medwireNews: A prespecified analysis of data from the DAPA-CKD trial suggests that add-on treatment with dapagliflozin slows decline in renal function among patients with chronic kidney disease (CKD) irrespective of the underlying etiology.
In the primary analysis of the trial, reported previously by medwireNews, the sodium-glucose cotransporter (SGLT)2 inhibitor reduced the risk for the composite outcome – a sustained reduction in estimated glomerular filtration rate of at least 50%, end-stage renal disease, and renal or cardiovascular death – when added to standard treatment for CKD.
“Crucially, and unlike CREDENCE, DAPA-CKD included many participants without type 2 diabetes (a third of the study population),” and “not all participants with type 2 diabetes at the time of recruitment had a diagnosis of diabetic nephropathy, with some having specific alternative aetiologies of chronic kidney disease,” say the investigators in The Lancet Diabetes & Endocrinology.
Among the 4304 DAPA-CKD participants, diabetic nephropathy was the most commonly reported cause of CKD (58%), followed by glomerulonephritis (16%), ischemic or hypertensive CKD (16%), and CKD of other or uncertain etiology (10%). A total of 14% of the 2906 participants with type 2 diabetes had CKD attributed to causes other than diabetic nephropathy.
David Wheeler (University College London, UK) and co-authors report that in patients with diabetic nephropathy, those treated with dapagliflozin had a significant 37% lower risk for the primary composite outcome than those given placebo, at rates of 5.4 versus 8.5 per 100 person–years.
Similarly, patients with glomerulonephritis had a significant 57% lower risk for the composite outcome with dapagliflozin compared with placebo (3.4 vs 7.5 per 100 person–years), while those with ischemic or hypertensive CKD (3.8 vs 4.9 per 100 person–years) or CKD of other or uncertain etiology (2.9 vs 5.5 per 100 person–years) had a numerically lower risk with dapagliflozin versus placebo, but the differences did not reach statistical significance.
The researchers also point out that the underlying cause of CKD “did not modify the beneficial effect of dapagliflozin on the secondary outcomes,” including all-cause mortality and kidney- or cardiovascular-specific composite outcomes.
In the safety analysis, rates of serious adverse events (AEs) in the dapagliflozin and placebo groups were consistent regardless of the cause of CKD, but Wheeler et al note that the proportion of patients discontinuing treatment due to AEs “did appear to vary by aetiological subgroup.”
The likelihood of discontinuation with the SGLT2 inhibitor versus placebo was highest in the group with CKD of other or uncertain etiology (odds ratio [OR]=4.55), and lowest in those with glomerulonephritis (OR=0.81).
Writing in an accompanying commentary, Katherine Tuttle (University of Washington, Seattle, USA) says that taken together, “these results are broadly applicable and impactful,” given that the DAPA-CKD study population “is representative of about 80–90% of patients with CKD.”
She says, however, that classifying people with type 2 diabetes and CKD as having “diabetic nephropathy” was a “notable limitation of the DAPA-CKD trial,” because the study entry criteria “did not include a definition that would make diabetic nephropathy highly probable,” and only approximately a fifth of participants had a biopsy-based CKD diagnosis.
“In order to provide the right treatment to the right patient at the right time, more precise clinical phenotyping will be important in the future, especially as therapeutic selection expands with new agents under study,” concludes Tuttle.
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Lancet Diabetes Endocrinol 2021; 9: 22–31
Lancet Diabetes Endocrinol 2021; 9: 3–5