Beyond diabetes: FDA now approves dapagliflozin for the treatment of chronic kidney disease

29 Jun 2021

Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor that was initially approved in 2014 for the treatment of type 2 diabetes mellitus (T2DM) and subsequently for heart failure with reduced ejection fraction (HFrEF), has recently received yet another approved indication by the United States Food and Drug Administration (FDA) for the risk reduction of kidney function decline, kidney failure, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease (CKD) who are at risk of disease progression.1,2 This approval was based on the favorable results of the DAPA-CKD trial of which dapagliflozin had significantly lowered the risk of a composite of a sustained decline in the estimated glomerular filtration rate (eGFR) of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes, among patients with CKD regardless of T2DM status when compared to placebo.3

Despite being recognized as one of the leading public health problems worldwide with an increased risk of accelerated cardiovascular disease and death, CKD is still a disease that lacks clinical trials when compared to other medical conditions.4-6 Currently, only limited drug classes such as angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers had demonstrated clinical benefit by slowing the deterioration of renal function.6,7 Therefore, there is a need to conduct more clinical trials in CKD to uncover potentially favorable therapeutic options for this condition.

While the underlying mechanism remains poorly understood, emerging data from clinical trials showed that SGLT2 inhibitors confer favorable outcomes to the kidney and the cardiovascular system that are independent of their blood glucose-lowering capability.3 In this regard, the SGLT2 inhibitor, dapagliflozin, which was already approved for the treatments of T2DM as well as HFrEF regardless of T2DM, was further investigated in the CKD population, with or without T2DM, under the DAPA-CKD trial.3

DAPA-CKD was a randomized, double-blind, placebo-controlled, multicenter trial that randomly assigned 4,304 adults with an eGFR of 25-75mL/min/1.73m2 and a urinary albumin-to-creatinine ratio of 200-5,000, regardless of T2DM diagnosis, to receive dapaglifozin 10mg once daily (n=2,152) or placebo (n=2,152).3 The primary assessment was a composite outcome of a sustained decline in eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.3

With a median assessment duration of 2.4 years, a significantly lower proportion of patients receiving dapagloflizin experienced the primary composite outcome than those receiving placebo (9.2% vs. 14.5%, HR=0.61; 95% CI: 0.51-0.72; p<0.001).3 Similar significant outcomes were also observed for the renal-specific composite outcome of a sustained decline in the eGFR of at least 50%, end-stage kidney disease, or death from renal causes (HR=0.56; 95% CI: 0.45-0.68; p<0.001), as well as the cardiovascular-specific composite outcome of death from cardiovascular causes or hospitalization for heart failure (HR=0.71; 95% CI: 0.55-0.92; p<0.009).3 Importantly, the benefit of dapagliflozin was independent of T2DM status and was consistent across participants with (HR=0.64; 95% CI: 0.52-0.79) or without T2DM (HR=0.50; 95% CI: 0.35-0.72).3

In terms of safety, the incidences of adverse events (AEs) and serious AEs were comparable between the dapagliflozin and placebo groups.3 Surprisingly, diabetic ketoacidosis was not reported in any participants receiving dapagliflozin but in 2 participants receiving placebo.3 Although death did occur in the dapagliflozin arm, it was significantly less than that of placebo (4.7% vs. 6.8%; 95% CI: 0.53-0.88; p=0.004).3

In fact, the trial was terminated early because of the profound efficacy demonstrated by dapagliflozin.3 With these favorable data substantiating the benefit of dapagliflozin in treating and preventing CKD, FDA granted approval of dapagliflozin in treatment CKD regardless of diabetes status.2 Dr. Aliza Thompson, Deputy Director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, concluded, “CKD is an important public health issue, and there is a significant unmet need for therapies that slow disease progression and improve outcomes. Today’s approval of dapagliflozin for the treatment of CKD is an important step forward in helping people living with kidney disease.”

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