The most popular type of diabetes is Type-2 diabetes mellitus (T2DM) accounting for 90-95% of diagnosed diabetes and continues to overgrow worldwide and in the USA. This rapid growth may be attributed to the increased elderly population, prevalence of obesity among adults and children, socioeconomic development, urbanization, unhealthy diets, and poor physical activities. The administration of antidiabetic agents in addition to cardio-renal protection is strongly required. Adequate glycemic control must be achieved with protection against cardiovascular and renal outcomes simultaneously. DPP-4 inhibitors are novel antidiabetic agents that have recently demonstrated protection against macro and macrovascular diabetes complications, particularly cardio-renal protection. To evaluate the efficacy and safety of DPP-4 inhibitors on chronic kidney disease patients. We used the PubMed database and searched for relevant articles on the topic. We used the Mesh word searching system; DPP-4 inhibitors; complications; adverse reactions. Type-2 Diabetes mellitus; Chronic kidney disease. DPP-4 inhibitors have demonstrated promising renal protection in healthy animal studies. Nevertheless, in humans with type-2 diabetes mellitus, the renal impact is still controversial. Several randomized clinical trials support the renoprotection effect of diabetic nephropathy.