Dapagliflozin - Five Years since CKD Approval: Revisiting 5 Milestones in CKD Care

Five years ago, the approval of dapagliflozin for chronic kidney disease (CKD) by the US FDA marked a pivotal shift in nephrology practice. ¹ What began as a glucose-lowering therapy for type 2 diabetes has since evolved into a cornerstone of nephron-protection, cardiorenal protection, fundamentally changing how clinicians approach CKD management. ² As the evidence base continues to expand, we revisit five key milestones on dapagliflozin that reshaped the treatment paradigm and redefined long-term kidney care.

Milestone 1: Moving from Glycemic Control to Kidney Protection in Diabetes

Prior to the advent of SGLT2 inhibitors, CKD management largely relied on renin–angiotensin–aldosterone system (RAAS) blockade, with few therapies demonstrating meaningful nephro-protection beyond blood pressure and glycemic control. Dapagliflozin was initially developed as a glucose-lowering agent, but the DAPA-CKD trial findings marked a paradigm shift by establishing kidney protection as a therapeutic utility. Among 4,304 patients with CKD, dapagliflozin significantly reduced the relative risk of the primary composite outcome of sustained ≥50% decline in eGFR, end-stage kidney disease (ESKD), or death from renal or cardiovascular causes by 39% compared with placebo (HR 0.61; 95% CI 0.51–0.72; p<0.001). ² More importantly, it challenged the long-held perception that SGLT2 inhibitors were primarily glucose-lowering drugs, ushering in a new era of disease-modifying, organ-protective therapy in CKD.

Milestone 2: Expanding Role in CKD Treatment Beyond Diabetic Kidney Disease (DKD)

DAPA-CKD marked another historic advance by demonstrating that the benefits of dapagliflozin extended beyond patients with type 2 diabetes. Nearly one-third of enrolled participants did not have diabetes, yet kidney and cardiovascular benefits remained consistent irrespective of glycemic status. In patients without diabetes, dapagliflozin reduced the relative risk of the primary composite endpoint by 50% compared with placebo (HR 0.50; 95% CI 0.35–0.72). ² These findings fundamentally shifted the treatment approach, establishing SGLT2 inhibitors as kidney-protective therapies rather than simply glucose-lowering agents. Importantly, subsequent analyses suggested that by slowing long-term eGFR decline, dapagliflozin could delay progression to end-stage kidney disease (ESKD) by approximately eight years in a typical DAPA-CKD patient, highlighting its significant disease-modifying potential. ³

Milestone 3: Redefining the Cardio-Renal Treatment Continuum

Conventionally, CKD and cardiovascular disease were managed as separate entities despite their close pathophysiological interaction. From a therapeutic approach perspective, dapagliflozin helped redefine this paradigm by demonstrating clinically meaningful benefits across both organ systems. In DAPA-CKD, dapagliflozin significantly reduced the relative risk of the primary composite outcome of sustained ≥50% decline in eGFR, ESKD, or death from renal or cardiovascular causes by 39% compared with placebo (HR 0.61; 95% CI 0.51–0.72; p<0.001). ² It also reduced the relative risk of hospitalization for heart failure or cardiovascular death by 29% (HR 0.71; 95% CI 0.55–0.92; p=0.009). ¹ Subsequent meta-analyses confirmed that SGLT2 inhibitors consistently reduce the risks of CKD progression, acute kidney injury, cardiovascular death, and HF hospitalization across diverse CKD populations. ⁴ More recently, expert reviews have emphasized that these benefits are observed across a broad range of eGFR levels and CKD etiologies, supporting a unified cardiorenal treatment strategy rather than organ-specific management. ⁵ Collectively, these findings supported the concept of cardiorenal care continuum as a central principle of modern CKD care and established dapagliflozin as a cornerstone of integrated risk reduction.

Milestone 4: Earlier Intervention and Broader CKD Eligibility Allowing Better Outcomes

A major evolution over the past five years has been the growing evidence supporting on the initiation of dapagliflozin in the CKD care continuum. Initial concerns regarding reduced glycemic efficacy at lower eGFR levels have gradually given way to recognition that its kidney-protective effects are largely independent of glucose lowering. ^{6, 7} Real-world evidence from the OPTIMISE-CKD study further demonstrated the feasibility of early dapagliflozin use in routine clinical practice, supporting favorable kidney function trajectories and cardiorenal outcomes across a broad CKD population. ⁷ Concurrently, accumulating evidence has expanded the understanding of dapagliflozin's benefits across CKD stages, reinforcing its role as a disease-modifying therapy rather than a late-stage intervention. ⁸ Reflecting this paradigm shift, recent NICE 2026 recommendations have broadened access to SGLT2i; including dapagliflozin, highlighting the growing consensus that earlier treatment offers the greatest opportunity to preserve kidney function and delay kidney failure.

Figure 1: Consistent kidney protection with Dapagliflozin across baseline eGFR categories in patients with (A) Diabetes and (B) without Diabetes ⁹

Milestone 5: Newer Pleiotropic Effects and Shaping the Future of CKD Care

Perhaps the most enduring impact of dapagliflozin has been its role in redefining the future of CKD care. The KDIGO 2022 guidelines established SGLT2 inhibitors as foundational therapy in CKD, reflecting a shift from supportive care toward disease modification. ¹⁰ Beyond slowing eGFR decline, dapagliflozin restores tubuloglomerular feedback, reduces intraglomerular pressure, improves renal oxygen utilization, and attenuates oxidative stress, inflammation, and fibrosis—key drivers of progressive nephron loss. These pleiotropic effects provide a biological basis for sustained kidney protection across diverse CKD populations, including those without diabetes. ¹⁰ More recently, attention has turned to combination strategies, particularly SGLT2 inhibitors with finerenone, which target complementary pathways involved in CKD progression and residual cardiorenal risk. ^11-14 Concurrently, emerging evidence suggests that future CKD management may increasingly rely on patient-specific risk profiles and disease phenotypes. ¹⁵ Together, these advances position dapagliflozin as a catalyst for a new era of precision cardiorenal care.

Final Message

Five years after its CKD approval, dapagliflozin has evolved from a glucose-lowering agent to a foundational disease-modifying therapy for nephron-protection. Clinicians may consider early initiation of dapagliflozin in eligible CKD patients or high-risk for CKD patients, to optimize kidney outcomes and cardiorenal protection. Beyond slowing eGFR decline, its benefits extend to reducing HF hospitalization and cardiovascular risk, allowing a unifying approach towards cardiorenal care as an integral to modern CKD management.