Canagliflozin Renal Outcomes Study Is Halted Early for Efficacy

Miriam E. Tucker

July 17, 2018

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 standard of care, which includes angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).

The study is sponsored by Janssen and is being conducted in collaboration with the George Institute for Global Health, Australia.

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 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.

FDA Pushes Back Decision on MACE for Canagliflozin

As Groop stressed before in a commentary for Medscape Medical News, "Cardiovascular disease [CVD] and renal disease are inextricably linked in diabetes."

"If you see a patient in your clinic with CVD, I urge you to watch out for kidney disease. If you have a patient with kidney disease, watch out for CVD. It will be there because they are linked."

The CANVAS outcome trial also showed a 14% reduction in cardiovascular events with canagliflozin, but at the same time a doubled risk for lower-limb amputation. More recent data suggest that risk is not elevated, but doubt remains, as does the boxed warning on amputation.

Nevertheless, Janssen has made a supplemental new drug application for canagliflozin to reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes who have established or are at risk of CVD.

However, the company revealed last week that the US Food and Drug Administration (FDA) has extended the review time for this new indication by 3 months, and a decision is now due by October 2018.

Empagliflozin already has a US indication for reducing cardiovascular death in patients with type 2 diabetes and CVD based on results from the landmark EMPA-REG OUTCOME trial (N Engl J Med. 2015; 373:2117-2128).

And the large cardiovascular outcomes trial with dapagliflozin in patients with type 2 diabetes at high risk of CVD, DECLARE, is due to report in 2019.

Groop has served as a global advisory board member for AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, and sanofi-aventis. He has served as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genzyme, Janssen, Medscape, MSD, Novartis, Novo Nordisk, and sanofi-aventis. He has received research grants from Eli Lilly and Roche.

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