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Diabetic nephropathy is a long-standing complication of diabetes mellitus and is responsible for more than 40% of end-stage renal disease cases in developed countries. Unfortunately, conventional renin–angiotensin–aldosterone system (RAAS) inhibitor medications only partially protect against the development and progression of diabetic nephropathy. Moreover, RAAS inhibitors have failed as primary prevention therapy in type 1 diabetes. Thus, agents targeting alternative pathogenic mechanisms leading to diabetic nephropathy have been intensively investigated, which is the topic of this review.Promising emerging agents have targeted neurohormonal activation (alternative components of the RAAS and neprilysin inhibition), tubuloglomerular feedback mechanisms (sodium glucose cotransporter 2 inhibition and incretin-based therapy) and renal inflammation/fibrosis.Evidence demonstrating the potential of these agents to protect and prevent progression of diabetic nephropathy is summarized in this review. There are dedicated clinical trials ongoing with these therapies, which have the potential to change the clinical practice.