Abstract
New drugs were recently developed to treat hyperglycemia in patients with type 2 diabetes mellitus (T2D). However, metformin remains the first-line anti-diabetic agent because of its cost-effectiveness. It has pleiotropic action that produces cardiovascular benefits, and it can be useful in diabetic nephropathy, although metformin-associated lactic acidosis is a hindrance to its use in patients with kidney failure. New anti-diabetic agents, including glucagon-like peptide-1 receptor (GLP-1R) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose transporter-2 (SGLT-2) inhibitors, also produce cardiovascular or renal benefits in T2D patients. Their glucose-independent beneficial actions can lead to cardiorenal protection via hemodynamic stabilization and inflammatory modulation. Systemic hypertension is relieved by natriuresis and improved vascular dysfunction. Enhanced tubuloglomerular feedback can be restored by SGLT-2 inhibition, reducing glomerular hypertension. Patients with non-diabetic kidney disease might also benefit from those drugs because hypertension, proteinuria, oxidative stress, and inflammation are common factors in the progression of kidney disease, irrespective of the presence of diabetes. In various animal models of non-diabetic kidney disease, metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors were favorable to kidney morphology and function. They strikingly attenuated biomarkers of oxidative stress and inflammatory responses in diseased kidneys. However, whether those animal results translate to patients with non-diabetic kidney disease has yet to be evaluated. Considering the paucity of new agents to treat kidney disease and the minimal adverse effects of metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors, these anti-diabetic agents could be used in patients with non-diabetic kidney disease. This paper provides a rationale for clinical trials that apply metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors to non-diabetic kidney disease.
Highlights
Chronic kidney disease (CKD) is a major public health burden, affecting more than 750 million people worldwide [1]
This paper provides a rationale for conducting clinical trials to test the use of metformin, glucagon-like peptide-1 receptor (GLP-1R) agonists, Dipeptidyl peptidase-4 (DPP-4) inhibitors, and Sodium-glucose transporter-2 (SGLT-2) inhibitors in various non-diabetic kidney diseases
The glucose lowering–independent pleiotropic action of metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors might extend their indications to non-diabetic diseases
Summary
Chronic kidney disease (CKD) is a major public health burden, affecting more than 750 million people worldwide [1]. A series of new anti-diabetic agents has been developed and validated to lower glycemia. Those drugs carry cardiovascular and renal benefits and risks for patients with T2D. In contrast with DKD, no remarkable agents have been identified as effective measures to treat nondiabetic kidney disease during the past decade. Recent clinical trials elucidated the ability of SGLT-2 inhibitors to treat heart failure [11] and CKD [12] in patients without diabetes mellitus. This paper provides a rationale for conducting clinical trials to test the use of metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors in various non-diabetic kidney diseases
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