Improving the residual risk of renal and cardiovascular outcomes in diabetic kidney disease: A review of pathophysiology, mechanisms, and evidence from recent trials

Abstract

Based on global estimates, almost 10% of adults have diabetes, of whom 40% are estimated to also have chronic kidney disease (CKD). Almost 2 decades ago, treatments targeting the renin-angiotensin system (RAS) were shown to slow the progression of kidney disease. More recently, studies have reported the additive benefits of antihyperglycaemic sodium-glucose co-transporter-2 inhibitors in combination with RAS inhibitors on both CKD progression and cardiovascular outcomes. However, these recent data also showed that patients continue to progress to kidney failure or die from kidney- or cardiovascular-related causes. Therefore, new agents are needed to address this continuing risk. Overactivation of the mineralocorticoid (MR) receptor contributes to kidney inflammation and fibrosis, suggesting that it is an appropriate treatment target in patients with diabetes and CKD. Novel, selective non-steroidal MR antagonists are being studied in these patients, and the results of two large recently completed clinical trials have shown that one such treatment, finerenone, significantly reduces CKD progression and cardiovascular events compared with standard of care. This review summarizes the pathogenic mechanisms of CKD in type 2 diabetes and examines the potential benefit of novel disease-modifying agents that target inflammatory and fibrotic factors in these patients.

Keywords: albuminuria; chronic; diabetes mellitus; diabetic nephropathies; glomerular filtration rate; mineralocorticoid receptor antagonist; renal insufficiency; renin-angiotensin system; sodium-glucose co-transporter-2 inhibitors.

FIGURE 1

Three interconnected processes contribute to the development and progression of chronic kidney disease in patients with type 2 diabetes. AGE, advanced glycation end product; CTGF, connective tissue growth factor; CXCL‐16, C‐X‐C motif chemokine ligand‐16; ET‐1, endothelin‐1; FGF‐23, fibroblast growth factor 23; ICAM‐1, intercellular adhesion molecule‐1; IL, interleukin; KRIS, kidney risk inflammatory signature; NO, nitric oxide; MCP‐1, monocyte chemoattractant protein‐1; RAGE, receptor for advanced glycation end products; RAS, renin‐angiotensin system; ROS, reactive oxygen species; SAA, serum amyloid A; SGLT‐2, sodium‐glucose co‐transporter‐2; TGF‐β, transforming growth factor beta; TNF‐α, tumour necrosis factor alpha; TNF‐R1/2, tumour necrosis factor receptor 1/2; VCAM‐1, vascular cell adhesion molecule‐1; VEGFA, vascular endothelial growth factor A

FIGURE 2

Residual risk for the primary composite endpoint at 30 months in RENAAL, IDNT, CREDENCE, and DAPA‐CKD. CI, confidence interval; eGFR, estimated glomerular filtration rate

FIGURE 3

Pathophysiological mechanisms involved in the deleterious effects of mineralocorticoid receptor activation in the heart and kidneys. AP‐1, activator protein‐1; MAPK, mitogen‐activated protein kinase; NADPH, nicotinamide adenine dinucleotide phosphate; NF‐κB, nuclear factor‐κB; SGK‐1, serum‐ and glucocorticoid‐induced protein kinase‐1

FIGURE 4

Key pharmacological differences between steroidal and non‐steroidal mineralocorticoid receptor antagonists