Combo Treatment Could Delay Kidney Failure for Years in Nondiabetic CKD

Combining the powers of SGLT2 and renin-angiotensin-aldosterone system (RAAS) inhibitor therapy could substantially reduce the risk of kidney failure or death for patients with albuminuric, nondiabetic chronic kidney disease (CKD), researchers predicted.

In an analysis calculated using trial-level estimates, adding an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to an SGLT2 inhibitor was projected to increase kidney failure-free survival time by years, according to Priya Vart, PhD, MPH, of the University Medical Center Groningen in The Netherlands, and colleagues.

Compared with no treatment at all, using these agents in combination may cut the risk for a composite primary endpoint of doubling of serum creatinine, kidney failure, or death by 65% (HR 0.35, 95% CI 0.30-0.41), the team wrote in the Clinical Journal of the American Society of Nephrology (CJASN).

Putting this into context, Vart’s group explained that a 50-year-old patient could gain 7.4 more years of event-free survival with combination treatment. While patients of this age were projected to see 9.6 event-free years without any of these agents, those on combination treatment would be expected to experience about 17 event-free years.

Even when assuming lower medication adherence or even less efficacy of the treatment regimen, these patients were estimated to have anywhere between 5.3 and 6.8 more event-free years.

“These results highlight the potential and the opportunity to lower the burden of CKD complications by delaying or even preventing kidney failure and premature death if currently available treatments can be appropriately utilized,” the researchers pointed out.

They noted that although the 2022 Kidney Disease: Improving Global Outcome clinical practice guidelines do recommend adding SGLT2 inhibitors to the treatment regimen of CKD patients without diabetes — which is about 40-60% of all CKD patients — uptake of this practice has been rather slow. Some of the reasons behind this are likely due to high cost, lack of awareness of the benefit, or even poor communication between clinicians and patients about the risks, said Vart’s group.

In an accompanying editorial, Evan Zeitler, MD, and Amy Mottl, MD, MPH, both of the University of North Carolina at Chapel Hill, praised the findings and called the treatment effects “remarkable,” but also not surprising.

“Over 3 years, combination therapy resulted in absolute risk reductions of 17%-29% for the primary endpoint and 15%-22% for the secondary endpoint,” Zeitler and Mottl wrote. “Corresponding numbers needed to treat were four to six and five to seven, respectively.”

The editorialists added that while these treatment benefits decline when therapy was initiated after age 50, the benefits were still significant.

“Nephrology is on the cusp of an era of evidence-based medical therapy that will reduce the morbidity and mortality associated with CKD,” Zeitler and Mottl said. “The development of new treatments has been critical to reaching this point, but equally essential is their implementation in order for patients to be afforded their benefit.”

In addition, “cardiology has led the way in guideline-directed medical therapy, and nephrology now has the opportunity to follow suit,” Zeitler and Mottl wrote. “A shared understanding of the benefits of combination medical therapy is a crucial first step.”

Clinical trial data were pulled from three studies of patients with albuminuric, nondiabetic CKD: the Ramipril Efficacy in Nephropathy (REIN) trial, the Guangzhou trial from China, and the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial. These trials utilized the agents ramipril, benazepril, and dapagliflozin (Farxiga).

The average age of trial participants ranged from 45 to 62, while mean estimated glomerular filtration rates were 20-43 mL/min/1.73 m², and median urinary albumin-creatinine ratios were 949-1,499 mg/g.

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