Type 2 diabetes mellitus (T2DM) is a critical disease of global proportions. The introduction of the clinical practice of sodium/glucose co-transporter 2 inhibitors (SGLT2i) for the treatment of T2DM has not only increased its therapeutic range, but has also unexpectedly opened interesting perspectives for the treatment of chronic kidney disease (CKD) in T2DM at risk of progressing to, or already with, impaired kidney function. Even more surprising was the evidence from the most recent trials—confirmed by specifically designed studies—that these drugs have a very important cardio-protective role against heart failure and a highly significant kidney-protective role against most non-diabetic CKD.

A potential barrier to their widespread use, however, could be related to an acute reduction in a patient’s glomerular filtration rate (GFR) commonly observed at the initiation of treatment, but which can be reversed. Such an event resembles the analogous effect perceptible within the initiation of the blockers of the renin–angiotensin–aldosterone system (RAAS), especially if carried out too aggressively. Indeed, with an excessive restriction of sodium, the analogous effect alongside the use of ACE inhibitors and sartanics has been known for years as a kidney-protective agent.

If not excessive, this acute reduction in GFR is to be considered a positive prognostic sign and far from being a negative prognostic sign, suggesting the possibility of preserving kidney function in the long term by reducing glomerular hyperfiltration, known as an important factor in the progression of CKD. Moreover, although the kidney-protective mechanism of SGT2i appears to be similar to that of RAS inhibitors, their kidney-protective effect adds up to and is not competitive with that of RASi. Moreover, the scientific community is continuously amazed by new pleiotropic effects emerging from the use of SGT2i, such as the correction of anemia with a mechanism that is not limited to simple dehydration.

Mineralocorticoid receptor overactivation contributes to inflammation and fibrosis, which in turn leads to the progression of CKD. For almost two decades, therapeutic interventions for slowing the progression of CKD were limited to the inhibition of the renin–angiotensin–aldosterone system. Recently, finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, has shown promising cardiac and reno-protective benefits in the CKD of patients with T2DM. It can be added to the treatment of SGLT2i if residual albuminuria is still present, with the final goal of slowing the progression of kidney disease and preventing kidney replacement therapy in patients with diabetic and non-diabetic albuminuric kidney disease.

All ESAs (epoetin alfa, beta, darbepoetin alfa, methoxy polyethylene glycol epoetin beta, and their biosimilars) efficaciously correct anemia by replacing erythropoietin (EPO) deficiency occurring in failing kidneys. At variance with ESAs and by activating the hypoxia-inducible factor (HIF) pathway, HIF-PHIs stimulate the endogenous EPO and upregulate the expression of genes involved in the transport of iron and its mobilization from stores. This peculiar mechanism of action may theoretically produce a more effective anemia correction with a less pronounced increase in circulating EPO levels as compared to ESAs. Moreover, substantially lower peak serum EPO levels have been found in patients treated with HIF-PHIs in comparison with ESA treatment. However, the majority of randomized controlled trials (RCTs) testified, at best, non-inferiority in comparison with ESAs. Nevertheless, these oral compounds are a valid alternative to ESAs, particularly for non-hemodialysis patients, considering their ability to improve enteric iron absorption and utilization.

Date: 14 November 2023

Time: 5:00 pm CET | 11:00 am EDT

Webinar ID: 811 0606 5962

Webinar Secretariat: journal.webinar@mdpi.com