An early halt has been called for a phase 3 randomized clinical trial investigating renal outcomes for the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin (Invokana, Janssen) in patients with type 2 diabetes and kidney disease because of achievement of prespecified efficacy criteria
The Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial is evaluating the efficacy and safety of adding canagliflozin 100 mg/day versus placebo to the standard of care, which includes angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).
The decision to halt the study nearly a year sooner than planned was based on the advice of the independent data monitoring committee following a planned interim analysis. The prespecified criteria for the primary composite endpoint — end-stage renal disease, doubling of serum creatinine, or cardiovascular death — had been achieved. No further details about the outcomes were provided in the company announcement made yesterday.
"We are excited about the possibility of bringing forth [canagliflozin] as the first therapy to treat patients with chronic kidney disease and type 2 diabetes in more than 15 years. We look forward to presenting the full data from the CREDENCE trial at an upcoming medical meeting and with health authorities in the near future," said James List, MD, Global Therapeutic Area Head, Cardiovascular & Metabolism, Janssen.
Asked to comment, Per-Henrik Groop, MD, DMSc, professor of Nephrology, Helsinki University Hospital, Finland, told Medscape Medical News: "The news that CREDENCE was stopped due to positive effects is absolutely fabulous, although…expected given the mode of action of the SGLT2 inhibitors."
"All SGLT2 inhibitors have a profound effect on renal hemodynamics by increasing the tone of the afferent arteriole with a subsequent decrease in renal blood flow, increase in renal vascular resistance, and reduction of hyperfiltration. All these are effects that spare the kidneys from further damage," Groop stressed.
Slowing Kidney Disease With SGLT2 Inhibitors
CREDENCE enrolled approximately 4400 patients with type 2 diabetes, an estimated glomerular filtration rate (eGFR) between 30 and 90 mL/min/1.73m2, and albuminuria (urinary albumin-creatinine ratio 300 to 5000 mg/g). All patients were required to be on the maximum labeled or tolerated dose of an ACE inhibitor or ARB for more than 4 weeks prior to randomization.
Currently, however, canagliflozin is not recommended for patients with eGFR persistently less than 45 mL/min/1.73m2 and is contraindicated for those with eGFR less than 30 mL/min/1.73m2, end-stage renal disease, or on dialysis.
Renal benefit for canagliflozin has been seen previously in the renal endpoints trial of the Canagliflozin Cardiovascular Assessment Study (CANVAS-R) (N Engl J Med. 2017; 377:644-657).
Patients taking the drug had a 40% lower rate of the composite renal endpoint (40% eGFR reduction, renal replacement therapy, or death) compared with placebo.
Delayed worsening of renal disease has also been seen with other SGLT2 inhibitors, for example, empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly). Indeed Boehringer Ingelheim and Eli Lilly have just announced a new clinical outcomes trial of empagliflozin for the treatment of chronic kidney disease.
The study will enroll around 5000 patients who have chronic kidney disease with or without diabetes. The primary endpoint is a composite of cardiovascular death and progression of kidney disease.
AstraZeneca is also investigating its SGLT2 inhibitor, dapagliflozin (Farxiga/Forxiga), in a dedicated chronic kidney disease trial (Dapa-CKD). Those results are expected in November 2020.