Patient Population:

Inclusion criteria:

  • Adults (≥18 years) with or without Type 2 diabetes (T2D) with an estimated glomerular filtration rate (eGFR) of 25 to 75 milliliters per minute per 1.73 m2 of body-surface area (mL/min/1.73m2) and a urinary albumin-to-creatinine ratio (UACR) measured in milligrams to grams of 200 to 5,000.

  • Participants were required to be receiving a stable dose of an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for at least four weeks before screening; those with documented reasons for being unable to take ACE inhibitors or ARBs were allowed to participate.

Exclusion criteria:

  • Adults with documented diagnosis of Type 1 diabetes, receiving therapy with a sodium glucose co-transporter 2 (SGLT2) inhibitor within eight weeks prior to enrollment, polycystic kidney disease, lupus nephritis or antineutrophil cytoplasmic antibody-associated vasculitis and immunotherapy for primary or secondary kidney disease within six months before enrollment.

Intervention: (n=2,152): Dapagliflozin 10 mg by mouth daily

Comparison: (n=2,152): Matching placebo by mouth daily

Outcome: The primary outcome was the composite of the first occurrence of any of the following assessed in a time-toevent analysis: a sustained 50% decline in eGFR (confirmed with a second serum creatinine measurement after ≥28 days), the onset of end-stage renal disease (ESRD, defined by maintenance dialysis for ≥28 days, kidney transplantation or an eGFR of <15 mL/min/1.73m2 confirmed by a second measurement after ≥28 days) or death from renal or cardiovascular causes.

The primary composite outcome of a sustained decline in eGFR of at least 50%, the onset of ESRD and death from renal or cardiovascular outcomes was observed in 197 participants (9.2%) in the dapagliflozin group and 312 participants (14.5%) in the placebo group (HR, 0.61; 95% CI 0.51 – 0.72; p <0.001). The reduction of the secondary renal outcome was similar in magnitude as the primary composite outcome, further demonstrating dapagliflozin’s favorability regarding renal function. The significance of the primary composite outcome was likely driven by the individual outcomes of sustained decline in eGFR and the onset of ESRD since both components demonstrated statistical significance. The statistical parameters for the outcomes of death from renal or cardiovascular causes were either not provided or not shown to be statistically significant. The secondary composite outcome of a decline in eGFR of at least 50%, ESRD or death from renal causes was observed in 142 participants (6.6%) in the dapagliflozin group and 243 participants (11.3%) in the placebo group (HR 0.56; 95% CI 0.45 – 0.68; p <0.001), further demonstrating dapagliflozin’s favorability regarding renal function.

During the first 2 weeks of treatment, there was a greater reduction in eGFR in the dapagliflozin group compared to the placebo group (−3.97±0.15 vs. −0.82±0.15 mL/min/1.73m2). Thereafter, the annual change in the mean eGFR was smaller with dapagliflozin versus placebo (−1.67±0.11 and −3.59±0.11 mL/min/1.73m2, respectively), with a between-group difference of 1.92 mL/min/1.73m2 per year (95% CI, 1.61 to 2.24). Data showed that use of dapagliflozin slowed the rate of eGFR decline compared to placebo 36 months after randomization.

Serious adverse events (SAE) occurred more frequently in the placebo group (33.9%) compared to dapagliflozin group (29.5%) (p=0.002). There were fewer hypoglycemic events in the dapagliflozin group compared to the placebo group, 0.7% versus 1.3% (p=0.04), respectively. However, there was a greater incidence of volume depletion in the dapagliflozin group compared to the placebo group, 5.9% versus 4.2% (p=0.01), respectively. There was no difference in incidence of amputation, diabetic ketoacidosis or fracture, which are other AEs associated with SGLT2 inhibitors. Data demonstrated dapagliflozin has a favorable safety profile.

Healthcare Professional Summary

DAPA-CKD, an international, multi-center, double-blinded, randomized, placebo-controlled trial analyzed with intention-to-treat principle, evaluated the efficacy and safety of dapagliflozin in patients with an eGFR of 25 to 75 mL/min/1.73m2 and UACR between 200 and 5,000 mg/g regardless of T2D diagnosis to observe its impact on renal outcomes. Analysis of the study design suggests that the trial is valid and has an overall low risk of bias. This study showed that the use of dapagliflozin had a 37% relative risk reduction and 5.3% absolute risk reduction of the primary outcome, with an NNT of 19 when compared to placebo. It was also well tolerated with a lower incidence of major hypoglycemia, however, had a greater incidence of volume depletion compared to placebo. Since there was a greater reduction in eGFR in the dapagliflozin group two weeks after treatment initiation, clinicians may need to closely monitor the patients with higher risk of acute kidney injury during that period. The rate of eGFR decline was slower afterwards compared to the placebo group and dapagliflozin was shown to have an overall renally protective effect. With its efficacy and safety profile, this study showed dapagliflozin’s renal protective benefit in patients with compromised kidney function regardless of diagnosis of T2D. ACE inhibitors and ARBs have long been the sole treatment options for patients with CKD; however, the results of this trial can potentially expand those options to include SGLT2 inhibitors to further improve clinical outcomes in this population.

Patient Summary

Dapagliflozin is a once-daily oral medication mainly used for patients with Type 2 diabetes; however, this study showed that patients with poor kidney function with or without diabetes who took this medication had a lower chance of worsening kidney function, requiring hemodialysis and death due to heart or kidney complications compared to those who did not take it. The results of study are not applicable to patients with Type 1 diabetes, kidney disease caused by lupus or other auto-immune diseases. Dapagliflozin was also well tolerated by study participants; therefore, it can be safe and effective in providing kidney protection in patients with chronic kidney disease.

About the Editor

Cynthia Jackevicius, BScPhm, PharmD, MSc, BCPS, BCCP, FCSHP, FAHA, FCCP, FCCS, FACC, a Professor of Pharmacy Practice at Western University of Health Sciences, is the Evidence-Based Practice Section Editor. Dr. Jackevicius teaches evidence-based practice skills to health care professionals. She advocates for the adoption of an evidence-based practice, incorporating the best available evidence, patients’ values and preferences, and clinicians’ expertise into clinical decision-making. She has no conflicts of interest to report.