Dapagliflozin in patients with chronic kidney disease

Dapagliflozin in patients with chronic kidney disease

• Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou F-F, et al. N Engl J Med. 2020;383:1436–46. doi:10.1056/NEJMoa2024816

Chronic kidney disease (CKD) is a major public health concern with an increasing prevalence worldwide. In 2017, global prevalence was estimated at 9.1% – roughly 700 million people¹.

CKD is known to be a leading cause of increased morbidity and mortality, projected to be responsible for up to 4 million deaths by 2040¹, yet treatment options are limited

There is a significant unmet need for treatments that will prevent, reverse or slow the progression of CKD. A key barrier to broadening treatment options for CKD has been the general tendency to exclude people with impaired kidney function from clinical trials for interventions to treat related chronic conditions such as type 2 diabetes or cardiovascular disease^2,3; indeed, up to 75% of clinical trials exclude people with CKD². To address this gap, Heerspink and colleagues designed the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial specifically to evaluate the efficacy and safety of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, for the treatment of CKD.

SGLT2 inhibitors are glucose-lowering drugs that block resorption of glucose from the proximal tubule of the kidneys and increase glucose excretion. This class of drugs, indicated for the treatment of type 2 diabetes, includes empagliflozin, canagliflozin and dapagliflozin. A series of clinical trials initiated to evaluate cardiovascular safety of SGLT2 inhibitors serendipitously found that these agents slowed the progression of renal and cardiovascular disease in patients with type 2 diabetes^4,5. Subsequent clinical trials confirmed that SGLT2 inhibitors conferred cardiovascular and renal protection in patients with type 2 diabetes^6–8; however, the cardioreno-protective effects of SGLT2 inhibitors were attributed to mechanisms that were independent of their glucose-lowering effects. Heerspink and colleagues reasoned, therefore, that SGLT2 inhibitors could conceivably preserve kidney function in non-diabetic kidney disease. They recruited patients with CKD, with or without co-existing type 2 diabetes, to participate in the DAPA-CKD trial⁹.

What did the DAPA-CKD investigators do?

DAPA-CKD was a randomised, double-blind, placebo-controlled clinical trial conducted at 386 sites in 21 countries (Figure 1).

Figure 1. Dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) clinical trial (Adapted¹⁰). ANCA, anti-neutrophilic cytoplasmic autoantibodies; eGFR, estimated glomerular filtration rate; uACR, urinary albumin-to-creatinine ratio.

Adults aged 18 years or older, with or without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73 m² and a urinary albumin-to-creatinine ratio of 200–5,000 were recruited to the study. Following screening, 4,304 participants were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo. A minimum of 30% of participants for the populations with and without type 2 diabetes were recruited to each group. Follow-up visits were conducted at 2 weeks, 2, 4 and 8 months after randomisation, and subsequently at intervals of 4 months. The primary endpoint, a composite outcome, was the first occurrence of a decline in eGFR of at least 50%, onset of end-stage kidney disease, or death from renal or cardiovascular causes. Secondary endpoints were a composite kidney outcome of a sustained decline in eGFR of at least 50%, end-stage kidney disease, or death from renal causes; a composite cardiovascular outcome of hospitalisation for heart failure or death from cardiovascular causes; and death from any cause. The investigators estimated that 681 primary outcome events would be needed to detect a 22% reduction in relative risk in the dapagliflozin group, compared with placebo group (hazard ratio [HR] of 0.78).

What did the DAPA-CKD investigators find?

Primary composite outcomes and renal-specific composite outcomes are shown in Figure 2.

Figure 2. Primary composite outcomes and secondary renal-specific outcomes of the DAPA-CKD trial (Adapted⁹). CI, confidence intervals; HR, hazard ratio.

The primary composite outcome occurred in 9.2% (197 participants) of the dapagliflozin group and 14.5% (312 participants) of the placebo group, with an HR of 0.61 (95% confidence interval [CI], 0.51–0.72; P<0.001). This meant that relative risk was 39% lower in the dapagliflozin group than in the placebo group, which exceeded the difference of 22% estimated before commencing the trial. HRs for the primary composite outcome comparing dapagliflozin and placebo were 0.64 (95% CI, 0.52–0.79) in participants with type 2 diabetes and 0.50 (95% CI, 0.35–0.72) in those without type 2 diabetes. HRs for the secondary endpoints were 0.56 (95% CI, 0.45–0.68; P<0.001) for composite kidney outcome and 0.71 (95% CI, 0.55–0.92; P=0.009) for composite of death from cardiovascular causes or hospitalization for heart failure (Figure 2). In view of these positive results and clear efficacy of dapagliflozin, an independent data monitoring committee recommended early termination of the trial.

There were 101 deaths (4.7%) in the dapagliflozin group and 146 (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53–0.88; P=0.004). The safety of dapagliflozin was confirmed as no differences were observed in the incidence of adverse events and serious adverse events between the dapagliflozin and placebo groups.

What was learned from the DAPA-CKD trial?

Dapagliflozin significantly reduced the risks of a decline in kidney function, progression to end-stage kidney disease and death from renal or cardiovascular causes in patients with CKD, with or without co-existing type 2 diabetes

The reduction in relative risk exceeded the expected reduction and was achieved with fewer primary outcome events than originally projected. The results of this clinical trial confirm that dapagliflozin is safe and effective in the treatment of CKD.

Learn more about CKD treatments

References

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2. Webster AC, Nagler E V., Morton RL, Masson P. Chronic Kidney Disease. Lancet. 2017;389(10075):1238–1252.
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7. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347–357.
8. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295–2306.
9. Heerspink HJL, Stefánsson B V., Correa-Rotter R, Chertow GM, Greene T, Hou F-F, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436–1446.
10. Heerspink HJL, Stefansson B V, Chertow GM, Correa-Rotter R, Greene T, Hou F-F, et al. Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020;35(2):274–282.