CREDENCE: Canagliflozin safely reduces risk for ESKD in patients with type 2 diabetes, CKD

Canagliflozin safely reduced the risk of kidney failure and prevented cardiovascular events in patients with type 2 diabetes and chronic kidney disease, according to phase 3 results from the CREDENCE study presented at a late-breaking clinical trials session at the International Society of Nephrology’s World Congress of Nephrology Annual Meeting in Melbourne, Australia.

Perspective from Julie R. Ingelfinger, MD

“We’re looking after an increasing number of patients with diabetes and chronic kidney disease,” David C. Wheeler, MD, FRCP, professor of kidney medicine at University College London, UK, said in a presentation. “According to data from the Global Burden of Disease Study, the number of deaths from this combination of type 2 diabetes and CKD doubled between 1990 and 2012. The outcomes for these patients are poor despite our current therapies.”

Researchers randomized 4,401 patients with type 2 diabetes and CKD to either placebo or 100 mg of canagliflozin (mean HbA1c, 8.3%; mean blood pressure, 140/78 mm Hg; 70% on statins). Primary endpoints of the study were the occurrence of ESKD, a doubling of serum creatinine, renal death or cardiovascular death with a median follow-up of 30 months.

Researchers found ESKD, doubling of serum creatine and renal or CV death occurred in 340 patients who took placebo and in 245 patients who took canagliflozin (HR= 0.70; 30% reduction with canagliflozin). Regarding renal-specific outcomes, a composite of ESKD, doubling of serum creatine or renal death occurred in 224 patients who took placebo and in 153 patients who took canagliflozin (HR = 0.66; 34% reduction with canagliflozin).

In addition, researchers observed a 32% risk reduction of ESKD in patients who took canagliflozin (HR = 0.68), as well as a 28% risk reduction for starting dialysis, having a kidney transplant or experiencing renal death.

Canagliflozin safely reduced the risk of kidney failure and prevented cardiovascular events in patients with type 2 diabetes and chronic kidney disease.

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Canagliflozin also attenuated the slope of chronic eGFR decline by 2.7 mL/min/1.73 m² per year.

Finally, after evaluating safety outcomes, researchers concluded there was no difference in risk of fracture or lower extremity amputation in those who took placebo vs. canagliflozin.

“If we look at the effects of canagliflozin on the broad range of renal outcomes, we see clear and consistent benefits, regardless of how we define the renal events, which were highly statistically significant for the majority,” Vlado Perkovic, MBBS, PhD, FRACP, FASN, executive director of The George Institute and professor of medicine at the University of New South Wales in Sydney, said. – by Melissa J. Webb

Reference:

Perkovic V and Wheeler DC. CREDENCE: Canagliflozin and renal events in diabetes with established nephropathy clinical evaluation. Presented at: ISN World Congress of Nephrology Annual Meeting. April 12-15, 2019; Melbourne, Australia.

Disclosures: Perkovic reports leading or serving on the steering committees of several trials and receiving honoraria for scientific presentations and/or advisory board attendance of Amgen, Eli Lily and Pfizer, among others. Wheeler reports consulting for Amgen, Bayer and Janssen, among others.

Perspective

Julie R. Ingelfinger, MD

The results of CREDENCE showed a clear benefit in preventing renal failure. For every 1,000 patients treated for 2.5 years with canagliflozin, 47 fewer patients developed the primary outcome of ESKD, renal transplant, or eGFR under 15 mL/min/1.73 m² for 30 days, with a doubling of serum creatinine. Further, death due to renal or cardiovascular (CV) disease occurred less often; among the same number of patients, the drug prevented 22 hospitalizations and 25 composite CV events (CV death, myocardial infarction, and stroke).

Results were disappointing in previous attempts to find agents conferring salutary effects when added to RAAS blockers - for example, sulodexide and bardoxolone methyl.

There are cautions when interpreting the CREDENCE results. The decision to end the trial early may have limited the power for some secondary outcomes. Further, off-treatment eGFR levels were not measured after trial completion; differences in eGFR at the end of the trial may be under- or overestimates. Finally, the CREDENCE results cannot be applied to patients with markedly advanced CKD (eGFR under 30 mL/minute/1.73 m²), as few were included in the study.

However, taken together, the trial results do seem applicable to many patients with type 2 diabetes with CKD, providing credence to a new approach. While we do not fully understand the mechanism by which canagliflozin accomplishes these effects, the results would appear generalizable and may offer new hope for these patients.

Julie R. Ingelfinger, MD

Professor of pediatrics

Harvard Medical School

Senior consultant in pediatric nephrology

Massachusetts General Hospital for Children

Boston, Mass

Disclosures: Ingelfinger reports no relevant financial disclosures.