BACKGROUND: Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease (CKD) and kidney failure worldwide. Over the past three decades, management has evolved from strict glycemic and blood pressure control to targeted therapies that modify disease progression.
SUMMARY: The DCCT/EDIC (1993) confirmed the impact of intensive glycemic and multifactorial risk factor management. But the early 1990s established the foundation of nephroprotective therapy with the Captopril trial (1993) in type 1 diabetes and subsequent IRMA-1 (2001), IDNT (2001), and the RENAAL (2001) studies established renin-angiotensin-system (RAAS) blockade as the first disease-specific therapy. More than a decade later, sodium-glucose cotransporter-2 (SGLT2) inhibitors transformed care, with EMPA-REG OUTCOME (2015) and CANVAS (2017) studies first demonstrating kidney benefits as secondary outcomes, which were confirmed in subsequent dedicated kidney trials: CREDENCE (2019), DAPA-CKD (2020), and EMPA-KIDNEY (2022) studies, demonstrating consistent reductions in kidney failure and cardiovascular mortality. Finerenone further advanced outcomes in FIDELIO-DKD (2020) and FIGARO-DKD (2021), and combination therapy with SGLT2 inhibition showed additive benefit in the CONFIDENCE (2025) study. Most recently, the FLOW (2024) trial confirmed glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as promising fourth pillar of nephroprotective therapies.
KEY MESSAGES: Together, these advances, termed the "Fantastic Four", have redefined standards of care in DKD. This review synthesizes pivotal clinical trials and highlights evolving strategies to guide individualized treatment and future research.
