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The SGLT-2 inhibitor canagliflozin showed a significant renal benefit in the phase III CREDENCE trial, researchers said.

Patients with type 2 diabetes and albuminuria chronic kidney disease (CKD) on 100 mg of once daily oral canagliflozin had a 30% reduced risk for a composite outcome of end-stage kidney disease (ESKD), doubling of serum creatinine, or renal or cardiovascular death (HR 0.70, 95% CI 0.59-0.82, P=0.00001) compared with placebo (event rates of 43.2 and 61.2 per 1,000 patient-years), reported Vlado Perkovic, MBBS, PhD, of The George Institute for Global Health in Sydney, and colleagues.

The findings were presented at the 2019 in Melbourne, Australia, and simultaneously published in the .

When removing the cardiovascular death outcome from the composite endpoint, this risk reduction with canagliflozin remained significant for just renal outcomes (HR 0.66, 95% CI 0.53-0.81). This benefit in the composite renal outcome was mainly driven by a risk reduction in the doubling of serum creatinine levels, which alone saw a 40% lowered risk versus placebo (HR 0.60, 95% CI 0.48-0.76).

Looking at ESKD alone among these patients, there was a 32% reduced risk seen with canagliflozin versus placebo, although the magnitude of this risk reduction slightly varied according to how ESKD was defined:

• eGFR <15 mL/min/1.73 m²: HR 0.60 (95% CI 0.45-0.80)
• Dialysis initiated or kidney transplantation: HR 0.74 (95% CI 0.55-1.00)

"The observed benefits were obtained on a background of renin-angiotensin system blockade, the only approved renoprotective medications in type 2 diabetes, a factor that highlights the clinical significance of the findings," Perkovic's group noted.

This was reinforced by the National Kidney Foundation, which released a statement reading in part: "If this supplemental indication is approved by the Food and Drug Administration (FDA), it would be the first new treatment for diabetic kidney disease (DKD) in decades."

Also in agreement, Mandeep Sahani, MD, of Banner-University Medicine Digestive Institute in Phoenix, who wasn’t involved with the study, told 番茄社区app how this “well-designed study” could serve as a catalyst for “making canagliflozin the standard of care along with the renin-angiotensin system for type 2 diabetes with chronic kidney disease.”

The included 4,401 patients with type 2 diabetes and stage 2 or 3 CKD, defined as an eGFR from ≥30 to <90 mL/min/1.73 m². All participants also had macroalbuminuria, which was defined as urinary albumin-to-creatinine ratio >300 to ≤5,000 mg/g. At enrollment, all patients were receiving the standard of care continued throughout the trial, which included receiving a stable dose of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker for a minimum of 4 weeks prior to randomization.

Although the trial stopped early because it met the pre-specified criteria for efficacy, the median follow-up period was 2.62 years.

"The underlying mechanisms of canagliflozin activity are probably both renal and systemic," suggested Julie Ingelfinger, MD, of Massachusetts General Hospital in Boston, and Clifford Rosen, MD, of the Tufts University School of Medicine in Boston, in an accompanying editorial.

"SGLT2 inhibition increases glucose and sodium delivery to the distal renal tubule, which is sensed by the juxtaglomerular apparatus as increased glomerular perfusion. This leads to increased vasoconstriction of the afferent arteriole, which decreases glomerular perfusion and intraglomerular pressure," they explained. They praised the trial as "well done" and stated that it's importance "cannot be overstated."

The findings from this trial add to the previously reported CANVAS findings which showed a significant cardiovascular benefit with canagliflozin in patients with type 2 diabetes, which led to a label expansion in October 2018 to include the prevention of MI, stroke, and death among patients with type 2 diabetes who have established cardiovascular disease.

As expected, the current trial also reported a significant cardiovascular benefit with canagliflozin, including a 20% reduction risk for a composite of cardiovascular death, MI, or stroke (HR 0.80, 95% CI 0.67-0.95). There was also a 39% reduced risk for hospitalization for heart failure (HR 0.61, 95% CI 0.47-0.80).

Based on the previous CANVAS clinical program, the FDA added a boxed warning to canagliflozin's label regarding increased risks of leg and food amputation. CREDENCE, however, showed no significantly increased risk for amputation among patients on canagliflozin (HR 1.11, 95% CI 0.79-1.56). No significantly increased risk was seen with canagliflozin for other adverse events, either, including hyperkalemia, acute kidney injury, or fracture. There was a significantly higher risk for diabetes ketoacidosis, though (HR 10.80, 95% CI 1.39-83.65).

Last month, Janssen these findings to the FDA as part of its application to expand the indication to include CKD treatment in patients with type 2 diabetes.