Once, in the not-too-distant past, one could not scan the latest issue of any top-tier medical journal without finding at least one trial extolling the benefits of statin therapy, which lead many to suggest — and not always facetiously — that it was time to add statins to the water.
Since late summer 2019 when the results of DAPA-HF were reported at the 2019 European Society of Cardiology Congress in Paris, SGLT2 inhibitors have displaced statins as the pharmaceutical of choice for those who like the “one-drug-fits-all-conditions” approach to the art of medicine.
The latest entry comes from David C. Wheeler, MB, ChB, MD of the George Institute for Global Health in Sydney, Australia, who with his co-investigators offers another look at the findings from DAPA-CKD in The Lancet Diabetes & Endocrinology.
The DAPA-CKD findings were first reported at the 2020 virtual ESC Congress in September, followed by an October report at the Heart Failure Society of America and simultaneous publication in The New England Journal of Medicine. In November, there was a another chance to review to findings in a presentation at the American Heart Association’s virtual scientific sessions.
Wheeler et al writing in The Lancet offered ample evidence of the benefit of dapagliflozin therapy via a “prespecified subgroup analysis of the DAPA-CKD primary and secondary endpoints by presence or absence of type 2 diabetes and by etiology of chronic kidney disease.”
In the trial, the primary outcome was a composite of sustained decline in estimated glomerular filtration rate of at least 50%, endstage kidney disease, or kidney-related or cardiovascular death. The secondary endpoints were “a kidney-specific composite (the same as the primary outcome but excluding cardiovascular death), a composite of cardiovascular death or hospital admission for heart failure, and all-cause mortality,” the authors explained.
Among the findings:
- For those with type 2 diabetes, there was a 46% relative risk reduction for the composite outcome (95% CI 0.52-0.79).
- For those without type 2 diabetes, there was 50% reduction in relative risk for the composite outcome (95% CI 0.35-0.72
- Kidney-specific composite outcome: (0.57 [0.45–0.73] vs 0.51 [0.34–0.75]; P interaction= 0.57); cardiovascular death or hospital admission for heart failure (0.70 [0.53–0.92] vs 0.79 [0.40–1.55]; P for interaction=0.78), and all-cause mortality (0.74 [0.56–0.98] vs 0.52 [0.29–0.93]; P for interaction=0.25).
Importantly, the researchers found that the “effect of dapagliflozin on the primary outcome was also consistent among patients with diabetic nephropathy (n=2510; HR 0.63, 95% CI 0.51–0.78), glomerulonephritides (n=695; 0.43, 0.26–0.71), ischemic or hypertensive chronic kidney disease (n=687; 0.75, 0.44–1.26), and chronic kidney disease of other or unknown cause (n=412; 0.58, 0.29–1.19; P for interaction=0.53), with similar consistency seen across the secondary outcomes.”
The DAPA-CKD trial recruited participants with a “urinary albumin-to-creatinine ratio of 200–5000 mg/g and an estimated glomerular filtration rate (eGFR) of 25–75 mL/min per 1.73m2,” who were randomized to 10 mg dapagliflozin or placebo.
Their study involved 4,304 participants who were evenly randomized and then followed for a median of 2.4 years. More than half of the participants, 2,906, had type 2 diabetes, and 396 of those participants also had chronic kidney disease not caused by diabetic nephropathy.
All of the participants were also required to be taking either an ACE-inhibitor or an angiotensin receptor blocker (ARB), both of which are known to be renal-protective.
Wheeler and colleagues noted that the broad benefits — across kidney disease of varying etiologies as well as in patients with or without type 2 diabetes — are not unique to DAPA-CKD. For example, according to findings from EMPEROR-Reduced, also reported at ESC 2020, a different SGLT2 inhibitor—empagliflozin—”improved clinical outcomes in patients with heart failure and reduced ejection fraction, again both with and without type 2 diabetes, suggesting similar effects of different SGLT2 inhibitors in reducing the risk of heart failure in patients irrespective of diabetes status. The ongoing EMPA-KIDNEY trial (NCT03594110) is being done to investigate the effect of empagliflozin on kidney disease progression and cardiovascular death in patients with chronic kidney disease. As EMPA-KIDNEY allows the inclusion of patients with an eGFR of 25–45 mL/min per 1.73m2 who do not have albuminuria, findings from the study might allow us to understand the effects of SGLT2 inhibitors in patients with reduced eGFR with but normoalbuminuria,” they wrote.
But positive findings, even when ubiquitous, still require a dose of caution, as Katherine R. Tuttle, MD, of Providence Medical Research Center, at Providence Health Care in Spokane, and the University of Washington in Seattle, pointed out in a thoughtful comment that accompanied the paper by Wheeler.
“One notable limitation of the DAPA-CKD trial relates to the classification of DKD as ’diabetic nephropathy,’” Tuttle wrote. “This classification is somewhat problematic because the diagnostic criteria did not include a definition that would make diabetic nephropathy highly probable. The study entry criteria were simply based on eGFR, urinary albumin-to-creatinine ratio, and investigator-ascribed cause of CKD. Therefore, DAPA-CKD participants who were classified as having diabetic nephropathy actually had type 2 diabetes and CKD. Biopsy series show that about a third of DKD cases are non-diabetic forms of CKD, another third are mixed lesions of histologically confirmed diabetic nephropathy with another form of CKD, and only about a third are diabetic nephropathy alone. Thus, there was a reasonable chance of misclassification of CKD etiology in the DAPA-CKD trial. Even though about a fifth of participants had a biopsy-based CKD diagnosis (about 800 participants), these data are unavailable for verification. 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—e.g., finerenone, GLP-1 receptor agonists, endothelin A receptor antagonists, and anti-inflammatory drugs.”
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Be aware that findings from the DAPA-CKD trial suggest treatment with dapagliflozin can benefit clinical kidney, cardiovascular, and heart failure outcomes.
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The benefits demonstrated in the DAPA-CKD trial suggest that dapagliflozin therapy may provide substantial cardiorenal benefit to a broad range of patients with impaired kidney function and proteinuria, including patients with non-diabetic chronic kidney disease.
Peggy Peck, Editor-in-Chief, BreakingMED™
The DAPA-CKD trial was funded by AstraZeneca
Wheeler provides ongoing consultancy services to AstraZeneca and has received honoraria for participation in advisory boards and other activities, consultancy fees, or both from Amgen, AstraZeneca, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Napp, Mundipharma, Medscape, Merck Sharp & Dohme, Pharmacosmos, Reata, Takeda, and Vifor Fresenius.
Tuttle served as a consultant on diabetes and kidney disease for Eli Lilly, Boehringer Ingelheim, AstraZeneca, Gilead, Goldfinch Bio, Bayer, Novo Nordisk, and Janssen; received honoraria for speaking engagements from Eli Lilly, Gilead, and Bayer; and received research support from Goldfinch Bio.
Cat ID: 127
Topic ID: 81,127,730,102,3,838,913,12,187,127,411,192,918,925
