SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions

Abstract

In 2020, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial first demonstrated that inhibition of the sodium–glucose transporter-2 (SGLT2) with dapagliflozin attenuates the progression of chronic kidney disease (CKD) with proteinuria in patients with or without diabetes at an unprecedented effect size. These results have far-reaching implications for a series of traditional concepts in Nephrology. It now became obvious that CKD with and without diabetes involves a predominant SGLT2-driven pathophysiology compared with the other pathogenic pathways currently under consideration. As SGLT2 inhibition is similarly efficacious in diabetic and non-diabetic CKD with proteinuria, treating CKD rather than ‘diabetic nephropathy’ becomes the central paradigm. Indeed, in older adults with type 2 diabetes, CKD is rather of multifactorial origin. As the DAPA-CKD trial included more patients with immunoglobulin A nephropathy (IgAN) than any of the previous IgAN trials, dual renin-angiotensin/SGLT2 inhibition may become the new standard. The same applies for patients with podocytopathy-related focal segmental glomerulosclerosis lesions. From now on, IgAN and podocytopathy trials without SGLT2 inhibition as background therapy and without glomerular filtration rate decline as primary outcome criterion will be of limited value. These and other potential implications will trigger broad discussions and secondary research activities with conclusions difficult to predict today. However, one is for sure: Nephrology after the DAPA-CKD trial will be not the same as it was before. Finally!

How will artificial intelligence and bioinformatics change our understanding of IgA Nephropathy in the next decade?

“…A multi-organ systematic analysis of IgAN, particularly incorporating different omics levels, spatial context [114], the microbiome [7], and histology [115] will likely shed light on the open questions around the pathophysiology of IgAN. This will ultimately improve treatment and, e.g., might stratify which patients would eventually benefit from systemic immunosuppression [116], gut-targeted immunosuppression [5] particularly against supportive care eventually combined with new drugs like the sodium-glucose transport protein 2 (SGLT2) inhibitors [117]. In summary, we believe that the application of bioinformatics and artificial intelligence, although there is still a long way to go, will enable personalized precision medicine in IgAN.…”

Glomerular Diseases in Diabetic Patients: Implications for Diagnosis and Management

“…The recent multicentre DAPA-CKD trial [ 39 ] with 4304 participants analyzed the effect of dapagliflozin on sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney-related or cardiovascular death. During this study, 115 patients with FSGS lesions confirmed by kidney biopsy were included [ 40 ], although subgroup analyses of primary and secondary forms are not yet available. From these 115 patients with FSGS, 22 patients had T2D [ 41 ], notably a greater sample than in the DUET study.…”

“…From these 115 patients with FSGS, 22 patients had T2D [ 41 ], notably a greater sample than in the DUET study. It is tempting to speculate that patients with FSGS lesions could benefit from dapagliflozin in terms of CKD progression [ 40 ], but full subgroup analysis of primary and secondary outcomes of patients with FSGS has still not been published. DAPA-CKD should provide exciting results backed by an important sample size and long term follow up.…”

“…The DAPA-CKD trial [ 39 ] included 270 patients with IgAN (38 with concomitant T2D) [ 40 ] and can be considered to be the largest IgAN trial so far, with the potential to provide robust evidence supporting the role of SGLT2 inhibitors in the progression of CKD in IgAN patients [ 41 ]. A full subgroup analysis of IgAN patients in the DAPA-CKD trial has recently been published [ 46 ].…”

“…Little evidence exists to guide management of primary glomerular diseases in diabetic patients due to underrepresentation in clinical trials of glomerular diseases. The DAPA-CKD trial included 43 patients with MN (10 with concomitant T2D) and 11 patients with minimal change disease (2 patients with T2D) [ 39 , 40 ]. The MENTOR trial [ 50 ], a randomized controlled trial that found rituximab to be noninferior to cyclosporine in treating patients with MN, excluded patients with diabetes.…”