New perspectives in the management of diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and is also associated with increased risk for cardiovascular events. Until recently, strict glycemic control and blockade of the renin-angiotensin system (RAS) constituted the mainstay of treatment of DN. However, randomized controlled trials showed that sodium-glucose cotransporter 2 inhibitors further reduce the progression of DN. Therefore, these agents are recommended in all patients with DN regardless of DN stage and HbA_1c levels. Moreover, additional blockade of the RAS with finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, was also shown to prevent both the decline of renal function and cardiovascular events in this population. Finally, promising preliminary findings suggest that glucagon-like peptide 1 receptor agonists might also exert reno- and cardioprotective effects in patients with DN. Hopefully, this knowledge will improve the outcomes of this high-risk group of patients.

Core Tip: The management of diabetic nephropathy evolved substantially in recent years with the accumulation of evidence showing that sodium-glucose cotransporter 2 inhibitors and potentially finerenone prevent both renal function deterioration and cardiovascular events.

INTRODUCTION

Diabetes mellitus (DM) is currently placing an enormous burden on individuals, families, healthcare systems and countries. In 2000, DM affected 171 million people worldwide and this number is projected to increase to 366 million by 2030[1]. This increase will have an even more noticeable impact on low-income countries with inadequate infrastructures to tackle this pandemic[1]. Nephropathy is a major microvascular complication of DM and is characterized by a gradual increase of albuminuria and a progressive decline in glomerular filtration rate (GFR)[2,3]. Diabetic nephropathy (DN) is estimated to develop in approximately one in two patients with type 2 DM and in one third of those with type 1 DM[4-7]. Additionally, DM is the most frequent cause of end-stage renal disease (ESRD)[4,8-10]. Accordingly, the joint American Diabetes Association (ADA) and the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines endorse annual screening of patients with DM for DN[11]. Patients with DN are also at very high risk for cardiovascular events[12,13]. Given the rising prevalence of DM, the incidence of DN is also expected to markedly rise[1].

Currently, the standard care of DN is based on strict blood pressure and glycemic control even in patients without established DN[8,14,15]. Regarding glycemic control, the most recent KDIGO guidelines recommended an individualized glycated hemoglobin (HbA_1c) target of < 6.5% to < 8.0%[11]. The presence of comorbidities, macrovascular complications, stage of DN, life expectancy and hypoglycemia risk determine the preferable target of HbA_1c[16]. The ADA also recommends a HbA_1c goal of < 7.0% to prevent microvascular complications in patients without high risk for hypoglycemia[11,17,18].

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the antidiabetic agents of choice in patients with DN[11]. Their renoprotective effects appear to be partly related to natriuresis and osmotic diuresis due to excretion of glucose, which subsequently leads to a reduction in intraglomerular pressure[19]. Also, SGLT2 inhibitors reduce blood pressure without increasing heart rate via a mechanism that appears to be independent of diuresis[20]. These agents also appear to exert antiinflammatory effects in renal cells[21]. Large randomized controlled trials showed that SGLT2 inhibitors reduce the risk of progression to ESRD or cardiovascular death by 28%-39% in patients with DN[22-24]. Notably, these benefits were observed on a background of treatment with renin-angiotensin system inhibitors[22-24]. Moreover, the renoprotective effects of SGLT2 inhibitors were consistent across different levels of baseline GFR[22-24]. Patients with more pronounced albuminuria appeared to benefit more from the administration of these agents[22].

Recently, glucagon-like peptide 1 receptor (GLP-1R) agonists have shown beneficial cardiovascular and renal effects in patients with DN[25]. These agents reduce blood pressure and induce weight loss; these actions might partly underpin their renoprotective effects[26,27]. In addition, GLP-1R is predominately expressed in glomerular cells but not in renal tubules or collecting ducts[27]. In a diabetic mouse model, GLP-1R deficiency inhibited the progression of DN by preventing podocyte reduction, mesangial expansion, basement membrane thickening and albuminuria through an antioxidant effect[27]. In humans, GLP-1R agonists increased natriuresis through the inhibition of the sodium–hydrogen exchanger 3 in renal proximal tubular cells[26,28,29].The reduction of blood pressure can be partially explained by this mechanism[26-28]. In the Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes (AWARD)-7 trial (n = 577 patients with stage 3-4 DN), the decline in GFR was smaller in those treated with dulaglutide than in those treated with insulin glargine[29]. More recently, in an analysis of the randomized, placebo-controlled Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome Results (LEADER) trial, patients with DN (eGFR < 60 mL/min/1.73 m²) showed greater reductions in the risk for cardiovascular events compared with patients with preserved renal function[25].

Regarding blood pressure control, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) at the highest tolerated dose are the agents of choice in patients with DM, hypertension, and albuminuria or reduced GFR[16,30]. These medications reduce albuminuria and delay the progression to ESRD[31-34] by reducing vasoconstriction of the efferent arteriole and therefore hyperfiltration.

More recently, accumulating data support the benefit of adding finerenone, a nonsteroidal, selective antagonist of mineralocorticoid receptors (MR), to an ACEi or ARB in patients with DN[16]. In preclinical models, this agent reduced oxidative stress, inflammation and fibrosis in the glomerular cells and subsequently limited albuminuria[35]. In mice, transition from acute kidney injury to chronic kidney disease was prevented by finerenone treatment through the modulation of oxidative stress and inflammation[35]. In the Finerenone in Reducing Kidney Failure and Disease Pro-gression in Diabetic Kidney Disease trial (n = 5734 patients with DN on maximum dose of ACEi or ARB treatment), finerenone delayed the progression of DN and lowered the risk for cardiovascular events[36]. In comparison to eplerenone,a steroidal MR antagonist, finerenone has been shown to be more effective in patients with heart failure (HF), CKD and DM[37,38]. Of note, in patients with DN, serum potassium levels increased less in the finerenone group than in the eplerenone group[37,38]. Hemodynamic, not tubular, changes underpin the renoprotective effects of finerenone and this probably explains the lower risk for hyperkalemia, because potassium excretion is less likely to be affected by this agent[39]. Finerenone improves cardiovascular outcomes and reduces the incidence of new onset of HF in patients with CKD and T2D on a maximum tolerated dose with ACEI or ARB[40].

CONCLUSION

To conclude, the treatment of DN requires a multifaceted management. It is important to treat the patient as a whole and provide comprehensive care. In the absence of contraindications, all patients with DN should be treated with a SGLT2 inhibitor and an ACEi (or an ARB). The addition of finerenone should also be strongly considered. If glycemic and blood pressure targets are not achieved with these agents, additional treatment should be added. It remains to be established whether GLP-1R agonists will further improve the outcomes of these high-risk patients.