APCN 2021: New paradigm in CKD treatment with SGLT2 inhibitors
Early screening of CKD
In 2017, there were 1–2 million deaths from CKD – a 41.5 percent increase from 1990. “The disease burden of CKD has continued to increase without improvement in mortality,” said Tang.
Kidney disease is associated with cardiovascular (CV) disease, diabetes, high blood pressure (BP), and other complications. [ISN-KDIGO screening booklet] With early screening, CKD is largely preventable and can be treated with readily available and inexpensive medications. Despite this, CKD awareness remains low in many parts of the world, and the condition and its related risk factors remain prevalent. [Lancet 2020;395:809-733]
“CKD awareness is low even among community-dwelling adults with kidney disease,” said Tang. “Awareness of CKD is moderately associated with greater poverty, having health insurance, inadequate health literacy, and more advanced CKD stage.” [Kidney Med 2019;1:43-50]
“Many patients may have ‘silent’ kidney disease, which may not be identified or treated until progression into end-stage kidney disease [ESKD],” Tang added.
Who to screen?
The population-based Screening for Hong Kong Asymptomatic Renal Population and Evaluation (SHARE) programme was set up with the goal of identifying undetected renal disease in asymptomatic adults. Results showed that 33 percent of adults aged >60 years had either hypertension or urine abnormalities, compared with 24 percent and 9.7 percent of adults aged 41–60 years and 20–40 years, respectively. Effective CKD screening programmes at the primary care level may help identify such asymptomatic adults for further evaluation. [Kidney Intl 2005;67:536-540]
“Regular monitoring should be carried out to prevent CKD in adults with diabetes mellitus [DM], hypertension, autoimmune diseases, and those with family history of CKD,” Tang pointed out.
Benefits of education
“A three-tiered approach comprising patient education, public education and physician education is needed to increase CKD awareness,” said Tang. “Patients with greater awareness of CKD are shown to have improved BP control, increased use of self-care dialysis modalities, as well as increased knowledge of NSAID-associated risks and intentions to limit NSAID use.” National programmes and CKD guidelines are critical for patient care and may help in deferring the initiation of dialysis treatment. [Clin J Am Soc Nephrol 2016;11:694-703]
New direction in CKD treatment
Until recently, the only classes of medication specifically proven to slow the progression of CKD were angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. [N Engl J Med 2001;345:851-860; Lancet 1999; 354:359-364]
More recently, trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promising results in renal and CV protection in patients with type 2 DM (T2DM). “The CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation] trial, for example, showed that patients with T2DM and CKD who received canagliflozin had a lower risk of the primary composite outcome of ESKD, and death from renal or CV causes,” stated Wheeler. [N Engl J Med 2020;383:1436-1446; N Engl J Med 2019;380:2295-2306]
The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial is the first dedicated renal outcome trial assessing the effects of an SGLT2 inhibitor, namely, dapagliflozin, in patients with CKD with or without T2DM. The trial was designed to assess the long-term efficacy and safety of dapagliflozin in patients with CKD in 386 sites across 21 countries. A total of 4,094 trial participants were randomly assigned to receive either dapagliflozin 10 mg QD or placebo. [N Engl J Med 2020;383:1436-1446]
Results of DAPA-CKD showed a relative risk reduction of 39 percent with dapagliflozin vs placebo in the primary outcome of a sustained ≥50 percent decline in estimated glomerular filtration rate (eGFR), ESKD, or death from renal or CV causes (9.2 percent vs 14.5 percent; hazard ratio [HR], 0.61; 95 percent confidence interval [CI], 0.51 to 0.72; p<0.001), with an absolute risk reduction of 5.3 percent, and a number needed to treat of 19. (Figure)
Significant risk reductions in secondary endpoints, including the renal-specific endpoint (composite of sustained ≥50 percent eGFR decline, ESKD or renal death; HR, 0.56; 95 percent CI, 0.45 to 0.68; p<0.001), composite CV endpoint (CV death or hospitalization for heart failure [HHF]; HR, 0.71; 95 percent CI, 0.55 to 0.92; p=0.009), and all-cause mortality (HR, 0.69; 95 percent CI, 0.53 to 0.88; p=0.004), were also found with dapagliflozin vs placebo.
“Dapagliflozin’s effects on the trial’s primary and secondary endpoints were similar between patients with and without T2DM, and across CKD aetiologies [except for CV death or HHF in patients with ischaemic/hypertensive CKD],” Wheeler noted. “In addition, dapaglifloz in attenuated the decline in eGFR over time, with a between-group eGFR slope difference of 0.93 mL/min/1.73 m2/year [95 percent CI, 0.61 to 1.25].”
The incidence of serious adverse events (AEs) and any AEs was similar between the dapagliflozin and placebo groups, without unexpected safety issues.
“Data from the DAPA-CKD trial supports the use of dapagliflozin as an addition to the treatment regimen for patients with CKD,” said Wheeler.
Dapagliflozin approval for CKD in the US & EU
Dapagliflozin was recently approved in the US and EU for treatment of CKD in patients with or without T2DM, based on results of the DAPA-CKD trial. Its use in CKD treatment is also currently under review in several other countries. Currently, dapagliflozin is indicated in Hong Kong as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM, and for the treatment of symptomatic chronic heart failure with reduced ejection fraction (HFrEF) in adults regardless of DM status. [N Engl J Med 2020;383:1436-1446; https://www.astrazeneca.com/media-centre/press-releases/2021/forxiga-approved-in-the-eu-for-ckd.html; Forxiga Hong Kong Prescribing Information, May 2021]
Early screening and programmes to increase awareness are of paramount importance in reducing CKD burden and mortality. Results of the DAPA-CKD trial have demonstrated the benefits of the SGLT2 inhibitor, dapagliflozin, in patients with CKD, delaying disease progression and reducing mortality rates.