DAPA-CKD: Dapagliflozin Drops Risk of Renal Decline or Kidney Failure Death 39%, Even Without Diabetes

Dapagliflozin, the sodium glucose co-transporter 2 (SGLT2) inhibitor sold as Farxiga (AstraZeneca), brought a stunning 39% decline in the risk of declining kidney function, the onset of end-stage kidney disease, or kidney failure death, according to results of the DAPA-CKD trial presented today. The findings confirm the powerful properties of a drug class that has been a star of the European Society of Cardiology 2020 Congress, which is taking place virtually.

For the second straight day, an ESC “hot line” trial yielded results for an SGLT2 inhibitor that equaled or exceeded previous findings for a competitor. Today, the DAPA-CKD findings proved to be comparable, if somewhat different, from the April 2019 results for canagliflozin (Invokana, Janssen) in CREDENCE, a landmark study that found a 30% risk reduction in renal decline and cardiovascular and renal death among T2D patients.

But one element distinguished the DAPA-CKD results: a third of its participants did not have diabetes, which raises the prospect of using dapagliflozin to prevent kidney failure in a new group of patients.

“For me, this was the most exciting part of the study,” said David C. Wheeler, MBChB, MD, professor of kidney medicine, University College, London. Wheeler is an investigator on DAPA-CKD and was also an author on CREDENCE.

“In CREDENCE, we knew that in diabetic patients, we were likely to see benefits,” he said. In DAPA-CKD, “What was quite surprising is that we saw those same benefits in patients who had chronic kidney disease, but didn't have type 2 diabetes. And in fact, those patients seem to behave just like the diabetic patients in the trial.”

What’s more, Wheeler said, none of the patients without diabetes developed severe hypoglycemia or ketoacidosis, which has been a complication of SGLT2 inhibitors. “So to me, that’s exciting, because that takes this drug into a new population of patients in whom there is a large unmet need.”

With the data presented today, Rachele Berria, MD, PhD, vice president, US Medical, BioPharmaceuticals for AstraZeneca, said the opportunity exists to prevent thousands of patients from reaching end-stage renal disease, which exacts huge financial and personal costs. “Over 100,000 Americans start dialysis each year due to end-stage renal disease, and half of them die within 5 years,” she said. “It’s an enormous cost to society,” she said.

The Study

DAPA-CKD investigators enrolled 4304 patients, age 18 and older, who had the following:

• Estimated glomerular filtration rate (eGFR) ≥25 and ≤75 mL/min/1.73m2
• Urinary albumin to creatinine ratio between ≥200 mg/g and ≤5000 mg/g
• Were stabilized on a maximum tolerated dose of an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless contraindicated, for at least 4 weeks.

Patients were randomized 1:1 to dapagliflozin 10 mg or placebo once daily alongside standard of care (ACE inhibitor or ARB). Average age was 61.8 years, 66.9% were male, and 67.5% had T2D. Patient check-ins were set at 2 weeks, 2 months, and 4 months, and then every 4 months until the study was stopped; a 6-week checkout process concluded the study.

FDA granted AstraZeneca fast track status a year ago for dapagliflozin in chronic kidney disease. Although DAPA-CKD was scheduled to run through November of this year, it was halted in March due to overwhelming efficacy (an early stop also occurred during the CREDENCE trial).

AstraZeneca funded the study.

The Results

Investigators did not publish a paper to coincide with the ESC Congress, but a full paper is anticipated during the European Association for the Study of Diabetes meeting next month. A statement from ESC contained the following data:

• During a median follow-up of 2.4 years, there were 197 primary end point events with dapagliflozin and 312 with placebo.
• HR for the primary end point was 0.61 (95% CI, 0.51-0.72; P = .00000028).
• The benefit was consistent for patients with and without diabetes.
• Dapagliflozin achieved all 3 secondary end points, including a 31% risk reduction in all-cause mortality (HR, 0.69; 95% CI, 0.53-0.88; P = .0035).
• Other secondary end points were a 29% risk reduction in hospitalization for heart failure or cardiovascular death (HR, 0.71; 95% CI, 0.55-0.92; P = .0089) and a 44% risk reduction in worsening renal function or death from kidney failure (HR, 0.56; 95% CI, 0.45-0.68; P < .0001).
• Slightly more patients had serious adverse events in the placebo group than in the dapagliflozin group (33.9% vs 29.5%) and the number that discontinued the drug was the same (5.7% vs 5.5%).

Taken together, experts said the results presented during ESC 2020 over the weekend show that SGLT2 inhibitors have clearly moved beyond their beginnings as glucose-lowering therapies in T2D. Commentators said the DAPA-CKD study in dapagliflozin and the EMPEROR-Reduced study in empagliflozin, which complement earlier findings for SGLT2 inhibitors in renal and heart failure, respectively, should dispel any doubts the drug class belongs in treatment—and, more importantly, prevention—of these chronic, costly ailments.

Will uptake of SGLT2 inhibitors in renal care increase? Wheeler thinks so. “The fact that these trials are consistent is really good,” he said. “That's going to be a little bit uncomfortable for some physicians. We're using a drug that was designed for diabetes, and we're going to use it in patients who don't have diabetes. But the trial is very reassuring in terms of the efficacy in those patients, and the safety.”

Wheeler said it remains to be seen if a review board calls for a halt to EMPA-KIDNEY, which is studying renal outcomes in empagliflozin; that trial was set to continue until 2022.

"Paradigm Shifting"

Kiersten Combs, vice president, Cardiovascular & Metabolic Disease, AstraZeneca, said the data presented in DAPA-CKD could be “paradigm shifting,” because it could lead to patients with renal disease being diagnosed and treated far earlier than they are today. She noted that patients in the study had stage 2 to 4 chronic kidney disease. As AstraZeneca proceeds in conversations with the FDA and ultimately with payers, Combs said, “It opens up a dialogue, that hasn't been able to be had for renal patients, just because the innovation and the promise of medical intervention that could slow the progression hasn't been available.”

Over the past year, CMS has looked to rein in dialysis costs by giving patients more options, better access to kidney transplants, and more focus on prevention. But early intervention will mean changing the behavior of physicians in every day clinical practice, and Combs said that will start with updating clinical guidelines, assuming dapagliflozin receives an expanded FDA indication.

Berria said putting today’s data into action for renal patients is a 3-step process: “We want to increase awareness of kidney disease, we want to expand early diagnosis, and then the third step, which is essential, we're using a science-driven approach to change the practice of medicine.”

SGLT2 Inhibitors in COVID-19?

What’s next for renal care with SGLT2 inhibitors? Given their potential in prevention, and the profile of the patients most at risk during the coronavirus disease 2019 (COVID-19) pandemic, The American Journal of Managed Care® asked Wheeler if it would make sense to study these drugs to protect at-risk patients from acute kidney injury, which has been on the rise during COVID-19.

“This is a great question,” Wheeler said. “if you look at the aggregate data from some of the biggest studies, these drugs can prevent what we call acute kidney injury. … So I think this is certainly a question that could be tested in a future trial if there is a resurgence of COVID, but I don't think we can answer the question.

“But I think we've got enough background science now to suggest that it’s worth testing,” he said.

Reference

Heerspink HJL, Stefansson BV, Chertow GM, et al. Dapagliflozin in patients with chronic kidney disease: DAPA-CKD. Presented at the European Society of Cardiology 2020 Congress: The Digital Experience. August 30, 2020. Hotline Session.