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DAPA-CKD Resets eGFR Floor for Safe SGLT2 Inhibitor Use

Mitchel L. Zoler, PhD

September 25, 2020

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-
glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause
death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this
treatment to those in the upper range of stage 4 CKD.

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29
mL/min per 1.73m2, an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The
results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the
virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30
mL/min per 1.73 m2.

Using SGLT2 Inhibitors When eGFR Is as Low as 25

"It's time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25," said Dr. Heerspink, a professor of clinical
pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he
believed was established by the DAPA-CKD findings: "We've shown that dapagliflozin can be safely used in these patients. It is
effective across the spectrum of kidney function."

Other experts not associated with the study agreed.

The trial researchers were "brave" to enroll patients with eGFRs as low as 25 mL/min per 1.73 m2, and "we urgently need these
agents in patients with an eGFR this low," commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at
Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings "spectacular,"
a "landmark trial," and a "winner."

The study also set a new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by
enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g,
noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to
quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, "it will change practice, and push the eGFR needle down" to as low as 25. It will
also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a
nephrologist at the University of Toronto. "It's just one study," he admitted, but the consistent renal benefits seen across several
studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well
as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

"I don't think we've ever had stronger evidence" for drugs that can benefit both heart and renal function, plus the drug class is
"very safe, and really easy to start" and maintain in patients, Dr. Cherney said in an interview. "It's wonderful for these patients
that we now have something new for treatment," a drug with a "very favorable benefit-to-risk ratio."

Results Show Many Dapagliflozin Benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important
consequence of DAPA-CKD, the study's primary finding – that dapagliflozin was as safe and effective for slowing CKD
progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target
patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled
4,304 patients, makes this treatment an option for "millions" of additional patients worldwide, said Dr. Heerspink. "These are the
most common patients nephrologists see." A major challenge now will be to do a better job finding patients with CKD who could
benefit from dapagliflozin.
DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34
countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy
for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these
drugs was because of poor tolerance.

The study's primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in
eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who
received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with
the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the
absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event
during 2.4 years, a "much lower" number needed to treat than reported for renin-angiotensin system inhibitors in these types of
patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, "a
major highlight" of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the
incidence of cardiovascular death or hospitalization for heart failure.

"Cardiovascular disease is the most common cause of death in patients with CKD," explained David C. Wheeler, MD, a
coinvestigator on the study and professor of kidney medicine at University College London. "The heart and kidney are
intertwined. This is about cardiorenal disease."

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and
received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he
has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had
relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research
funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from
several other companies.

mzoler@mdedge.com

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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Cite this: DAPA-CKD Resets eGFR Floor for Safe SGLT2 Inhibitor Use - Medscape - Sep 25, 2020.