation before and after the procedure, and markers of myocardial damage at the admission and 24 hours after PCI. CI-AKI was defined as an increase in serum creatinine levels ≥ 0.3 mg / dL (26.5 μmol / L) or greater than 25% of the base value, occurred 24-48 hours after administration of the contrast medium. Results It was observed a significant increase in delta creatinine between pre and post PCI in the group treated with standard-antidiabetic therapy (0.91 ± 0.22 mg / dL vs 0.94 ± 0.23 mg / dL, p= 0.008), but not in the group treated with new-antidiabetic drugs that showed a delta creatinine close to zero (1.01 ± 0.33 mg / dL vs 1.01 ± 0.35 mg / dL, p = 0.945), similar to that observed in non-diabetic patients (1.01 ± 0.30 mg / dL vs 0.99 ± 0.31 mg / dL, p = 0.020). The patients treated with SGLT-2 inhibitors presented pre-PCI mean creatinine levels significantly lower (0.83 ± 0.16 mg / dL) than those treated with DPP-4 inhibitors (1.04 ± 0.34 mg / dL) and GLP-1 analogues (1.05 ± 0.39 mg / dL), (p for trend = 0.009). However, the creatinine delta between the pharmacological classes was similar (p = 0.881). The incidence of CI-AKI, defined as an increase of serum creatinine 24-48 hours after contrast medium administration ≥ 25%, was 9.6% in patients treated with standard-antidiabetic therapy, 4.4% in patients treated with new-antidiabetic drugs and 3.7% in non-diabetic patients (p for trend = 0.080). The incidence of CI-AKI, defined as an increase of serum creatinine 24-48 hours after contrast medium administration ≥0.3 mg / dL, was 5.1% in the standard-antidiabetic therapy group, 3.8% in the new-antidiabetic drugs group and 2.9% in the non-diabetic patients (p for trend = 0.911). Conclusions The study demonstrated in diabetic patients undergoing PCI and in treatment with new anti-diabetic drugs (GLP-1 analogues, DPP-4 inhibitors, SGLT-2 inhibitors) a reduced incidence of CI-AKI compared to diabetic patients in treatment with traditional antidiabetic drugs (metformin, sulfonylureas, thiazolidinediones, insulin) and a similar incidence of CI-AKI compared to non-diabetic patients. The results of this study underline a possible protective role of new anti-diabetic drugs for the prevention of CI-AKI.