Management of Diabetic Kidney Disease: The Era of the Four Pillars

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Until 2019, management of chronic kidney disease (CKD) in the setting of diabetes was limited to the renin-angiotensin system (RAS) blockade, in conjunction with blood pressure and glycemic control (1). With the CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) trial (2), canagliflozin became the first new agent to be approved for the management of type 2 diabetes (T2D) and CKD, swiftly followed by dapagliflozin and empagliflozin. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are currently a cornerstone in the management of T2D and CKD in addition to atherosclerotic cardiovascular disease and heart failure (3). More recently, with FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease] Trial Programme Analysis), nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) have also been approved for the management of T2D and albuminuric CKD as an add-on to the RAS blockade and SGLT2 inhibitors (4). Finally, with highly anticipated results of the FLOW (A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease) trial (5), in which semaglutide lowered the risk of kidney events by 24%, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are expected to be the fourth pillar of CKD management in the setting of T2D. GLP-1RAs are already recommended to be used in the setting of T2D and atherosclerotic cardiovascular disease (6).

SGLT2 inhibitors, nsMRAs, and GLP-1RAs are being increasingly used in combination in the management of T2D and albuminuric CKD (7). However, the combined use of these agents has yet to be studied in large outcome trials. To estimate the combined cardiorenal-protective effects of these agents, Neuen et al. (8) performed an age-based analysis using pooled participant-level data from the CANVAS (Canagliflozin Cardiovascular Assessment) program, CREDENCE, FIGARO-DKD, and FIDELIO-DKD, as well as a trial-level meta-analysis of eight GLP-1RA outcome trials. Conventional care with the RAS blockade served as the control therapy in this analysis. The primary outcome was major adverse cardiovascular events (MACEs), with secondary heart failure hospitalization and CKD progression outcomes, and an assumption of independent and additive effects of all therapeutic classes. Compared with conventional care, combination therapy was estimated to have a hazard ratio (HR) of 0.65 (95% confidence interval [CI], 0.55–0.76) with respect to MACEs and a HR of 0.42 (95% CI, 0.31–0.56) with respect to kidney disease progression. When estimating absolute risk reductions with combination therapy, 23 patients would need to be treated for 3 years to prevent one MACE and one CKD progression outcome, and 33 patients would need to be treated to prevent one death. These gains were noted across all age groups studied, with the greatest absolute benefit noted in younger patients.

The combined use of SGLT2 inhibitors, nsMRAs, and GLP-1RAs will soon be recommended by cardiology, nephrology, and endocrinology guidelines in the management of T2D and CKD. Faced with increasing therapeutic options and the associated “pill burden,” side-effect profiles, and economic costs, patients and practitioners alike require adequate information to guide clinical decision-making. Although trials studying these agents in combination are underway, the analysis by Neuen and colleagues (8) offers an early estimate of anticipated benefits in cardiorenal outcomes in this new era of diabetic kidney disease management.