Diabetic nephropathy has now become a common cause of chronic kidney disease, exacerbated by obesity, and the rise in mortality in patients with type 1 or type 2 diabetes is significantly associated with the presence of kidney disease. Currently, diabetic nephropathy is mainly treated by controlling hyperglycemia and hypertension, and the treatment of hypertension is based on inhibition of the renin-angiotensin-aldosterone system. Diabetic nephropathy remains a major challenge in clinical management today. In this regard, Dr. Himmelfarb and others from the Renal Research Institute at the University of Washington School of Medicine provide a comprehensive review of the current state of treatment and drug research in diabetic nephropathy. Clinical studies have shown that intensive therapy maximizes inhibition of the renin-angiotensin-aldosterone system and that intensive therapy to control traditional risk factors does not improve diabetes outcomes. In older patients with type 2 diabetes, intensive glycemic therapy with the primary goal of lowering glycosylated hemoglobin resulted in a small reduction in the risk of proteinuria or progression, but was associated with a risk of severe hypoglycemia. Moreover, lowering glycosylated hemoglobin does not reduce the risk of death, cardiovascular disease, or ESRD. Dual blockade therapy reduces the risk of proteinuria and decreases the risk of ESRD, but the risk of adverse events is increased. Therefore, there is still an urgent need to develop new therapeutic agents. Previous experimental data suggest that oxidative stress and inflammation are two important mediators of diabetic nephropathy. The small molecule compound mebadoxolone activates Nrf2, a transcription factor that regulates antioxidant genes. Results from a previous phase 2 CKD/type 2 diabetic kidney function clinical trial showed that mebadoxolone increased glomerular filtration rate in patients with moderate to severe diabetic nephropathy. However, there was an increased incidence of proteinuria, decreased body weight, and increased adverse events in the mebadoxolone treatment group. The phase 3 clinical trial of mebadoxolone in patients with chronic kidney disease and type 2 diabetes was terminated early from the BEACON trial at only 9 months of follow-up due to significant adverse safety prognosis with mebadoxolone, which included an increased incidence of heart failure and cardiovascular events, increased levels of hypertension, heart rate and proteinuria, weight loss, and increased gastrointestinal and muscle-related symptoms. The researchers speculate that fluid retention, increased afterload and increased heart rate may have contributed to the development of heart failure in the patients. It is also possible that the toxic effects of the drug itself may have contributed. There are lessons to be learned from the mebadoxolone study. First and foremost, a more in-depth analysis of the new drug is needed before clinical trials. In preclinical studies, diabetic rats given mebadoxolone treatment showed renal injury, hypertension, proteinuria, and weight loss, a phenomenon similar to that seen in clinical trials. However, these data were published only after the termination of the BEACON clinical trial. Second, the presence of off-target effects of potent agonists of transcription factors is not surprising. In addition to Nrf2, mebadoxolone also activates the peroxisome proliferator activator receptor gamma, which may result from fluid retention and heart failure (especially in patients with advanced diabetes). Finally, vigilance is needed when treatment with diabetic nephropathy drugs increases rather than decreases proteinuria levels. The failure rate of new drugs in clinical trials is very high, over 90%, and remains as high as 50% even in phase 3 clinical trials. In addition to mebadoxolone, a number of other new therapies for diabetic nephropathy have been previously declared failures during studies, including late stage glycation end product inhibitors, aldose reductase inhibitors, sulodexide, anti-liver fibrosis therapies, and protein kinase C inhibitors. How can we increase the success rate of drug studies? A redesign of scientific discovery and clinical trial translation is needed. Data from drug-related preclinical studies are currently being comprehensively entered, and novel technologies such as “microchip organs” can improve the assessment of potential off-target effects. In addition, rigorous evaluation of drug doses, biomarkers of disease occurrence, and therapeutic feedback are also key concerns. Regulatory models and business environments that encourage innovation are also needed. Given the current rising number of diabetic nephropathy patients and the cost to society, it is extremely important to find new safe and effective therapies.