Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside

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.

Urinary Potassium and Kidney Function Decline in the Population—Observational Study

“…Inhibitors or blockers of the renin-angiotensin system are generally considered preferable due to specific effects on glomerular hemodynamics [ 2 ]. Similar favorable effects on glomerular dysfunction are ascribed also to antidiabetic drugs inhibiting the sodium-glucose transporter-2 [ 3 ] and to reduced protein intake [ 4 ].…”

Sitagliptin's renoprotective effect in a diabetic nephropathy model in rats: The potential role of PI3K/AKT pathway

“…Thus, several substrates might contribute to the pleiotropic action of DPP-4 inhibitors. The antiinflammatory, antioxidative, and antiapoptotic actions of DPP-4 inhibitors are mediated via GLP-1-dependent and GLP-1-independent mechanisms [72]. The involvement of GLP-1-independent mechanisms were similarly reported, the renoprotective effects of DPP-4 inhibitors were observed to a similar extent, in GLP1R-/knockout mice, compared with wild-type mice [19].…”

“…This effect was partly attributed to regulating ROS/p38MAPK/ERK and stimulating PI3K/AKT pathways [70]. However, it was shown that in the rat remnant kidney model, SIT improved renal functional and morphological changes by attenuating activation of the PI3K/AKT pathway [71,72]. These conflicting results have been related to different strains used and different experimental model induced in these studies.…”

Non-Insulin Novel Antidiabetic Drugs Mechanisms in the Pathogenesis of COVID-19

“…It cleaves a wide variety of substrates, including the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), cytokines, and growth factors. It also acts as a binding protein and a ligand of extracellular factors [ 18 , 30 , 31 , 32 ], hence the pleiotropic effects of DPP-4 enzyme [ 32 ].…”

“…[ 27 ]. Some indirect anti-inflammatory effects of DPP-4i may be mediated by GLP-1-dependent mechanisms as well, since GLP-1 also exerts anti-inflammatory properties [ 16 , 30 ].…”