Dapagliflozin Shown to Be Safe, Effective in Patients With CKD

Treatment with dapagliflozin substantially reduced the risk of chronic kidney disease progression in patients with immunoglobulin A (IgA) nephropathy when added to renin-angiotensin-system blockade, according to a new study published in Kidney International.

The findings demonstrate that dapagliflozin reduced the risk of severe loss of kidney function, end-stage kidney disease (ESKD), or death by a kidney disease–related or cardiovascular cause by 71% and of a kidney-specific outcome by 75%.

Although the patient cohorts were relatively small, the authors said, “no prior trial of any therapeutic agent in IgA nephropathy has demonstrated an effect of this magnitude.”

IgA nephropathy, also known as Berger’s disease, is the most common form of primary glomerular disease worldwide, with inflammation resulting from the IgA protein getting stuck in the kidneys and causing inflammation. Over a span of 4 to 15 years, approximately 30% of patients with the disease progress to kidney failure. Risk factors for deterioration include decline in estimated glomerular filtration rate (eGFR), persistence of protein in the urine, and high blood pressure.

There are no commercially available treatments for the disease because none have demonstrated success in large-scale randomized clinical trials, the authors said. The predominant strategy is to use supportive measures, including renin-angiotensin-aldosterone blockade. Fish oil is often used as well. Immunosuppressive therapy is controversial and usually reserved for patients who don’t respond to supportive measures.

Dapagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that reduces glucose reabsorption, thereby enhancing urinary glucose excretion. SGLT2 inhibitors were originally developed for glycemic control in type 2 diabetes (T2D), but trials have shown reductions in eGFR as well, suggesting the drug class may reduce intraglomerular pressure, which may preserve long-term kidney function, the authors said.

In the Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in patients with or without T2D, including those with IgA nephropathy. Average rates of eGFR decline were –3.5 mL/min/1.73m2/year on dapagliflozin and –4.7 mL/min/1.73m2/year on placebo. The SGLT2 inhibitor reduced the urinary albumin-to-creatinine ratio by 26% compared with placebo.

Patients were required to have been on angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARBs) for at least 4 weeks prior to study enrollment. The study excluded those on immunotherapy within 6 months of enrollment.

The study involved 270 patients with an IgA nephropathy diagnosis. Those receiving dapagliflozin received a 10-mg dose. Six patients in the dapagliflozin group (4%) experienced a 50% decline or greater in eGFR, had onset of ESKD, or died compared with 20 participants (15%) in the placebo group. The absolute risk difference was −10.7% (95% CI, −17.6% to −3.7%).

Similar results for a kidney-specific outcome (HR, 0.24; 95% CI, 0.09-0.65; P = .002) were seen. Five participants (4%) in the dapagliflozin group and 16 (12%) in the placebo group developed ESKD during the trial (HR, 0.30; 95% CI, 0.11-0.83; P = .014).

Adverse events were similar in both groups, with no cases of diabetic ketoacidosis or major hyperglycemia reported among patients on the SGLT2 inhibitor.

“This prespecified analysis of the DAPA-CKD study demonstrates that in patients with IgA nephropathy, when added to ACEi/ARB therapy,” the authors concluded, “dapagliflozin significantly and substantially reduces the risk of CKD progression with a favorable safety profile.”

Reference

Wheeler DC, Toto RD, Stefánsson BV, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. Published online April 17, 2021. doi:10.1016/j.kint.2021.03.033