麻豆传媒

In chronic kidney disease (CKD), dapagliflozin (Farxiga) reduced renal events and substantially improved overall survival, regardless of diabetes status, the DAPA-CKD trial showed.

The SGLT2 drug reduced by a relative 39% the primary endpoint of worsening kidney function (more than 50% sustained decline in estimated glomerular filtration rate [eGFR] or onset of end-stage kidney disease) or death due to kidney disease or cardiovascular disease (312 vs 197 events at a median 2.4 years, HR 0.61, 95% CI 0.51-0.72).

The number needed to treat to prevent one such event was just 19, reported Hiddo Heerspink, PharmD, PhD, of the University Medical Center Groningen, the Netherlands, at the European Society of Cardiology virtual meeting.

The effect was significant for those with type 2 diabetes and without it (HR 0.64 and 0.50, P=0.24 for interaction).

Most notable among the secondary endpoints was the 31% relative reduction in all-cause mortality (P=0.0035, with 101 vs 146 events with placebo).

Clinical Implications

"For nephrologists who are struggling with the epidemic of kidney disease and the few options available to treat its progression effectively, the possibility of this new effective treatment is cause to celebrate," commented Ladan Golestaneh MD, a nephrologist at Montefiore Medical Center in New York City, predicting changes to the CKD care guidelines.

Until recently, ACE inhibitors and angiotensin receptor blockers (ARBs) were the only medications specifically proven to slow CKD progression, Heerspink noted at the ESC hot-line session.

But the effect size with dapagliflozin was higher than seen with the ACE/ARB drugs versus placebo in patients with and without type 2 diabetes for composite CKD events, noted Holly Kramer, MD, president of the National Kidney Foundation.

It was larger than the relative effects of lower blood pressure targets on composite CKD outcomes in adults with and without type 2 diabetes, she pointed out. The trial "greatly increases the impact these drugs will have on reducing end-stage renal disease," she told 麻豆传媒.

Golestaneh noted that SGLT2 inhibitors have already been increasingly used in nephrologist clinic practice as a means to decrease the progression of diabetic nephropathy and predicted that the demonstration of efficacy in non-diabetic kidney disease would drive that higher.

For cardiologists, too, "it's really exciting," even if not surprising, commented Milton Packer, MD, of the Baylor Heart and Vascular Institute in Dallas, who presented at the conference positive findings in heart failure with reduced ejection fraction with fellow SGLT2 inhibitor empagliflozin (Jardiance), including benefits for renal endpoints.

"We know that SGLT2 inhibitors protect the heart and the kidney," he said. "In many ways, chronic kidney disease trials are in parallel to chronic heart failure trials, because SGLT2 inhibitors benefit both organs."

ESC session moderator Frank Ruschitzka, MD, of the Heart Center at University Hospital Zurich, agreed, calling DAPA-CKD fantastic.

"We are thinking as cardiologists probably too much into boxes, compartmentalization," he said. "Maybe we need a more holistic view... They're certainly not just glucose-lowering drugs. They're not just only diuretics. Maybe we should just move to organ protection."

Trial Details

The trial included 4,304 adults with CKD (eGFR 25 to 75 mL/min/1.73 m² and urine albumin to creatinine ratio of 200 to 5,000 mg/g), about 67% of whom had type 2 diabetes, and all on a maximally-tolerated dose of an ACE inhibitor or ARB. They were randomized to 10 mg dapagliflozin once daily or matching placebo. People with type 1 diabetes were excluded.

The trial was stopped early for efficacy after a median follow-up of 2.4 years with 60% of the planned events.

Dapagliflozin also significantly improved each component of the primary composite (with the exception of a nonsignificant trend for cardiovascular death) as well as secondary composite outcomes:

• 44% lower risk of worsening renal function or renal death
• 34% lower risk of chronic dialysis, kidney transplantation, or renal death
• 29% lower risk of CV death or heart failure hospitalization

No cases of diabetic ketoacidosis occurred in the dapagliflozin group. Serious adverse events were actually numerically less common with the drug, which Heerspink said was in keeping with dapagliflozin's established safety profile.

The Future for SGLT2 Inhibitors

Packer noted that a similar CKD trial is underway with empagliflozin (, with data expected in 2022) in a population with and without diabetes. The drug has FDA fast track designation for an indication in that regard. The trial previously showed that SGLT2 inhibitor canagliflozin (Invokana) improved outcomes in CKD patients with type 2 diabetes.

"The thing really amazing about SGLT2 inhibitors is that it's not like our evidence is one or two trials -- it's going to be like nine or 10 large scale trials, which is extraordinary," Packer said. "For most classes of drugs, we don't have that kind of evidence base. ... Physicians have to start using SGLT2 inhibitors across the board for these patients. It's not only the consistency of these results, it's the magnitude."

And with multiple agents in the class proving their chops for organ protection, "it's going to be very hard for insurers to say no to drugs like this," commented Dipti Itchhaporia, MD, vice president of the American College of Cardiology. "The more data, the easier it is for us to get these covered."

"Patients balk at the idea of all these additional drugs and the cost of all these drugs," she acknowledged, noting that SGLT2 inhibitors are looking to be the fourth cornerstone of heart failure therapy. "But if you make the case, and you explain to them why they need to take these drugs, they usually are amenable. When you say you're going to live longer, feel better, you're not going to come into the hospital as much, it's hard to argue against that."

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