# Molecular Mechanisms and Clinical Evidence Supporting the Four Pillars of Therapy in Diabetic Kidney Disease: Emerging Therapeutic Perspectives

## TL;DR

This paper reviews current and emerging therapies for diabetic kidney disease, focusing on their molecular mechanisms and clinical effectiveness.

## Contribution

The paper provides a comprehensive overview of the four pillars of DKD therapy and introduces safer alternatives for patients with renal impairment.

## Key findings

- Renin-angiotensin system inhibitors and other drugs are effective in improving DKD prognosis.
- Imeglimin, pemafibrate, and dotinurad offer safer alternatives for patients with renal impairment.
- Emerging therapies for DKD require further high-level evidence research.

## Abstract

Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and the leading cause of end-stage renal disease worldwide. Recently, renin-angiotensin system inhibitors, non-steroidal mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists were proposed as the four pillars for treating DKD. To understand the molecular mechanisms by which these drugs improve DKD, we described the histological and molecular changes due to diabetes. Based on our understanding of the molecular changes in DKD, we present evidence on the efficacy of these drugs in improving DKD and discuss why such drugs improve the prognosis of DKD. In addition to diabetes and hypertension, insulin resistance, dyslipidemia and hyperuricemia are risk factors for DKD. Metformin, fibrates, and febuxostat have been reported to improve DKD; however, caution is required when administering these drugs to patients with renal impairment due to concerns about the onset of lactic acidosis, rhabdomyolysis, and deterioration of renal function, respectively. Imeglimin, pemafibrate, and dotinurad have similar chemical structures or effects to metformin, fibrates, and febuxostat, respectively, but are safer in patients with renal impairment. Furthermore, they have specific mechanisms to improve DKD and may offer new options for its treatment. This article is a narrative review. Regarding emerging therapies for DKD, no high-evidence-level research has yet been published, and further progress in this area is warranted.